Tout sur les médicaments הכל על תרופות كل شيئ عن الأدوية Все о наркотиках 关于药品的一切 డ్రగ్స్ గురించి అన్ని 마약에 관한 모든 것 Όλα για τα Ναρκωτικά Complete Tracking of Drugs Across the World by Dr Anthony Melvin Crasto, Worldpeacepeaker, worlddrugtracker, PH.D (ICT), MUMBAI, INDIA, Worlddrugtracker, Helping millions, 9 million hits on google on all websites, 2.5 lakh connections on all networks, “ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
Nanotechnology is the use of tiny structures – less than 1,000 nanometres across – that are designed to have specific properties. Nanotechnology is an emerging field in science that is used in a wide range of applications, from consumer goods to health products.
In medicine, nanotechnology has only partially been exploited. It is being investigated as a way to improve the properties of medicines, such as their solubility or stability, and to develop medicines that may provide new ways to:
deliver medicines to the body;
target medicines in the body more accurately;
diagnose and treat diseases;
support the regeneration of cells and tissues.
Activities at the European Medicines Agency
The European Medicines Agency follows the latest developments in nanotechnology that are relevant to the development of medicines. Recommendations from the Agency’sCommittee for Medicinal Products for Human Use (CHMP) have already led to the approval of a number of medicines based on nanotechnology. These include medicines containing:
liposomes (microscopic fatty structures containing the active substance), such asCaelyx (doxorubicin), Mepact (mifamurtide) and Myocet (doxorubicin);
nano-scale particles of the active substance, such as Abraxane (paclitaxel), Emend(aprepitant) and Rapamune (sirolimus).
The development of medicines using newer, innovative nanotechnology techniques may raise new challenges for the Agency in the future. These include discussions on whether the current regulatory framework is appropriate for these medicines and whether existing guidelines and requirements on the way the medicines are assessed and monitored are adequate.
The Agency also needs to consider the acceptability of new testing methods and the availability of experts to guide the Agency’s opinion-making.
An overview of the initiatives taken by European Union (EU) regulators in relation to the development and evaluation of nanomedicines and nanosimilars was published in the scientific journal Nanomedicines. The article describes the regulatory challenges and perspectives in this field:
In 2009, the CHMP established an ad hoc expert group on nanomedicines.
This group includes selected experts from academia and the European regulatory network, who support the Agency’s activities by providing specialist input on new scientific knowledge and who help with the review of guidelines on nanomedicines. The group also helps the Agency’s discussions with international partners on issues concerning nanomedicines.
In 2011, the CHMP began to develop in 2011 a series of four reflection papers on nanomedicines to provide guidance to sponsors developing nanomedicines.
These documents cover the development both of new nanomedicines and of nanosimilars (nanomedicines that are claimed to be similar to a reference nanomedicine), since the first generation of nanomedicines, including liposomal formulations, iron-based preparations and nanocrystal-based medicines, have started to come off patent:
The fourth document, a draft reflection paper on the data requirements for intravenous iron-based nanocolloidal products developed with reference to an innovator medicine, will be released for a six-month public consultation in 2013.
International workshops on nanomedicines
The Agency organises workshops on nanomedicines to explore the scientific aspects of nanomedicines and enable the sharing of experience at an international level, in order to assist future developments in the field:
Molecular formula of calcitonin is C145H241N43O49S2
• Molecular weight is 3434.8 g/mol
Calcitonin-related polypeptide alpha
NMR solution structure of salmon calcitonin in SDS micelles.[1]
Calcitonin
CAS Registry Number: 9007-12-9
Additional Names: Thyrocalcitonin; TCA; TCT
Therap-Cat: Calcium regulator.
The structural formula
Calcitonin (also known as thyrocalcitonin) is a 32-amino acid linear polypeptide hormone that is produced in humansprimarily by the parafollicular cells (also known as C-cells) of the thyroid, and in many other animals in the ultimobranchial body.[2] It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH).[3]
Calcitonin has been found in fish, reptiles, birds, and mammals. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal calcium homeostasis.[4] It belongs to the calcitonin-like protein family.
UV – range
Conditions : Concentration – 53 mg / 100 ml
Solvent designation schedule
Methanol
Water
0.1М HCl
0.1M NaOH
The absorption maximum
278 nm
–
275 nm
–
4.9
–
4.4
–
with
1670
–
1500
–
IR – spectrum
Wavelength (μm)
Wavenumber (cm -1 )
Links
UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV
NIST/EPA/NIH Mass Spectral Library 2008
Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.
Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.
Calcitonin-related polypeptide alpha
NMR solution structure of salmon calcitonin in SDS micelles.[1]
However, effects of calcitonin that mirror those of PTH include the following:
Inhibits phosphate reabsorption by the kidney tubules[11]
In its skeleton-preserving actions, calcitonin protects against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation.
Other effects are in preventing postprandial hypercalcemia resulting from absorption of Ca2+. Also, calcitonin inhibits food intake in rats and monkeys, and may have CNS action involving the regulation of feeding and appetite.
Calcitonin was purified in 1962 by Copp and Cheney.[13] While it was initially considered a secretion of the parathyroid glands, it was later identified as the secretion of the C-cellsof the thyroid gland.[14]
It has been investigated as a possible non-operative treatment for spinal stenosis.[16]
The following information is from the UK Electronic Medicines Compendium[17]
General characteristics of the active substance
Salmon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration.
Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).
Calcitonin has short absorption and elimination half-lives of 10–15 minutes and 50–80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30% to 40%.
Characteristics in patients
There is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations. Following parenteral administration of 100 IU calcitonin, peak plasma concentration lies between about 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nausea, vomiting, and secretory diarrhea.
Preclinical safety data
Conventional long-term toxicity, reproduction, mutagenicity, and carcinogenicity studies have been performed in laboratory animals. Salmon calcitonin is devoid of embryotoxic, teratogenic, and mutagenic potential.
An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance. Salmon calcitonin does not cross the placental barrier.
In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.
Pharmaceutical manufacture
Calcitonin was extracted from the ultimobranchial glands (thyroid-like glands) of fish, particularly salmon. Salmon calcitonin resembles human calcitonin, but is more active. At present, it is produced either by recombinant DNA technology or by chemical peptide synthesis. The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.[17]
Oral calcitonin may have a chondroprotective role in osteoarthritis (OA), according to data in rats presented in December, 2005, at the 10th World Congress of the Osteoarthritis Research Society International (OARSI) in Boston, Massachusetts. Although calcitonin is a known antiresorptive agent, its disease-modifying effects on chondrocytes and cartilage metabolisms have not been well established until now.
This new study, however, may help to explain how calcitonin affects osteoarthritis. “Calcitonin acts both directly on osteoclasts, resulting in inhibition of bone resorption and following attenuation of subchondral bone turnover, and directly on chondrocytes, attenuating cartilage degradation and stimulating cartilage formation,” says researcher Morten Karsdal, MSC, PhD, of the department of pharmacology at Nordic Bioscience in Herlev, Denmark. “Therefore, calcitonin may be a future efficacious drug for OA.”[18]
Subcutaneous injections of calcitonin in patients suffering from mania resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder.[19] However no further work on this potential application of calcitonin has been reported.
Diagnostics
It may be used diagnostically as a tumor marker for medullary thyroid cancer, in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on biopsy samples from suspicious lesions (e.g., lymph nodes that are swollen) to establish whether they are metastasis of the original cancer.
Cutoffs for calcitonin to distinguish cases with medullary thyroid cancer have been suggested to be as follows, with a higher value increasing the suspicion of medullary thyroid cancer:[20]
females: 5 ng/L or pg/mL
males: 12 ng/L or pg/mL
children under 6 months of age: 40 ng/L or pg/mL
children between 6 months and 3 years of age: 15 ng/L or pg/mL
When over 3 years of age, adult cutoffs may be used
Increased levels of calcitonin have also been reported for various other conditions. They include: C-cell hyperplasia, Nonthyroidal oat cell carcinoma, Nonthyroidal small cell carcinoma and other nonthyroidal malignancies, acute and chronic renal failure, hypercalcemia, hypergastrinemia and other gastrointestinal disorders, and pulmonary disease.[21]
Structure
Calcitonin is a polypeptide hormone of 32 amino acids, with a molecular weight of 3454.93 daltons. Its structure comprises a single alpha helix.[1] Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type.[22]
The following are the amino acid sequences of salmon and human calcitonin:[23]
Compared to salmon calcitonin, human calcitonin differs at 16 residues.
Description: Cellular and molecular coordination of tissues which secrete chemical compounds to regulate growth, reproduction, metabolism, and ion homeostasis.
References
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Grani, G; Nesca, A; Del Sordo, M; Calvanese, A; Carbotta, G; Bianchini, M; Fumarola, A (Jun 2012). “Interpretation of serum calcitonin in patients with chronic autoimmune thyroiditis.”. Endocrine-related cancer19 (3): 345–9. doi:10.1530/ERC-12-0013.PMID22399011.
Calcium regulating hormone secreted from the mammalian thyroid gland and in non-mammalian species from the ultimobranchial gland. Postulation of a plasma-calcium lowering substance: Copp et al.,Endocrinology70, 638 (1962).
Recognition as a hormone: Hirsch et al.,ibid.73, 244 (1963); of thyroid origin: Foster et al.,Nature202, 1303 (1964).
Over-all action is to oppose the bone and renal effects of parathyroid hormone, q.v.; inhibits bone resorption of Ca2+, with accompanying hypocalcemia and hypophosphatemia and decreased urinary Ca2+ concentrations. Also abolishes the osteolytic effect of toxic doses of vitamins A and D. Calcitonin is highly active biologically, e.g. 50 mg/min infused into a 100 g rat leads to a significant (1 mg/100 ml) decrease in the concn of the plasma calcium within 60 min (together with a corresponding fall in plasma phosphate). Activity is destroyed by trypsin, chymotrypsin, pepsin, polyphenol oxidase; also by hydrogen peroxide oxidation, photooxidation, and treatment with N-bromosuccinimide. Calcitonin structures are single polypeptide chains containing 32 amino acid residues. Structure of porcine: Neher et al.,Helv. Chim. Acta51, 917 (1968); Potts et al.,Proc. Natl. Acad. Sci. USA59, 1321 (1968); Bellet al.,J. Am. Chem. Soc.90, 2704 (1968); eidem,Biochemistry9, 1665 (1970).
Synthesis of porcine: Rittel et al.,Helv. Chim. Acta51, 924 (1968); Guttmann et al.,ibid. 1155.
Isoln of human calcitonin from non-pathological thyroid glands: Haymovits, Rosen, Endocrinology81, 993 (1967); from medullary carcinoma of the thyroid: Neher et al.,Nature220, 984 (1968); Helv. Chim. Acta51, 1738 (1968); Neher, Riniker, DE1929957 (1970 to Ciba), C.A.73, 28902b (1970).
