The S-oxidative degradation of a novel corticosteroid tipredane (INN) Part III. Detailed investigations into the disulphoxidation of tipredane

The methyl- and ethylsulphoxide diastereoisomers (V and VI) of the corticosteroid tipredane (INN I) have been shown to undergo further stereoselective S-oxidation to yield diastereoisomeric disulphoxides (II).Interactive computer optimisation software was employed to develop semi-preparative chromatography conditions for the isolation of the disulphoxide diastereoisomers (II) and to develop a multiselective gradient HPLC analysis of tipredane (I), the four monosulphoxide diastereoisomeric pairs (V, VI, IX and X), the four disulphoxide diastereoisomers (II), the vinyl methyl and ethyl derivatives (XI and XII) and the methylsulphone of tipredane (VII). The four diastereoisomeric disulphoxides (II) have been isolated by semi-preparative HPLC and their structures unambiguously confirmed by high resolution multinuclear NMR and mass spectrometry. The stereochemical assignment of the four disulphoxide diastereoisomers (II), the ethylsulphoxide diastereoisomeric pair (VI), and the vinyl methyl and ethylsulphoxide diastereoisomeric paris (IX and X) was determined by degradation/synthesis and relation to the S/R-disulphoxide (II) whose stereochemistry was determined by X-ray crystallography. The monosulphoxides (V and VI) showed a high degree of site and stereoselectivity towards further S-oxidation. S-Oxidation on the C-17 β-substituent of tipredane occurred at a rate approximately 50-fold faster than that on the α-substituent.The disulphoxides (II) have been shown to be susceptible to thermolysis yielding the vinyl methylsulphoxide diastereoisomers (IX) preferentially. The loss of the ethylsulphenic acid from the disulphoxide diastereoisomers (II) could be rationalised in terms of the preferred rotamers of the C-17 substituents.     

Oxidation and degradation products of papaverine. Part II[1]: investigations on the photochemical degradation of papaverine solutions

The structure of the final degradation product formed in papaverine solutions in either water or chloroform was found to be a 2, 3, 9, 10-tetramethoxy-12-oxo-12H-indolo [2, 1-a] isoquinolinylium salt (a dibenzo [b, g] pyrrocolonium derivative). Its formation from papaverine oxidation products that is papaverinol, papaveraldine, and papaverine-N-oxide chloroform solutions under the influence of UV light, was investigated and possible reaction pathways are discussed.     

Next generation pharmaceutical impactor (a new impactor for pharmaceutical inhaler testing). Part I: Design.

A new cascade impactor has been designed specifically for pharmaceutical inhaler testing. This impactor, called the Next Generation Pharmaceutical Impactor (NGI), has seven stages and is intended to operate at any inlet flow rate between 30 and 100 L/min. It spans a cut size (D50) range from 0.54-microm to 11.7-microm aerodynamic diameter at 30 L/min and 0.24 microm to 6.12 microm at 100 L/min. The aerodynamics of the impactor follow established scientific principles, giving confident particle size fractionation behavior over the design flow range. The NGI has several features to enhance its utility for inhaler testing. One such feature is that particles are deposited on collection cups that are held in a tray. This tray is removed from the impactor as a single unit, facilitating quick sample turn-around times if multiple trays are used. For accomplishing drug recovery, the user can add up to approximately 40 mL of an appropriate solvent directly to the cups. Another unique feature is a micro-orifice collector (MOC) that captures in a collection cup extremely small particles normally collected on the final filter in other impactors. The particles captured in the MOC cup can be analyzed in the same manner as the particles collected in the other impactor stage cups. The user-friendly features and the aerodynamic design principles together provide an impactor well suited to the needs of the inhaler testing community.     

Preliminary toxicological investigations of 3-hydroxy-3-methylglutaric acid (HMG). I: Study of acute toxicity and of teratogenic activity in rats and mice.

The acute toxicity of 3-hydroxy-3-methylglutaric acid (HMG) was studied in mice. The LD50 was shown to be 7.33 g/kg p.o. and 3.23 g/kg i.p. Subtoxic and pharmacological doses applied to mice and rats during gestation did not induce malformation of the foetuses and offspring and did not affect the reproductive performances of the dams. This compound is being investigated for its hypolipidemic activity.     

Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part I).