Structure of human: Neher et al.,Helv. Chim. Acta51, 1900 (1968). Synthesis of human: Sieber et al.,ibid. 2057; J. Hirt et al.,Rec. Trav. Chim.98, 143 (1979).
Biosynthetic studies: J. W. Jacobs et al.,J. Biol. Chem.254, 10600 (1979); S. G. Amara et al.,ibid.255, 2645 (1980).
Amino acid sequence differs among mammalian species, salmon calcitonin showing a marked difference from that of the higher vertebrae as well as a more potent biological activity. Mechanism of action: E. M. Brown, G. D. Aurbach, Vitam. Horm.38, 236 (1980). Anorectic activity in rats: W. J. Freed et al.,Science206, 850 (1979).
Growth inhibition of human breast cancer cells in vitro: Y. Iwasaki et al.,Biochem. Biophys. Res. Commun.110, 235 (1983).
Review of early literature: Munson, Hirsch, Clin. Orthop.49, 209 (1966).
Review of isoln, structure, synthesis: Behrens, Grinnan, Annu. Rev. Biochem.38, 83 (1969); Potts et al.,Vitam. Horm.29,41 (1971).
Comprehensive review: Calcitonin, Proc. Symp. on Thyrocalcitonin and the C Cells, S. Taylor, Ed. (Springer-Verlag, New York, 1968); Foster et al., “Calcitonin” in Clinics in Endocrinology and Metabolism, I. MacIntyre, Ed. (W. B. Saunders, Philadelphia, 1972) pp 93-124.
Review of pharmacology and therapeutic use: J. C. Stevenson, I. M. A. Evans, Drugs21, 257-272 (1981).
Literature References: Clinical trial in postmenopausal osteoporosis: C. H. Chesnut et al.,Am. J. Med.109, 267 (2000). LC determn in biological fluids: M. Aguiar et al., J. Chromatogr. B818, 301 (2005).
A long-acting decanoateester of haloperidol is used as an injection given every four weeks to people with schizophrenia or related illnesses who have poor adherence to medication regimens (most commonly due to them forgetting to take their medication, or due to poor insight into their illness) and suffer frequent relapses of illness, or to overcome the drawbacks inherent to its orally administered counterpart.[6] Such long acting injections are controversial because it can be seen as denying people their right to stop taking their medication.
Haloperidol was discovered by Paul Janssen.[70] It was developed in 1958 at the Belgian company Janssen Pharmaceutica and submitted to the first of clinical trials in Belgiumlater that year.[71]
Coincident with civil unrest in the United States in the 1960s and 1970s, schizophrenia was racialized to match the behavior of angry/violent black men. Haldol was promoted as a way to pacify them, and was marketed to appeal to feelings of racial unease. (cf. Metzl 2010. The Protest Psychosis)
Soviet dissidents, including medical staff, have reported several times on the use of haloperidol in the Soviet Union for punitive purposes or simply to break the prisoners’ will.[72][73][74] Notable dissidents who were administered haloperidol as part of their court-ordered treatment were Sergei Kovalev and Leonid Plyushch.[75] The accounts Plyushch gave in the West, after he was allowed to leave the Soviet Union in 1976, were instrumental in triggering Western condemnation of Soviet practices at the World Psychiatric Association‘s 1977 meeting.[76] The use of haloperidol in the Soviet Union’s psychiatric system was prevalent because it was one of the few psychotropic drugs produced in quantity in the USSR.[77]
Haloperidol has been used for its sedating effects during the deportations of immigrants by the United States Immigration and Customs Enforcement (ICE). During 2002-2008, federal immigration personnel used haloperidol to sedate 356 deportees. By 2008, following court challenges over the practice, it was given to only three detainees. Following lawsuits, U.S. officials changed the procedure so the drug is administered only by the recommendation of medical personnel and under court order.[78][79]
Brand names
Haloperidol is sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol (common tradename in the US and UK), Halosten, Keselan, Linton, Peluces, Serenace and Sigaperidol.
Veterinary use
Haloperidol is also used on many different kinds of animals. It appears to be particularly successful when given to birds, e.g., a parrot that will otherwise continuously pluck its feathers out.[80]
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Smith, Thomas J.; Ritter, Joseph K.; Poklis, Justin L.; Fletcher, Devon; Coyne, Patrick J.; Dodson, Patricia; Parker, Gwendolyn (2012). “ABH Gel is Not Absorbed from the Skin of Normal Volunteers”. Journal of Pain and Symptom Management43(5): 961–6. doi:10.1016/j.jpainsymman.2011.05.017. PMID22560361.
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Jump up^ Kawashima, Hidekazu; Iida, Yasuhiko; Kitamura, Youji; Saji, Hideo (2004). “Binding of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium ion (HPP+), a metabolite of haloperidol, to synthetic melanin: Implications for the dopaminergic neurotoxicity of HPP+“. Neurotoxicity Research6 (7–8): 535–42. doi:10.1007/BF03033449.PMID15639785.
Jump up^ Bishnoi, Mahendra; Chopra, Kanwaljit; Kulkarni, Shrinivas K. (2008). “Activation of striatal inflammatory mediators and caspase-3 is central to haloperidol-induced orofacial dyskinesia”. European Journal of Pharmacology590 (1–3): 241–5.doi:10.1016/j.ejphar.2008.06.033. PMID18590723.
Jump up^ Eyles, Darryl W.; Avent, Kathryn M.; Stedman, Terry J.; Pond, Susan M. (1997). “Two pyridinium metabolites of haloperidol are present in the brain of patients at post-mortem”.Life Sciences60 (8): 529–34. doi:10.1016/S0024-3205(96)00656-X. PMID9042387.
Jump up^ Ulrich, Sven; Neuhof, Sabine; Braun, Verena; Danos, Peter; Pester, Uwe; Hoy, Ludwig (2000). “Disposition of Haloperidol Pyridinium and Reduced Haloperidol Pyridinium in Schizophrenic Patients: No Relationship with Clinical Variables During Short-Term Treatment”. Journal of Clinical Psychopharmacology20 (2): 210–9.doi:10.1097/00004714-200004000-00014. PMID10770460.
Jump up^ Ulrich, S.; Sandmann, U.; Genz, A. (2005). “Serum Concentrations of Haloperidol Pyridinium Metabolites and the Relationship with Tardive Dyskinesia and Parkinsonism: A Cross-Section Study in Psychiatric Patients”. Pharmacopsychiatry38 (4): 171–7.doi:10.1055/s-2005-871240. PMID16025420.
Jump up^ Seeman, P; Tallerico, T (1998). “Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors”. Molecular Psychiatry3 (2): 123–34.doi:10.1038/sj.mp.4000336. PMID9577836.
Jump up^ Leysen, JE; Janssen, PM; Megens, AA; Schotte, A (1994). “Risperidone: A novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity”. The Journal of Clinical Psychiatry55 (Suppl): 5–12.PMID7520908.
Jump up^ Cobos, Enrique J.; Del Pozo, Esperanza; Baeyens, José M. (2007). “Irreversible blockade of sigma-1 receptors by haloperidol and its metabolites in guinea pig brain and SH-SY5Y human neuroblastoma cells”. Journal of Neurochemistry102 (3): 812–25.doi:10.1111/j.1471-4159.2007.04533.x. PMID17419803.
Jump up^ Colabufo, Nicolaantonio; Berardi, Francesco; Contino, Marialessandra; Niso, Mauro; Abate, Carmen; Perrone, Roberto; Tortorella, Vincenzo (2004). “Antiproliferative and cytotoxic effects of some σ2 agonists and σ1 antagonists in tumour cell lines”. Naunyn-Schmiedeberg’s Archives of Pharmacology370 (2): 106–13. doi:10.1007/s00210-004-0961-2. PMID15322732.
^ Jump up to:abcdefghijk Kroeze, Wesley K; Hufeisen, Sandra J; Popadak, Beth A; Renock, Sean M; Steinberg, Seanna; Ernsberger, Paul; Jayathilake, Karu; Meltzer, Herbert Y; Roth, Bryan L (2003). “H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs”. Neuropsychopharmacology28 (3): 519–26.doi:10.1038/sj.npp.1300027. PMID12629531.
^ Jump up to:ab Kornhuber, Johannes; Schultz, Andreas; Wiltfang, Jens; Meineke, Ingolf; Gleiter, Christoph H.; Zöchling, Robert; Boissl, Karl-Werner; Leblhuber, Friedrich; Riederer, Peter (1999). “Persistence of Haloperidol in Human Brain Tissue”. The American Journal of Psychiatry156 (6): 885–90. PMID10360127.
Jump up^ Kornhuber, Johannes; Wiltfang, Jens; Riederer, Peter; Bleich, Stefan (2006). “Neuroleptic drugs in the human brain: Clinical impact of persistence and region-specific distribution”. European Archives of Psychiatry and Clinical Neuroscience256 (5): 274–80. doi:10.1007/s00406-006-0661-7. PMID16788768.
Jump up^ de Boer, S. P.; E. J. Driessen; H. L. Verhaar (1982). Biographical Dictionary of Dissidents in the Soviet Union, 1956-1975. The Hague: Martinus Nijhoff Publishers.ISBN90-247-2538-0.[page needed]
Pantoprazole is a proton pump inhibitor drug used for short-term treatment of erosion and ulceration of the esophagus caused by gastroesophageal reflux disease.
Use
Pantoprazole is used for short-term treatment of erosion and ulceration of the oesophagus caused by gastroesophageal reflux disease. Initial treatment is generally of eight weeks’ duration, after which another eight week course of treatment may be considered if necessary. It can be used as a maintenance therapy for long term use after initial response is obtained.
Adverse effects
Antacid preparations such as pantoprazole work by suppressing the acid-mediated breakdown of proteins. This leads to an elevated risk of developing food and drug allergies due to undigested proteins passing into the gastrointestinal tract where sensitisation occurs. It is unclear whether this risk occurs with short-term or only long-term use.[1]
Nutrition: May reduce the absorption of important nutrients, vitamins and minerals, as well as medications, leaving users at increased risk for pneumonia.[2]
Cardiovascular: Increase in a chemical that suppresses the production of nitric oxide by 25% in humans, which have proven to relax and protect arteries and veins. Causes blood vessels to constrict, a development that could lead to a number of cardiovascular problems if continued for a prolonged period of time.[2]
Pharmacology
Wyeth pantoprazole 20mg.
Pantoprazole is metabolized in the liver by the cytochrome P450 system.[3] Metabolism mainly consists of demethylation by CYP2C19followed by sulfation. Another metabolic pathway is oxidation by CYP3A4. Pantoprazole metabolites are not thought to have any pharmacological significance. Pantoprazole is relatively free of drug interactions;[4] however, it may alter the absorption of other medications that depend on the amount of acid in the stomach, such as ketoconazole or digoxin. Generally inactive at acidic pH of stomach, thus it is usually given with a pro kinetic drug. Pantoprazole binds irreversibly to H+K+ATPase (proton pumps) and suppresses the secretion of acid. As it binds irreversibly to the pumps, new pumps have to be made before acid production can be resumed. The drug’s plasma half-life is about 2 hours.[5]
Pharmacokinetics
Absorption
Bioavailability: (oral, delayed release tablets), approximately 77%
Effect of food: (oral, delayed-release tablets), AUC and Cmax no effect, Tmax variable, absorption delayed, no net effect
Effect of food: (oral, for-delayed-release suspension), administer 30 minutes before a meal
Tmax, Oral, delayed-release suspension: 2 to 2.5 h
Tmax, Oral, delayed-release tablets: 2.5 h
Tmax, Oral, delayed-release tablets: 1.5 to 2 hours (pediatrics)
Distribution
Protein binding: about 98% to primarily albumin
Vd, extensive metabolizers (IV): approximately 11 L to 23.6 L
Vd, pediatrics (oral): 0.21 to 0.43 L/kg.
Metabolism
Hepatic; cytochrome P450 CYP2C19; minor metabolism from CYP3A4, 2D6, and 2C9
Excretion
Fecal: (oral or IV, normal metabolizers), 18%
Renal: (oral or IV, normal metabolizers), approximately 71%, none as unchanged
Dialyzable: no (hemodialysis)
Total body clearance: (IV) 7.6 to 14 L/hour.
Total body clearance: (oral, pediatrics) 0.18 to 2.08 L/h/kg
Elimination Half Life
Oral or IV, 1 hour
Oral or IV, slow metabolizers, 3.5 to 10 hours
Pediatrics, 0.7 to 5.34 hours
Availability
Pantoprazole was developed by Altana (owned by Nycomed) and was licensed in the USA to Wyeth (which was taken over by Pfizer). It was initially marketed under the brand name Protonix by Wyeth-Ayerst Laboratories and now is available as a generic. It is available by prescription in delayed-release tablets. It is also available for intravenous use.
On 24 December 2007, Teva Pharmaceutical released an AB-rated generic alternative to Protonix.[6] This was followed by generic equivalents from Sun Pharma and Kudco Pharma. Wyeth sued all three for patent infringement and launched its own generic version of Protonix with Nycomed.[7][8]
Pantoprazole is the international non-proprietary name of the chemical product 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfmyl]-lH-benzimidazole of formula
Pantoprazole This product is an active ingredient used in the treatment of gastric ulcers, usually in the form of its sodium salt.
The product was described for the first time in European patent application EP-A-0166287 that also describes several processes for the preparation of products assignable to a general formula among which pantoprazole is to be found. The reaction sequences of these processes, applied precisely to the preparation of pantoprazole, are given in Scheme 1.
Scheme 1
In Scheme 1, the variables Y, Z, Z’ and Z” are leaving groups, for example atoms of halogen, and the variables M and M’ are atoms of alkali metals.
Austrian patent AT-B-394368 discloses another process based on a different route of synthetis, the reaction sequence of which is given in Scheme 2.
Pantoprazole Scheme 2
Nevertheless, this process has obvious drawbacks, since the methylation can take place not only in OH in the 4-position of the pyridine ring, but also in the nitrogen linked to a hydrogen of the benzimidazole ring, which can give place to mixtures of the desired product with the two possible methylated isomers of the benzimidazole compounds obtained, 3- methyl or 1 -methyl, which means that additional chromatographic purification steps are needed and the yields obtained are low.
PCT application WO97/29103 discloses another process for the preparation of pantoprazole, the reaction sequence of which is given in Scheme 3.
Scheme 3 As may be seen, different synthesis strategies have been proposed for the preparation of pantoprazole, some of them recently, which is an indication that the preparation of the product is still not considered to be sufficiently well developed, whereby there is still a need for developing alternative processes that allow pantoprazole to be prepared by means of simpler techniques and more accessible intermediate compounds and with good chemical yields.
EXAMPLES
Example 1. – Preparation of compound (IX)
47.5 ml (0.502 mol) of acetic anhydride were mixed with 1.65 g (0.0135 mol) of 4-dimethylaminopyridine, giving a transparent yellow solution which was heated to 65° – 70°C. This temperature was held by cooling since the reaction is exothermic. 25 g (0.1441 mol) of 2-methyl-3- methoxy-4-chloropyridine N-oxide (X) were added over a period of about 70 minutes. Once the addition was completed, the reaction was held at 65° – 70°C for a further 2h 20 minutes and after this time it was allowed to cool down to below 65°C and 90 ml of methanol were added gradually, while holding the temperature below 65°C. The resulting reaction mass was distilled at reduced pressure in a rotavap to remove the volatile components and the residue containing compound (IX) was used as such for the following reaction. Thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15: 1), showed a single spot at Rf – 0.82, indicating that the reaction has been completed.
Example 2. – Preparation of compound fVIII
(IX) (VIII)
11.5 ml methanol and 11.5 ml of water were added over the crude residue from Example 1 containing compound (IX), and thereafter, while holding the temperature to between 25° and 30°C with a water bath, the residual acetic acid contained in the crude residue was neutralized by the addition of 33% aqueous NaOH. Once the residual acid had been neutralized, 19 ml (0.2136 mol) of the 33% aqueous NaOH were added over 20 minutes, while holding the temperature to between 25° and 30°C, and, on completion of the addition, the hydrolysis reaction at pH 11.7 – 11.8 was held for 2h 30 minutes, to between 25° and 30°C. On completion of the reaction, the pH was adjusted to 7.0 – 7.5 by the addition of HC1 35%, while holding the temperature to 25°C. Thereafter, 50 ml of methylene chloride were added and, after stirring and allowing to rest, the phases were decanted. A further five extractions were carried out with 30 ml methylene chloride each and the pooled organic phases were dried with anhydrous sodium sulfate, were filtered and washed, and were evaporated at reduced pressure in a rotavap, providing a solid residue having a melting point around 73°C and containing compound (VIII). Thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15: 1), gave a main spot at Rf = 0.55, showing that the reaction was complete. The thus obtained crude residue was used as such in the following reaction.
Example 3. – Preparation of compound (VI)
24.5 g of the residue obtained in Example 2, containing approximately 0.142 mol of the compound 2-hydroxymethyl-3-methoxy-4-chloropyridine (VIII), were mixed with 0.5 ml of DMF and 300 ml of anhydrous methylene chloride, to give a brown solution which was cooled to 0° – 5°C in an ice water bath. Thereafter, a solution of 11.5 ml (0.1585 mol) of thionyl chloride in 50 ml of anhydrous methylene chloride was added over 20 minutes, while holding the above-mentioned temperature,. Once the addition was complete, the reaction was held at 0° – 5°C for a further 90 minutes and then 120 ml of water and NaOH 33% were added to pH 5 – 6, requiring approximately 29 ml of NaOH. The phases were then decanted and separated. The organic phase was extracted with a further 120 ml of water and the pooled aqueous phases were extracted with a further 4×25 ml of methylene chloride, in order to recover the greatest possible amount of product. The pooled organic phases were dried over anhydrous sodium sulfate, filtered and washed, and evaporated at reduced pressure in a rotavap, to give a residue containing the compound 2-chloromethyl-3- methoxy-4-chloropyridine (VI). Thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15:1), showed a main spot at Rf = 0.83, indicating that the reaction was complete. The thus obtained crude residue was used as such in the following reaction. Example 4. – Preparation of compound (III)
26.11 g of the residue obtained in the Example 3 containing approximately 0.136 mol of the compound 2-chloromethyl-3-methoxy-4- chloropyridine (VI) were mixed with 370 ml of methylene chloride, to give a brown solution over which were added, at 20° – 25°C, 29.3 g (0.136 mol) of 5-difluoromethoxy-2-mercaptobenzimidazole (VII) and 17.10 ml (0.136 mol) of tetramethylguanidine (TMGH). The mixture was stirred at this temperature for 2 hours, after which 450 ml of water were added, with the pH being held to between 9.5 and 10. Thereafter the phases were decanted and the organic phase was washed 5×50 ml of a IN NaOH aqueous solution and, thereafter, with 2×50 ml of water. The organic phase was treated with 50 ml of water and an amount of HC1 30% sufficient to adjust the pH to between 5 and 6. Thereafter, the phases were decanted, and the organic phase was dried over anhydrous sodium sulfate, was filtered and washed, and evaporated at reduced pressure in a rotavap, to give a solid residue of melting point 64° – 73 °C that contains the compound (III). Thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15: 1), presented a main spot at Rf = 0.52. Yield 82%. The thus obtained compound 5-(difluoromethoxy)-2-[[(3-methoxy-4-chlorine-2 pyridinyl)methyl]mercapto]- lH-benzimidazole (III) was used as such in the following reaction Example 5. – Preparation of compound (IV)
25.8 g (0.0694 mol) of the compound (III) obtained in the Example 4 were mixed with 88 ml of methanol, to give a brown solution to which 3.7 ml of water, 0.99 g of ammonium molybdate and 0.78 g of sodium carbonate were added. The system was cooled to 0°C – 5°C, 3.4 ml (0.0756 mol) of 60% hydrogen peroxide were added, and the reaction mixture was held at 0°C – 5°C for 1 – 2 days, the end point of the reaction being checked by thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15: l).
During the reaction the presence of hydrogen peroxide in the reaction medium was controlled by testing with potassium iodide, water and starch. When effected on a sample containing hydrogen peroxide, it provides a brown-black colour. If the assay is negative before the chromatographic control indicates completion of the reaction, more hydrogen peroxide is added.
On completion of the reaction, 260 ml of water were added, the system was cooled to 0°C – 5°C again and the mixture was stirred for 2 hours at this temperature. The solid precipitate was filtered, washed with abundant water, and dried at a temperature below 60°C, to give 5-(difluoromethoxy)-2-[[(3- methoxy-4-chlorine-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole (IV), melting point 130° – 136°C, with an 83.5% yield. Thin layer chromatography on silica gel 60 F254, eluting with CHCl3/MeOH (15: 1), gave a main spot at Rf = 0.5.
Compound (IV) can be purified, if desired, by the following crystallization method:
5 g of crude product was suspended in 16 ml of acetone and was heated to boiling until a dark brown solution was obtained. Thereafter the thus obtained solution was allowed to cool down to room temperature and then was then chilled again to -20°C, at which temperature the mixture was held for 23 hours without stirring. Thereafter the solid was filtered and washed with 6×4 ml of acetone chilled to -20°C. Once dry, the resulting white solid weighed 2.73 g, had a point of melting of 142°C and gave a single spot in thin layer chromatography. The IR spectrum of the compound on KBr is given in Figure 1.
The acetonic solution comprising the mother liquors of filtration and the washes was concentrated to a volume of 20 ml and a further 5 g of crude compound were added. The above described crystallization process was repeated to obtain a further 4.11 g of purified product of characteristics similar to the previous one.
The acetonic solution from the previous crystallization was concentrated to a volume of 17 ml and a further 4 g of crude compound were added. The above described crystallization process was repeated to obtain a further 2.91 g of purified product of similar characteristics to the previous ones.
The acetonic solution from the previous crystallization was concentrated to a volume of 15 ml and a further 4 g of crude compound were added. The above described crystallization process was repeated to obtain a further 3.3 g of purified product of similar characteristics to the previous ones.
The acetonic solution from the previous crystallization was concentrated to a volume of 16 ml and a further 4.36 g of crude compound were added. The above described crystallization process was repeated to obtain a further 3.62 g of purified product of similar characteristics to the previous ones.
Finally, the acetonic solution from the previous crystallization was concentrated to a volume of 10 – 12 ml and held at -20°C for two days without stirring. Thereafter, the solid was filtered and washed with 5×3 ml of acetone chilled to -20°C. Once dry, the solid weighed 1.26 g and had similar characteristics to the previous ones.
The total yield of all the crystallizations was 80%.
Example 6. – Preparation of pantoprazole
12.95 g (0.0334 mol) of compound (IV) purified by crystallization of Example 5 were mixed with 38 ml of N,N-dimethylacetamide and thereafter 7.03 g (0.1003 mol) of potassium methoxide were added, while holding the temperature to between 20°C and 30°C, whereby a dark brown mixture was obtained. The system was held at approximately 25°C for about 23 hours, after which, once the reaction was complete, the pH was adjusted to 7 with the addition of 3.82 ml of acetic acid. The N,N-dimethylacetamide was removed at reduced pressure at an internal temperature of not more than 75°C. 65 ml of water and 50 ml of methylene chloride were added over the thus obtained residue, followed by decantation of the phases. Once the phases were decanted, the aqueous phase was extracted a with further 3×25 ml of methylene chloride, the organic phases were pooled and the resulting solution dried over anhydrous sodium sulfate, was filtered and washed, and evaporated at reduced pressure in a rotavap, to give a crude residue over which 55 ml of water were added, to give a suspension (if the product does not solidify at this point the water is decanted and a further 55 ml of water are added to remove remains of N,N-dimethylacetamide that hinder the solidification of the product). The solid was filtered and, after drying, 11.61 g of crude pantoprazole of reddish brown colour were obtained (Yield 90%). The thus obtained crude product was decoloured by dissolving the crude product in 150 ml of methanol, whereby a dark brown solution was obtained. 7.5 g of active carbon were added, while maintaining stirring for 45 minutes at 25°C – 30°C, after which the carbon was filtered out and the filter was washed. The methanol was then removed in the rotavap at reduced pressure, a temperature below 40°C. 10.33 g of a solid residue were obtained and were mixed with 14.9 ml of methylethylketone, and the suspension was heated to 45°C for about 10 minutes, after which it was cooled, first to room temperature and then to -20°C. This temperature was held over night and thereafter the solid was filtered, washed with 6×5 ml of methylethylketone chilled to -20°C. Once dry, 7.75 g of a white solid, melting point 140°C – 141 °C, were obtained. Thin layer chromatography on silica gel F254, eluting with CHCl3/MeOH (15: 1), gave a single spot at Rf =
0.41 and a IR spectrum corresponding identically with that of pantoprazole.
The ketonic solution comprising the mother liquors of filtration and the washes, was concentrated to 9.7 ml, was heated to 40°C, was held at this temperature for about five minutes and was then cooled, first to room temperature and then to -20°C, this temperature being held for 4 hours. At the end of this time, the solid was filtered and was washed with 4×2 ml of methylethylketone chilled to -20°C. Once dry, 0.42 g of a white solid of similar characteristics to the previous one was obtained.
The ketone solution from the previous treatment was concentrated to 3.1 ml, was heated to 40°C, was held to this temperature for about five minutes and then was cooled, first to room temperature and then to -20°C, this temperature being held for 4 hours. At the end of this time, the solid was filtered and was washed with 5×3 ml of methylethylketone chilled to – 20°C. Once dry, 0.41 g of a white-beige solid of similar characteristics to the previous one was obtained. The total yield, including purifications, was 67%.
If a whiter solid is desired, one or several washes can be carried with isopropyl acetate as follows: 6.6 g of pantoprazole from the methylethylketone treatment were suspended in 50 ml of isopropyl acetate. The system (white suspension) was stirred for about 30 minutes at 25°C, was then cooled to 0°C – 5°C, was stirred for about 15 minutes at this temperature and the solid was then filtered, was washed with 3×15 ml of isopropyl acetate. Once dry, 6.26 g of a pure white solid were obtained.
Trade Names
Country
Trade name
Manufacturer
Germany
Pantozol
Nycomed
Rifun
– “-
France
Eupantol
Altana
Inipomp
Sanofi-Aventis
United Kingdom
Protium
ALTANA
Italy
Pantekta
Abbott
Pantopan
Pharmacia
Pantork
Altana
USA
Protonix
Wyeth
Ukraine
Kontrolok
Nycomed Oranienburg GmbH, Germany
Nolpaza
Krka
Pultset
Nobel Ilach Sanayi ve Ticaret AS, Turkey
Proksium
JSC “Lubnyfarm”, Ukraine
various generic drugs
Formulations
ampoule 40 mg;
Tablets 40 mg
UV – spectrum
Conditions : Concentration – 1 mg / 100 ml
Solvent designation schedule
Methanol
Water
0.1 M HCl
0.1M NaOH
The absorption maximum
289 nm
291nm
Observed
decay
295 nm
391
346
–
418
ε
16600
14700
–
17700
IR – spectrum
Wavelength (μm)
Wavenumber (cm -1 )
NMR Spectrum
will be added
Links
EP 134 400 (Byk Gulden Lomberg; appl. 1.5.1984; CH-prior. 3.5.1983).
US 4,555,518 (Byk Gulden Lomberg; 26.11.1985; appl. 1.5.1984; CH-prior. 3.5.1983).
US 4,758,579 (Byk Gulden Lomberg; 19.7.1988; appl. 28.4.1987; CH-prior. 16.6.1984).
UV and IR Spectra. H.-W. Dibbern, RM Muller, E. Wirbitzki, 2002 ECV
NIST / EPA / NIH Mass Spectral Library 2008
Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman.Academic Press, 2000.
Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.
[Dr. John Cooke, chair of Methodist Hospital’s cardiovascular services] [Houston Chronicle Health Zone dated Thursday, July 11, 2013 chron.com/refluxmeds] (Journal: Circulation)
Jump up^ Meyer, U A (1996). “Metabolic interactions of the proton-pump inhibitors lansoprazole, omeprazole and pantoprazole with other drugs”. European journal of gastroenterology & hepatology8 (Suppl 1): S21–25. doi:10.1097/00042737-199610001-00005.
Steinijans, V. W.; Huber, R.; Hartmann, M.; Zech, K.; Bliesath, H.; Wurst, W.; Radtke, H. W. (1996). “Lack of pantoprazole drug interactions in man: An updated review”. International Journal of Clinical Pharmacology and Therapeutics34 (6): 243–262. PMID8793611.
Phase 3 drug, UncategorizedComments Off on Cortendo AB: First Patient Enrolled into NormoCort Phase 3 SONICS Trial Following a Successful EU Investigator Meeting
An antimicrobial agent that destroys fungi by suppressing their ability to grow or reproduce. Antifungal agents differ from industrial fungicides in that they defend against fungi present in human or animal tissues.
An antimicrobial agent that destroys fungi by suppressing their ability to grow or reproduce. Antifungal agents differ from industrial fungicides in that they defend against fungi present in human or animal tissues.
Ketoconazole, 1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3– dioxolan-4-yl]methoxy]phenyl]piperazine, is a racemic mixture of the cis enantiomers (-)-(2S,4R) and (+)-(2R,4S) marketed as an anti-fungal agent. Ketoconazole inhibits fungal growth through the inhibition of ergosterol synthesis.(-)-Ketoconazole, the (2S,4R) enantiomer contained in the racemate of ketoconazole, is in phase III clinical trials at Cortendo for the treatment of endogenous Cushing’s syndrome. The company and licensee DiObex had also been developing the drug candidate for the treatment of type 2 diabetes; however, no recent development has been reported for this research.Preclinical studies have demonstrated the drug candidate’s ability to inhibit the synthesis of cortisol, resulting in substantial clinical benefits including lowering both blood pressure and cholesterol in addition to controlling glucose levels. It has also been shown that (-)-ketoconazole is responsible for virtually all of the cortisol synthesis inhibitory activity present in the racemate. Rights to the compound are shared with Cortendo.In 2012, orphan drug designation was assigned in the U.S. for the treatment of endogenous Cushing’s syndrome.
GÖTEBORG, Sweden.–(BUSINESS WIRE)–Cortendo AB (OSE:CORT) today announced that the first patient has been enrolled into the Phase 3 SONICS trial, i.e., “Study Of NormoCort In Cushing’s Syndrome.”
“The enrollment of the first patient into the SONICS trial represents a significant milestone for Cortendo”
The patient was enrolled by one of the trial’s lead principal investigators at a Pituitary Center from a prestigious institution in Baltimore, Maryland. “The enrollment of the first patient into the SONICS trial represents a significant milestone for Cortendo”, said Dr. Theodore R Koziol. ”The SONICS clinical trial team is acutely focused on the implementation of the trial following a successful EU Investigator’s meeting in Barcelona in July, which we believe further solidified the foundation for the trial.”
Cortendo successfully completed its European Investigator meeting supporting SONICS held in Barcelona, Spain on July 17-18. More than 35 investigators/study coordinators, including many of the world’s leading Cushing’s experts from 24 study sites, were in attendance and received training for the trial. Based on the positive feedback from the meeting, Cortendo has gained further confidence that NormoCort (COR-003) has the potential to be an important future treatment option for patients afflicted with Cushing’s Syndrome. A second US Investigator meeting is also being planned for later this year.
”It was gratifying to participate in the NormoCort SONICS trial investigator meeting in my home town of Barcelona with so many esteemed colleagues dedicated to treating patients with Cushing’s Syndrome”, said Susan Webb M.D. Ph.D. Professor of Medicine Universitat Autonoma de Barcelona. ”There remains a significant unmet medical need for patients, and I am delighted to be part of the development of this new therapy”.
Cortendo has also further strengthened its internal as well as external teams to support the study and to position the trial for an increased recruitment rate. In July, Cortendo added both an experienced physician and internal Clinical Operations Director to the NormoCort development team. Cortendo, working in concert with its CROs supporting the SONICS trial, now has a team of approximately 20 personnel on the NormoCort development program.
Cortendo has previously communicated its plan to meet the recruitment goal by increasing the number of study sites from 38 to 45 worldwide. The company is at various levels of activation with more than 30 study sites to date. Therein, Cortendo expects a large proportion of the sites to be activated by the end of the third quarter this year and remains confident that essentially all sites will be open by the end of 2014.
Risk and uncertainty
The development of pharmaceuticals carries significant risk. Failure may occur at any stage during development and commercialization due to safety or clinical efficacy issues. Delays may occur due to requirements from regulatory authorities not anticipated by the company.
About Cortendo
Cortendo AB is a biopharmaceutical company headquartered in Göteborg, Sweden. Its stock is publicly traded on the NOTC-A-list (OTC) in Norway. Cortendo is a pioneer in the field of cortisol inhibition and has completed early clinical trials in patients with Type 2 diabetes. The lead drug candidate NormoCort, the 2S, 4R-enantiomer of ketoconazole, has been re-focused to Cushing’s Syndrome, and has entered Phase 3 development. The company’s strategy is to primarily focus its resources within orphan drugs and metabolic diseases and to seek opportunities where the path to commercialization or partnership is clear and relatively near-term. Cortendo’s business model is to commercialize orphan and specialist product opportunities in key markets, and to partner non-specialist product opportunities such as diabetes at relevant development stages.
Alexander Lindström
Chief Financial Officer Office
+1 610 254 9200
Mobile : +1 917 349 7210
E-mail : alindstrom@cortendo.com
Ketoconazole, 1-acetyl-4- [4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolan-4-yl] methoxy] phenyl] piperazine, is a racemic mixture of the cis enantiomers (-)-(2S, 4R) and (+)-(2R, 4S) marketed as an anti-fungal agent. Ketoconazole inhibits fungal growth through the inhibition of ergosterol synthesis. Ergosterol is a key component of fungal cell walls.
More recently, ketoconazole was found to decrease plasma cortisol and to be useful, alone and in combination with other agents, in the treatment of a variety of diseases and conditions, including type 2 diabetes, Metabolic Syndrome (also known as the Insulin Resistance Syndrome, Dysmetabolic Syndrome or Syndrome X), and other medical conditions that are associated with elevated cortisol levels. SeeU.S. Patent Nos. 5,584,790 ; 6,166,017 ; and 6,642,236 , each of which is incorporated herein by reference. Cortisol is a stress-related hormone secreted from the cortex of the adrenal glands. ACTH (adenocorticotropic hormone) increases cortisol secretion. ACTH is secreted by the pituitary gland, a process activated by secretion of corticotropin releasing hormone (CRH) from the hypothalamus.
Cortisol circulates in the bloodstream and activates specific intracellular receptors, such as the glucocorticoid receptor (GR). Disturbances in cortisol levels, synthetic rates or activity have been shown to be associated with numerous metabolic complications, including insulin resistance, obesity, diabetes and Metabolic Syndrome. Additionally, these metabolic abnormalities are associated with substantially increased risk of cardiovascular disease, a major cause of death in industrialized countries. See Mårin P et al., “Cortisol secretion in relation to body fat distribution in obese premenopausal women.” Metabolism 1992; 41:882-886, Bjorntorp, “Neuroendocrine perturbations as a cause of insulin resistance.” Diabetes Metab Res Rev 1999; 15(6): 427-41, and Rosmond, “Role of stress in the pathogenesis of the metabolic syndrome.” Psychoneuroendocrinology 2005; 30(1): 1-10, each of which is incorporated herein by reference.
While ketoconazole is known to inhibit some of the enzymatic steps in cortisol synthesis, such as, for example, 17α hydroxylase (Wachall et al., “Imidazole substituted biphenyls: a new class of highly potent and in vivo active inhibitors of P450 17 as potential therapeutics for treatment of prostate cancer.” Bioorg Med Chem 1999; 7(9): 1913-24, incorporated herein by reference) and 11b-hydroxylase (Rotstein et al., “Stereoisomers of ketoconazole: preparation and biological activity.” J Med Chem 1992; 35(15): 2818-25) and 11β-hydroxy steroid dehydrogenase (11β-HSD) (Diederich et al., “In the search for specific inhibitors of human 11β-hydroxysteroid-dehydrogenases (11β-HSDs): chenodeoxycholic acid selectively inhibits 11β-HSD-L” Eur J Endocrinol 2000; 142(2): 200-7, incorporated herein by reference) the mechanisms by which ketoconazole decreases cortisol levels in the plasma have not been reported. For example, there is uncertainty regarding the effect of ketoconazole on the 11β-hydroxy steroid dehydrogenase (11β-HSD) enzymes. There are two 11β-HSD enzymes. One of these, 11β-HSD-I, is primarily a reductase that is highly expressed in the liver and can convert the inactive 11-keto glucocorticoid to the active glucocorticoid (cortisol in humans and corticosterone in rats). In contrast, the other, 11β-HSD-II, is primarily expressed in the kidney and acts primarily as an oxidase that converts active glucocorticoid (cortisol in humans and corticosterone in rats) to inactive 11-keto glucocorticoids. Thus, the plasma concentration of active glucocorticoid is influenced by the rate of synthesis, controlled in part by the activity of adrenal 11β-hydroxylase and by the rate of interconversion, controlled in part by the relative activities of the two 11β-HSD enzymes. Ketoconazole is known to inhibit these three enzymes (Diederich et al., supra) and the 2S,4R enantiomer is more active against the adrenal 11β-hydroxylase enzyme than is the 2R,4S enantiomer (Rotstein et al., supra). However, there are no reports describing the effect of the two ketoconazole enantiomers on either of 11β-HSD-I or 11β-HSD-II, so it is not possible to predict what effects, if any, the two different ketoconazole enantiomers will each have on plasma levels of the active glucocorticoid levels in a mammal.
Ketoconazole has also been reported to lower cholesterol levels in humans (Sonino et al. (1991). “Ketoconazole treatment in Cushing’s syndrome: experience in 34 patients.” Clin Endocrinol (Oxf). 35(4): 347-52; Gylling et al. (1993). “Effects of ketoconazole on cholesterol precursors and low density lipoprotein kinetics in hypercholesterolemia.” J Lipid Res. 34(1): 59-67) each of which is incorporated herein by reference). The 2S,4R enantiomer is more active against the cholesterol synthetic enzyme 14 αlanosterol demethylase than is the other (2R,4S) enantiomer (Rotstein et al infra). However, because cholesterol level in a human patient is controlled by the rate of metabolism and excretion as well as by the rate of synthesis it is not possible to predict from this whether the 2S,4R enantiomer of ketoconazole will be more effective at lowering cholesterol levels.
The use of ketoconazole as a therapeutic is complicated by the effect of ketoconazole on the P450 enzymes responsible for drug metabolism. Several of these P450 enzymes are inhibited by ketoconazole (Rotsteinet al., supra). This inhibition leads to an alteration in the clearance of ketoconazole itself (Brass et al., “Disposition of ketoconazole, an oral antifungal, in humans.” Antimicrob Agents Chemother 1982; 21(1): 151-8, incorporated herein by reference) and several other important drugs such as Glivec (Dutreix et al., “Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects.” Cancer Chemother Pharmacol 2004; 54(4): 290-4) and methylprednisolone (Glynn et al., “Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion.” Clin Pharmacol Ther 1986; 39(6): 654-9). As a result, the exposure of a patient to ketoconazole increases with repeated dosing, despite no increase in the amount of drug administered to the patient. This exposure and increase in exposure can be measured and demonstrated using the “Area under the Curve” (AUC) or the product of the concentration of the drug found in the plasma and the time period over which the measurements are made. The AUC for ketoconazole following the first exposure is significantly less than the AUC for ketoconazole after repeated exposures. This increase in drug exposure means that it is difficult to provide an accurate and consistent dose of the drug to a patient. Further, the increase in drug exposure increases the likelihood of adverse side effects associated with ketoconazole use.
[0008]
Rotstein et al. (Rotstein et al., supra) have examined the effects of the two ketoconazole cis enantiomers on the principal P450 enzymes responsible for drug metabolism and reported “…almost no selectivity was observed for the ketoconazole isomers” and, referring to drug metabolizing P450 enzymes: “[t]he IC50 values for the cis enantiomers were similar to those previously reported for racemic ketoconazole”. This report indicated that both of the cis enantiomers could contribute significantly to the AUC problem observed with the ketoconazole racemate.
One of the adverse side effects of ketoconazole administration exacerbated by this AUC problem is liver reactions. Asymptomatic liver reactions can be measured by an increase in the level of liver specific enzymes found in the serum and an increase in these enzymes has been noted in ketoconazole treated patients (Sohn, “Evaluation of ketoconazole.” Clin Pharm 1982; 1(3): 217-24, and Janssen and Symoens, “Hepatic reactions during ketoconazole treatment.” Am J Med 1983; 74(1B): 80-5, each of which is incorporated herein by reference). In addition 1:12,000 patients will have more severe liver failure (Smith and Henry, “Ketoconazole: an orally effective antifungal agent. Mechanism of action, pharmacology, clinical efficacy and adverse effects.” Pharmacotherapy 1984; 4(4): 199-204, incorporated herein by reference). As noted above, the amount of ketoconazole that a patient is exposed to increases with repeated dosing even though the amount of drug taken per day does not increase (the “AUC problem”). The AUC correlates with liver damage in rabbits (Ma et al., “Hepatotoxicity and toxicokinetics of ketoconazole in rabbits.” Acta Pharmacol Sin 2003; 24(8): 778-782 incorporated herein by reference) and increased exposure to the drug is believed to increase the frequency of liver damage reported in ketoconazole treated patients.
Additionally, U.S. Patent No. 6,040,307 , incorporated herein by reference, reports that the 2S,4R enantiomer is efficacious in treating fungal infections. This same patent application also reports studies on isolated guinea pig hearts that show that the administration of racemic ketoconazole may be associated with an increased risk of cardiac arrhythmia, but provides no data in support of that assertion. However, as disclosed in that patent, arrhythmia had not been previously reported as a side effect of systemic racemic ketoconazole, although a particular subtype of arrhythmia, torsades de pointes, has been reported when racemic ketoconazole was administered concurrently with terfenadine. Furthermore several published reports (for example, Morganroth et al. (1997). “Lack of effect of azelastine and ketoconazole coadministration on electrocardiographic parameters in healthy volunteers.” J Clin Pharmacol. 37(11): 1065-72) have demonstrated that ketoconazole does not increase the QTc interval. This interval is used as a surrogate marker to determine whether drugs have the potential for inducing arrhythmia. US Patent Number 6,040,307 also makes reference to diminished hepatoxicity associated with the 2S,4R enantiomer but provides no data in support of that assertion. The method provided in US Patent Number 6,040,307 does not allow for the assessment of hepatoxicity as the method uses microsomes isolated from frozen tissue.
DIO-902 is the single enantiomer 2S,4R ketoconazole and is derived from racemic ketoconazole. It is formulated using cellulose, lactose, cornstarch, colloidal silicon dioxide and magnesium stearate as an immediate release 200 mg strength tablet. The chemical name is 2S,4R cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl] methoxyl]phenyl] piperazine, the formula is C26H28Cl2N4O4, and the molecular weight is 531.44. The CAS number is 65277-42-1, and the structural formula is provided below. The chiral centers are at the carbon atoms 2 and 4 as marked.
[0132]
Ketoconazole is an imidazole-containing fungistatic compound. DIO-902 is an immediate release tablet to be taken orally and formulated as shown in the table below.
Component
Percentage
2S,4R ketoconazole;
DIO-902
50%
Silicified Microcrystalline Cellulose, NF
(Prosolv HD 90)
16.5
Lactose Monohydrate, NF (316 Fast-Flo)
22.4
Corn Starch, NF (STA-Rx)
10
Colloidal Silicon Dioxide, NF (Cab-O-Sil M5P)
0.5
Magnesium Stearate, NF
0.6
The drug product may be stored at room temperature and is anticipated to be stable for at least 2 years at 25° C and 50% RH. The drug is packaged in blister packs.
A new process has been developed to separate ketoconazole (KTZ) enantiomers by membrane extraction, with the oppositely preferential recognition of hydrophobic and hydrophilic chiral selectors in organic and aqueous phases, respectively. This system is established by adding hydrophobic l-isopentyl tartrate (l-IPT) in organic strip phase (shell side) and hydrophilic sulfobutylether-β-cyclodextrin (SBE-β-CD) in aqueous feed phase (lumen side), which preferentially recognizes (+)-2R,4S-ketoconazole and (−)-2S,4R-ketoconazole, respectively. The studies performed involve two enantioselective extractions in a biphasic system, where KTZ enantiomers form four complexes with SBE-β-CD in aqueous phase and l-IPT in organic phase, respectively. The membrane is permeable to the KTZ enantiomers but non-permeable to the chiral selector molecules. Fractional chiral extraction theory, mass transfer performance of hollow fiber membrane, enantioselectivity and some experimental conditions are investigated to optimize the separation system. Mathematical model of I/II = 0.893e0.039NTU for racemic KTZ separation by hollow fiber extraction, is established. The optical purity for KTZ enantiomers is up to 90% when 9 hollow fiber membrane modules of 30 cm in length in series are used.
I, (−)-2S,4R-ketoconazole;
II, (+)-2R,4S-ketoconazole;
CDs, cyclodextrin derivatives;
l-IPT, l-isopentyl tartrate;
d-IPT, d-isopentyl tartrate;
HP-β-CD, hydroxypropyl-β-cyclodextrin;
Me-β-CD, methyl-β-cyclodextrin;
β-CD, β-cyclodextrin;
NTU, number of transfer units;
HTU, height of a transfer unit;
PVDF,polyvinylidene fluoride
…………………….
Stereoselective synthesis of both enantiomers of ketoconazole from (R)- and (S)-
Pelayo Camps, Xavier Farrés, Ma Luisa García, Joan Ginesta, Jaume Pascual, David Mauleón, Germano Carganico
Bromobenzoates (2R,4R)- and (2S,4S)-18, prepared stereoselectively from (R)- and (S)-epichlorohydrin, were transformed into (2R,4S)-(+)- and (2S,4R)-(−)-Ketoconazole, respectively, following the known synthetic protocols for the racemic mixture.
Tetrahedron Asymmetry 1995, 6(6): 1283
Stereoselective syntheses of both enantiomers of ketoconazole (1) from commercially available (R)- or (S)-epichlorohydrin has been developed. The key-step of these syntheses involves the selective substitution of the methylene chlorine atom by benzoate on a mixture of and or of their enantiomers, followed by crystallization of the corresponding cis-benzoates, (2S,4R)-18 or(2S,4S)-18, from which (+)- or (−)-1 were obtained as described for (±)-1. The ee’s of (+)- and (−)-ketoconazole were determined by HPLC on the CSP Chiralcel OD-H.
The incidence of fungal infections has considerably increased over the last decades. Notwithstanding the utility of the antifungal compounds commercialized in the last 15 years, the investigation in this field is however very extensive. During this time, compounds belonging to the azole class have beer, commercialized for both the topical and oral administrations, such a class including imidazoles as well as 1,2,4-triazoles. Some of these compounds car. show m some degree a low gastrointestinal tolerance as well as hepatotoxycity.
A large number of pharmaceutically active compounds are commercialized as stereoisomeric mixtures. On the other hand, the case in which only one of said stereoisomers is pharmaceutically active is frequent.
The undesired enantiomer has a lower activity and it sometimes may cause undesired side-effects.
Ketoconazole (1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine), terconazole (1-[4-[[2(2,4-dichlorophenyl)-2-[(1H-1 , 2 ,4-triazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]-4-(1-methylethyl)piperazine) and other related azole antifungal drugs contain in their structure a substituted 1,3-dioxolane ring, in which carbon atoms C2 and C4 are stereogenic centres, therefore four possible stereoisomers are possible. These compounds are commercialized in the form or cis racemates which show a higher antifungal activity than the corresponding trans racemates.
The cis homochiral compounds of the present invention, which are intermediates for the preparation of enantiomerically pure antifungal drugs, have been prepared previously in the racemic form and transformed into the different azole antifungal drugs in the racemic form [J. Heeres et al., J . Med . Chem . , 22 , 1003 (1979). J . Med . Chem . , 26, 611 (1983), J . Med . Chem . , 27 , 894 (1984) and US 4,144,346, 4,223,036, 4,358,449 and 4,335,125].
Scheme 1 shows the synthesis described for racemic ketoconazole [J. Heeres et al., J . Med . Chem . , 22 , 1003 (1979)]. Scheme 1
)
The synthesis of racemic terconazole [J. Heeres et al., J. Med . Chem . , 26 , 611 11983)] is similar. differing in the introduction of a 1 H- 1 , 2,4-triazol-1-yl substituent in place of 1H-imidazol-1-yl and in the nature of the phenol used in the last step of the synthetic sequence, which phenol is 1-methylethyl-4-(4- hydroxyphenyl)piperazme instead of 1-acetyl-4-(4-nydroxyphenyl)piperazine.
The preparation of racemic itraconazole [J. Heeres et al., J. Med . Chem. , 27 , 894 (1984)] is similar to that of terconazole, differing only in the nature of the phenol used in the last step of the synthetic sequence.
In the class of azoles containing a 1,3-dioxolane ring and a piperazine ring and moreover they are pure enantiomers, only the preparation of (+)- and (-)-ketoconazole has been described [D. M. Rotstein et al., J. Med . Chem . , 35, 2818 (1992)] (Scheme 2) starting from the tosylate of (+)- and (-) 2,2-dimethyl-1,3-dioxolane-4-methanol.
Scheme 2
This synthesis suffers from a series of drawbacks, namely: a) the use of expensive, high molecular weight starting products which are available only on a laboratory scale, and b) the need for several chromatographies during the process in order to obtain products of suitable purity, which maKes said synthesis economically unattractive and difficult to apply industrially.
Recently (N. M. Gray, WO 94/14447 and WO 94/14446) the use of (-)-ketoconazole and (+)-ketoconazole as antifungal drugs causing less side-effects than (±)-ketoconazole has been claimed.
The industrial preparation of enantiomerically pure antifungal drugs with a high antifungal activity and less side-effects is however a problem in therapy. The present invention provides novel homochiral compounds which are intermediates for the industrial preparation of already known, enantiomerically pure antifungal drugs such as ketoconazole enantiomers, or of others which have not yet been reported in literature, which are described first in the present invention, such as (+)-terconazole and (-)-terconazoie, which show the cited antifungal action, allowing to attain the same therapeutical effectiveness using lower dosages than those required for racemic terconazole
Example 14 : (2S,4R)-(-)-1-acetyl-4-[4-[ [2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine, (2S,4R) -(- )-ketoconazole.
This compound is prepared following the process described above for (2R,4S)-(+)-ketoconazole. Starting from HNa (60-65% dispersion in paraffin, 32 mg, 0.80 mmol), 1-acetyl-4-(4-hydroxyphenyl)piperazine (153 mg, 0.69 mol) and (2S,4S)-(-)-IV (Ar = 2,4-dichlorophenyl, Y = CH, R = CH3) (250 mg, 0.61 mmol), upon crystallization from an acetone:ethyl acetate mixture, (2S,4R) -(-)-ketoconazole is obtained [(2S,4R)-V Ar = 2,4-dichlorophenyl, Y = CH, Z = COCH3] (196 mg, 61% yield) as a solid, m.p. 153-155ºC (lit. 155-157ºC); [α]D20 = -10.50 (c = 0.4, CHCl3) (lit. [α]D25 = -10.58. c = 0.4, CHCl3) with e.e. > 99% (determined by HPLC using the chiral stationary phase CHIRALCEL OD-H and ethanol:hexane 1:1 mixtures containing 0.1 % diethylamine as the eluent).
+ KETOCONAZOLE…. UNDESIRED
Example 7: (2 R ,4S)-(+)-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine (22, 4 S)-(+)-ketoconazole.
To a suspension of NaH (dispersed in 60-65% paraffin, 19.2 mg, 0.48 mmol) in anhydrous DMSO (3 ml),
1-acetyl-4-(hydroxyphenyl)piperazine (102 mg, 0.46 mmol) is added and the mixture is stirred for 1 hour at room temperature. Then, a solution of (2R,4R) – (+)-IV (Ar = 2,4-dichlorophenyl, Y = CH, R = CH3) (160 mg, 0.39 mmol) in anhydrous DMSO (5 ml) is added, and the mixture is heated at 80ºC for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with water
(20 ml) and extracted with CH2Cl2 (3 × 25 ml). The combined organic phases are washed with water (3 × 25), dried with Na2SO4 and the solvent is evaporated off under vacuum. The oily residue thus obtained is crystallized from an acetone:ethyl acetate mixture to give (2R,4S)-(+)-ketoconazole ( (2R, 4 S) -V , Ar 2,4-dichlorophenyl, Y = CH , Z = COCH3 ) ( 110 mg , 5 3 % yie ld ) as a white solid, m.p. 155-156°C (lit. 154-156ºC), [α]D20 = + 8.99 (c = 0.4, CHCl3) (lit. [α]D25 = + 8.22, c = 0.4, CHCl3), with e.e. > 99% (determined by HPLC using the chirai stationary phase CHIRALCEL OD-H and ethanol:hexane 1:1 mixtures containing 0.1% of diethylamine, as the eluent; (+)-Ketoconazole retention time 73,28 min. (-)-Ketoconazole, retention time 79.06 min).
Experimental and theoretical analysis of the interaction of (+/-)-cis-ketoconazole with beta-cyclodextrin in the presence of (+)-L-tartaric acid
J Pharm Sci 1999, 88(6): 599
1H NMR spectroscopy was used for determining the optical purity of cis-ketoconazole enantiomers obtained by fractional crystallization. The chiral analysis was carried out using β-cyclodextrin in the presence of (+)-l-tartaric acid. The mechanism of the chiral discrimination process, the stability of the complexes formed, and their structure in aqueous solution were also investigated by 1H and 13C chemical shift analysis, two-dimensional NOE experiments, relaxation time measurements, and mass spectrometry experiments. Theoretical models of the three-component interaction were built up on the basis of the available NMR data, by performing a conformational analysis on the relevant fragments on ketoconazole and docking studies on the components of the complex. The model derived from a folded conformation of ketoconazole turned out to be fully consistent with the molecular assembly found in aqueous solution, as inferred from NOE experiments. An explanation of the different association constants for the complexes of the two enantiomers is also provided on the basis of the interaction energies.
Linnaeus named the genus Aesculus after the Roman name for an edible acorn. Common names for these trees include “buckeye” and “horse chestnut”. Some are also called white chestnut or red chestnut (as in some of the Bach flower remedies). In Britain, they are sometimes called conker trees because of their link with the game of conkers, played with the seeds, also called conkers. Aesculus seeds were traditionally eaten, after leaching, by the Jōmon people of Japan over about four millennia, until 300 AD.[6]
Aesculus species have stout shoots with resinous, often sticky, buds; opposite, palmately divided leaves, often very large—to 65 cm (26 in) across in the Japanese horse chestnut Aesculus turbinata. The seeds of the Aesculus are traditionally used in a game called conkers in Europe. Species are deciduous or evergreen. Flowers are showy, insect- or bird-pollinated, with four or five petals fused into a lobedcorolla tube, arranged in a panicle inflorescence. Flowering starts after 80–110 growing degree days. The fruit matures to a capsule, 2–5 cm (25⁄32–1 31⁄32 in) diameter, usually globose, containing one to three seeds (often erroneously called a nut) per capsule. Capsules containing more than one seed result in flatness on one side of the seeds. The point of attachment of the seed in the capsule (hilum) shows as a large circular whitish scar. The capsule epidermis has “spines” (botanically: prickles) in some species, while other capsules are warty or smooth. At maturity, the capsule splits into three sections to release the seeds.[7][8][9]
The most familiar member of the genus worldwide is the common horse chestnut Aesculus hippocastanum. The yellow buckeye Aesculus flava (syn. A. octandra) is also a valuable ornamental tree with yellow flowers, but is less widely planted. Among the smaller species, the bottlebrush buckeye Aesculus parviflora also makes a very interesting and unusual flowering shrub. Several other members of the genus are used as ornamentals, and several horticultural hybrids have also been developed, most notably the red horse chestnut Aesculus × carnea, a hybrid between A. hippocastanum and A. pavia.
Use in alternative medicine
Aesculus has been listed as one of the 38 substances used to prepare Bach flower remedies,[10] a kind of alternative medicine promoted for its effect on health. However according to Cancer Research UK, “there is no scientific evidence to prove that flower remedies can control, cure or prevent any type of disease, including cancer”.[11]
Jump up^ Ogg, James G.; Gradstein, F. M; Gradstein, Felix M. (2004). A geologic time scale 2004. Cambridge, UK: Cambridge University Press.ISBN0-521-78142-6.
Jump up^ Hardin, JW. 1957. A revision of the American Hippocastanaceae I. Brittonia 9:145-171.
Jump up^ Judd, WS, RW Sanders, MJ Donoghue. 1994. Angiosperm family pairs. Harvard Papers in Botany. 1:1-51.
Jump up^ Harrington, Mark G.; Edwards, Karen J.; Johnson, Sheila A.; Chase, Mark W.; Gadek, Paul A. (Apr–Jun 2005). “Phylogenetic inference in Sapindaceae sensu lato using plastid matK and rbcL DNA sequences”. Systematic Botany30 (2): 366–382. doi:10.1600/0363644054223549. JSTOR25064067.
Jump up^ Harlan, Jack R. (1995). The Living Fields: Our Agricultural Heritage (1. publ. ed.). Cambridge [u.a.]: Cambridge Univ. Press. p. 15. ISBN0-521-40112-7.Harlan cites Akazawa, T & Aikens, CM, Prehistoric Hunter-Gathers in Japan (1986), Univ. Tokyo Press; and cites Aikens, CM & Higachi, T, Prehistory of Japan (1982), NY Academic Press.
Jump up^ Hardin, JW. 1957. A revision of the American Hippocastanaceae I. Brittonia 9:145-171
Jump up^ Hardin, JW. 1957. A revision of the American Hippocastanaceae II. Brittonia 9:173-195
Jump up^ Hardin, JW. 1960. A revision of the American Hippocastanaceae V, Species of the Old World. Brittonia 12:26-38
Forest, F., Drouin, J. N., Charest, R., Brouillet, L., & Bruneau A. (2001). A morphological phylogenetic analysis of Aesculus L. and Billia Peyr. (Sapindaceae). Canad. J. Botany79 (2): 154-169. Abstract.
A. hippocastanum grows to 36 metres (118 ft) tall, with a domed crown of stout branches; on old trees the outer branches often pendulous with curled-up tips. The leaves are opposite and palmately compound, with 5–7 leaflets; each leaflet is 13–30 cm long, making the whole leaf up to 60 cm across, with a 7–20 cm petiole. The leaf scars left on twigs after the leaves have fallen have a distinctive horseshoe shape, complete with seven “nails”. The flowers are usually white with a small red spot; they are produced in spring in erect panicles 10–30 cm tall with about 20–50 flowers on each panicle. Usually only 1–5 fruit develop on each panicle; the shell is a green, spiky capsule containing one (rarely two or three) nut-like seeds called conkers or horse-chestnuts. Each conker is 2–4 cm diameter, glossy nut-brown with a whitish scar at the base.[2]
Etymology
The common name “horse-chestnut” (often unhyphenated) is reported as having originated from the erroneous belief that the tree was a kind of chestnut (though in fact only distantly related), together with the observation that eating the fruit cured horses of chest complaints[3] despite this plant being poisonous to horses.
In Britain and Ireland, the nuts are used for the popular children’s game conkers. During the First World War, there was a campaign to ask for everyone (including children) to collect horse-chestnuts and donate them to the government. The conkers were used as a source of starch for the fermentation via the Clostridium acetobutylicum method devised by Chaim Weizmann to produce acetone. Any starch plant would have done, but they chose to ask for conkers to avoid causing starvation by using food. Weizmann’s process could use any source of starch, but it was never particularly efficient and the factory only produced acetone for three months. The aim was to produce acetone for use as solvent which aided in the production of cordite, which was then used in military armaments.
A selection of fresh conkers from a horse-chestnut
The nuts, especially those that are young and fresh, are slightly poisonous, containing alkaloidsaponins and glucosides. Although not dangerous to touch, they cause sickness when eaten; consumed by horses, they can cause tremors and lack of coordination.[6] Somemammals, notably deer, are able to break down the toxins and eat them safely.[citation needed]
Though the seeds are said to repel spiders there is little evidence to support these claims. The presence of saponin may repel insects but it is not clear whether this is effective on spiders.[7]
Horse-chestnuts have been threatened by the leaf-mining moth Cameraria ohridella, whose larvae feed on horse chestnut leaves. The moth was described from Macedonia where the species was discovered in 1984 but took 18 years to reach Britain.[8]
The flower is the symbol of the city of Kiev, capital of Ukraine.[9] Although the horse-chestnut is sometimes known as the buckeye, this name is generally reserved for the New World members of the Aesculus genus.
Medical uses
The seed extract standardized to around 20 percent aescin (escin) is used for its venotonic effect, vascular protection, anti-inflammatory and free radical scavenging properties.[10][11] Primary indication is chronic venous insufficiency.[11][12] A recent Cochrane Review found the evidence suggests that Horse Chestnut Seed Extract is an efficacious and safe short-term treatment for chronic venous insufficiency.[13]
Aescin reduces fluid leaks to surrounding tissue by reducing both the number and size of membrane pores in the veins.
Safety in medical use
Two preparations are considered; whole horsechestnut extract (whole HCE) and purified β-aescin. Historically, whole HCE has been used both for oral and IV routes (as of year 2001). The rate of adverse effects are low, in a large German study, 0.6%, consisting mainly of gastrointestinal symptoms. Dizziness, headache and itching have been reported. One serious safety issue is rare cases of acute anaphylactic reactions, presumably in a context of whole HCE. Purified β-aescin would be expected to have a better safety profile.
Another is the risk of acute renal failure, “when patients, who had undergone cardiac surgery were given high doses of horse chestnut extract i.v. for postoperative oedema. The phenomenon was dose dependent as no alteration in renal function was recorded with 340 μg kg−1, mild renal function impairment developed with 360 μg kg−1 and acute renal failure with 510 μg kg−1”.[14] This almost certainly took place in a context of whole HCE.
Three clinical trials were since performed to assess the effects of aescin on renal function. A total of 83 subjects were studied; 18 healthy volunteers given 10 or 20 mg iv. for 6 days, 40 in-patients with normal renal function given 10 mg iv. two times per day (except two children given 0.2 mg/kg), 12 patients with cerebral oedema and normal renal function given a massive iv. dose on the day of surgery (49.2 ± 19.3 mg) and 15.4 ± 9.4 mg daily for the following 10 days and 13 patients with impaired renal function due to glomerulonephritis or pyelonephritis, who were given 20–25 mg iv. daily for 6 days. “In all studies renal function was monitored daily resorting to the usual tests of renal function: BUN, serum creatinine, creatinine clearance, urinalysis. In a selected number of cases paraaminohippurate and labelled EDTA clearance were also measured. No signs of development of renal impairment in the patients with normal renal function or of worsening of renal function in the patients with renal impairment were recorded.” It is concluded that aescin has excellent tolerability in a clinical setting.[15]
Raw Horse Chestnut seed, leaf, bark and flower are toxic due to the presence of esculin and should not be ingested. Horse chestnut seed is classified by the FDA as an unsafe herb.[11] The glycoside and saponin constituents are considered toxic.[11]
Aesculus hippocastanum is used in Bach flower remedies. When the buds are used it is referred to as “chestnut bud” and when the flowers are used it is referred to as “white chestnut”.
A famous specimen of the horse-chestnut was the Anne Frank Tree in the centre of Amsterdam, which she mentioned in her diary and which survived until August 2010, when a heavy wind blew it over.[17][18] Eleven young specimens, sprouted from seeds from this tree, were transported to the United States. After a long quarantine in Indianapolis, each tree was shipped off to a new home at a notable museum or institution in the United States, such as the 9/11 Memorial Park, Central H.S. in Little Rock, and two Holocaust Centers. One of them was planted outdoors in March 2013 in front of the Children’s Museum of Indianapolis, where they were originally quarantined. [1]
Bonsai
The horse-chestnut is a favourite subject for bonsai.[19]
Diseases
Bleeding Canker. Half of all horse-chestnuts in Great Britain are now showing symptoms to some degree of this potentially lethal bacterial infection.[20][21]
Guignardia leaf blotch, caused by the fungus Guignardia aesculi
Wood rotting fungi, e.g. such as Armillaria and Ganoderma
The European Medicines Agency relies on the results of clinical trials carried out by pharmaceutical companies to reach its opinions on the authorisation of medicines. Although the authorisation of clinical trials occurs at Member State level, the Agency plays a key role in ensuring that the standards of good clinical practice (GCP) are applied across the European Economic Area in cooperation with the Member States. It also manages a database of clinical trials carried out in the European Union.
Clinical trials are studies that are intended to discover or verify the effects of one or more investigational medicines. The regulation of clinical trials aims to ensure that the rights, safety and well-being of trial subjects are protected and the results of clinical trials are credible.
Regardless of where they are conducted, all clinical trials included in applications for marketing authorisation for human medicines in the European Economic Area (EEA) must have been carried out in accordance with the requirements set out in Annex 1 ofDirective 2001/83/EC. This means that:
clinical trials conducted in the EEA have to comply with European Union (EU) clinical-trial legislation (Directive 2001/20/EC);
In the EEA, approximately 4,000 clinical trials are authorised each year. This equals approximately 8,000 clinical-trial applications, with each trial involving two Member States on average. Approximately 61% of clinical trials are sponsored by the pharmaceutical industry and 39% by non-commercial sponsors, mainly academia.
Role of the Agency
Clinical-trial data is included in clinical-study reports that form a large part of the application dossiers submitted by pharmaceutical companies applying for a marketing authorisation via the Agency.
The Agency’s Committee for Medicinal Products for Human Use (CHMP) is responsible for conducting the assessment of a human medicine for which an EU-wide marketing authorisation is sought. As part of its scientific evaluation work, the CHMP reviews the clinical-trial data included in the application.
Assessments are based on purely scientific criteria and determine whether or not the medicines concerned meet the necessary quality, safety and efficacy requirements in accordance with EU legislation, particularly Directive 2001/83/EC.
Good clinical practice
The Agency plays a central role in ensuring application of good clinical practice (GCP). GCP is the international ethical and scientific quality standard for designing, recording and reporting clinical trials that involve the participation of human subjects.
The Agency works in cooperation with GCP inspectors from medicines regulatory authorities (‘national competent authorities’) in EEA Member States on the harmonisation and coordination of GCP-related activity at an EEA level.
The Agency does not have a role in the approval of clinical-trial applications in the EEA. The approval of clinical-trial applications is the responsibility of the national competent authorities.
EudraCT database and the EU Clinical Trials Register
The Agency is responsible for the development, maintenance and coordination of the EudraCT database. This is a database used by national competent authorities to enter clinical-trial data from clinical trial sponsors and paediatric-investigation-plan (PIP) addressees.
A subset of this data is made available through the European Union Clinical Trials Register, which the Agency manages on behalf of EU Member States and forms part ofEudraPharm, the EU database of medicines.
Users are able to view:
the description of phase-II to phase-IV adult clinical trials where the investigator sites are in the EEA;
the description of any clinical trials in children with investigator sites in the EU and any trials that form part of a PIP including those where the investigator sites are outside the EU.
As of 21 July 2014, it will be mandatory for sponsors to post clinical trial results in the EudraCT database. A subset of the data included in EudraCT is made available to the public in the European Union Clinical Trials Register. The content and level of detail of these summary results is set out in a European Commission guideline and in its technical guidance. A typical set of summary results provides information on the objectives of a given study, explains how it was designed and gives its main results and conclusions.
The Agency is also working towards the proactive publication of data from clinical trials carried out on the medicines that it authorises. For more information, see release of data from clinical trials.
Clinical trials conducted in countries outside the EU
Clinical trials conducted outside the EU but submitted in an application for marketing authorisation in the EU have to follow the principles which are equivalent to the provisions of the Directive 2001/20/EC.
In April 2012, the Agency published the final version of this paper:
This paper aims to strengthen existing processes to provide assurance that clinical trials meet the required ethical and GCP standards, no matter where in the world they have been conducted.
The number of clinical trials and clinical-trial subjects outside Western Europe and North America has been increasing for a number of years. More information is available in this document:
The U.S. Food and Drug Administration today approved Cologuard, the first stool-based colorectal screening test that detects the presence of red blood cells and DNA mutations that may indicate the presence of certain kinds of abnormal growths that may be cancers such as colon cancer or precursors to cancer.
Colorectal cancer primarily affects people age 50 and older, and among cancers that affect both men and women, it is the third most common cancer and the second leading cause of cancer-related death in the United States, according to the Centers for Disease Control and Prevention (CDC). Colorectal cancer screening is effective at reducing illness and death related to colon cancer. The CDC estimates that if everyone age 50 or older had regular screening tests as recommended, at least 60 percent of colorectal cancer deaths could be avoided.
Colorectal cancer occurs in the colon (large intestine) or rectum (the passageway that connects the colon to the anus). Most colorectal cancers start as abnormal raised or flat tissue growths on the wall of the large intestine or rectum (polyps). Some very large polyps are called advanced adenomas and are more likely than smaller polyps to progress to cancer.
Using a stool sample, Cologuard detects hemoglobin, a protein molecule that is a component of blood. Cologuard also detects certain mutations associated with colorectal cancer in the DNA of cells shed by advanced adenomas as stool moves through the large intestine and rectum. Patients with positive test results are advised to undergo a diagnostic colonoscopy.
“This approval offers patients and physicians another option to screen for colorectal cancer,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health at the FDA’s Center for Devices and Radiological Health. “Fecal blood testing is a well-established screening tool and the clinical data showed that the test detected more cancers than a commonly used fecal occult test.”
Today’s approval of the Cologuard does not change current practice guidelines for colorectal cancer screening. Stool DNA testing (also called “fecal DNA testing”) is not currently recommended as a method to screen for colorectal cancer by the United States Preventive Services Task Force (USPSTF). Among other guidelines, the USPSTF recommends adults age 50 to 75, at average risk for colon cancer, be screened using fecal occult blood testing, sigmoidoscopy, or colonoscopy.
The safety and effectiveness of Cologuard was established in a clinical trial that screened 10,023 subjects. The trial compared the performance of Cologuard to the fecal immunochemical test (FIT), a commonly used non-invasive screening test that detects blood in the stool. Cologuard accurately detected cancers and advanced adenomas more often than the FIT test. Cologuard detected 92 percent of colorectal cancers and 42 percent of advanced adenomas in the study population, while the FIT screening test detected 74 percent of cancers and 24 percent of advanced adenomas. Cologuard was less accurate than FIT at correctly identifying subjects negative for colorectal cancer or advanced adenomas. Cologuard correctly gave a negative screening result for 87 percent of the study subjects, while FIT provided accurate negative screening results for 95 percent of the study population.
Today the Centers for Medicare & Medicaid Services (CMS) issued a proposed national coverage determination for Cologuard. Cologuard is the first product reviewed through a joint FDA-CMS pilot program known as parallel review where the agencies concurrently review medical devices to help reduce the time between the FDA’s approval of a device and Medicare coverage. This voluntary pilot program is open to certain premarket approval applications for devices with new technologies and to medical devices that fall within the scope of a Part A or Part B Medicare benefit category and have not been subject to a national coverage determination.
“Parallel review allows the last part of the FDA process to run at the same time as the CMS process, cutting as many as six months from the time from study initiation to coverage,” said Nancy Stade, CDRH’s deputy director for policy. “The pilot program is ongoing, but we will apply what we have learned to improve the efficiency of the medical device approval pathway for devices that address an important public health need.”
“This is the first time in history that FDA has approved a technology and CMS has proposed national coverage on the same day,” said Patrick Conway, chief medical officer and deputy administrator for innovation and quality for CMS. “This parallel review represents unprecedented collaboration between the two agencies and industry and most importantly will provide timely access for Medicare beneficiaries to an innovative screening test to help in the early detection of colorectal cancer.”
CMS proposes to cover the Cologuard test once every three years for Medicare beneficiaries who meet all of the following criteria:
age 50 to 85 years,
asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test or fecal immunochemical test), and
average risk of developing colorectal cancer (no personal history of adenomatous polyps, of colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of colorectal cancers or an adenomatous polyp, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).
Cologuard is manufactured by Exact Sciences in Madison, Wisconsin.
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry & Collaborative Innovation Center of Suzhou Nano Science and Technology, University of Science and Technology of China, Hefei, P. R. China E-mail: zwang3@ustc.edu.cn; Fax: (+86) 551-360-3185
Green Chem., 2014, Advance Article
DOI: 10.1039/C4GC00932K
A catalyst-free sulfonylation of activated alkenes developed under mild conditions in water.
A catalyst-free sulfonylation reaction of activated alkenes with sulfonyl hydrazides was efficiently developed under mild and environmentally benign conditions, in water without any ligand or additive. The reaction gave a range of structurally diverse mono-substituted ethyl sulfones with excellent yields, in which the by-product was nitrogen.
Microsponges are polymeric delivery systems composed of porous microspheres. They are tiny sponge-like spherical particles with a large porous surface. Moreover, they may enhance stability, reduce side effects and modify drug release favorably. Microsponge technology has many favorable characteristics, which make it a versatile drug delivery vehicle. Microsponge Systems are based on microscopic, polymer-based microspheres that can suspend or entrap a wide variety of substances, and can then be incorporated into a formulated product such as a gel, cream, liquid or powder. The outer surface is typically porous, allowing a sustained flow of substances out of the sphere. Microsponges are porous, polymeric microspheres that are used mostly for topical use and have recently been used for oral administration. Microsponges are designed to deliver a pharmaceutical active ingredient efficiently at the minimum dose and also to enhance stability, reduce side effects, and modify drug release.
Kaity S, Maiti S, Ghosh AK, Pal D, Ghosh A, Banerjee S. Microsponges: A novel strategy for drug delivery system. J Adv Pharm Technol Res 2010;1:283-90
Kaity S, Maiti S, Ghosh AK, Pal D, Ghosh A, Banerjee S. Microsponges: A novel strategy for drug delivery system. J Adv Pharm Technol Res [serial online] 2010 [cited 2014 Aug 10];1:283-90. Available from: http://www.japtr.org/text.asp?2010/1/3/283/72416
cas 57014-02-5
and 
or of their enantiomers, followed by crystallization of the corresponding cis-benzoates, (2S,4R)-18 or(2S,4S)-18, from which (+)- or (−)-1 were obtained as described for (±)-1. The ee’s of (+)- and (−)-ketoconazole were determined by HPLC on the CSP Chiralcel OD-H.