Anxiolytic and hypnotic drugs are extensively prescribed for elderly individuals throughout Western society. Old age may be associated with an altered clinical response to this class of compounds, and there is a considerable ethical and economic stake in understanding these changes so that therapy may be approached with a maximum likelihood of therapeutic benefit and a minimum risk of side effects. Old age may lead to altered pharmacokinetics of sedative-anxiolytic drugs, causing higher plasma concentrations (relative to young individuals) after single or multiple doses. By far the majority of the available scientific data refer to the benzodiazepines, which have become the most widely prescribed class of sedative-anxiolytic drugs. Although there is not complete consistency in the available data, the weight of evidence indicates that old age is associated with impaired clearance of the benzodiazepines which are biotransformed by microsomal oxidation (such as diazepam, desmethyldiazepam, desalkylflurazepam, bromazepam, alprazolam, triazolam and others). For those benzodiazepines metabolised mainly by glucuronide conjugation (oxazepam, lorazepam, temazepam) or nitroreduction (nitrazepam), there are minimal, if any, age-related decrements in clearance. Only in the case of triazolam is there direct evidence linking impaired clearance to enhanced clinical effects in the elderly. The logical suggestion that benzodiazepines biotransformed by conjugation or by nitroreduction may be safer for the elderly than those biotransformed by oxidation has not yet been directly validated. Reasonable epidemiological evidence has linked the use of long (versus short) half-life benzodiazepines (regardless of the specific metabolic pathway) with an increased incidence of adverse reactions such as confusion, falls and hip fractures in elderly persons. However, the decreased clearance and increased accumulation of the benzodiazepines in question are not clearly validated as the cause of the increased frequency of adverse reactions. Old age may also be associated with an increased intrinsic sensitivity to benzodiazepines; that is, enhanced pharmacodynamic response, relative to young individuals, at any given plasma or target organ concentration. This change in sensitivity may coexist with, or be independent of, alterations in pharmacokinetics. Altered benzodiazepine sensitivity has been documented both in the course of clinical use of benzodiazepines prior to endoscopy or cardioversion, and in placebo-controlled laboratory trials. Animal models of aging have validated an enhanced response to benzodiazepines as a consequence of impaired clearance, increased intrinsic sensitivity or both. However, many studies directly assessing benzodiazepine receptor affinity, density and function in aging animals have failed to identify significant age-related changes.(ABSTRACT TRUNCATED AT 400 WORDS)     

The Metabolism of Tamoxifen (I.C.I. 46,474) Part I : In Laboratory Animals

Abstract

1. The metabolism and excretion of a non-steroidal oestrogen antagonist, tamoxifen (I.C.I. 46,474) [trans-1-(p-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene], has been studied in rat, mouse, rhesus monkey and dog using the ¹⁴C-labelled compound.

2. In all species the compound was well absorbed and extensively metabolized after oral administration. The ¹⁴C was slowly eliminated, largely in the faeces. No loss of ¹⁴C as carbon dioxide could be detected in expired air from small animals.

3. In most of the species levels in the blood were low and showed two maxima following oral dosing. Enterohepatic circulation was demonstrated in rat and dog.

4. Metabolic patterns were qualitatively similar in all the species examined. Metabolites were isolated from faecal extracts and bile. Most of the ¹⁴C-labelled material was present as glucuronides and other conjugates. Hydroxylation was a significant metabolic pathway in all species.

5. A novel metabolite formed by deamination of the side chain, hydroxylation of an aromatic ring and oxidation of the ethyl group was present in rat bile.     

Recent progress on curcumin-based therapeutics: a patent review (2012-2016). Part I: Curcumin

Introduction: curcumin is the main bioactive component contained in Curcuma Longa, largely employed in traditional medicine. Recently, beneficial properties, useful for prevention and treatment of several disorders, have been discovered for this compound. Peculiar structural feature is an α,β-unsaturated carbonyl system essential for establishing contacts with critical cysteine residues of several targets. This distinctive mechanism of action imparts to the molecule the ability to affect a large number of targets, accounting for its pleiotropic behaviour and definition of “privileged structure”.

Areas covered: The objective of the review is an examination of the recent developments in the field of the anti-cancer applications of curcumin, together with formulation issues, considering the patent literature in the years 2012-2016.

Expert opinion: The wide therapeutic efficacy of curcumin is related to synergistic interactions with several biological targets, along with the modulation of several signaling pathways. This peculiar behaviour could be useful in the treatment of multifactorial diseases such as cancer. Combination of curcumin with a first line antineoplastic drug proved to be a valuable strategy to obtain an amplified response with minimized side effects. Innovative curcumin formulations based on the nanotechnology approach allowed improving both bioavailability and therapeutic efficacy.     

The Metabolism of Tamoxifen (I.C.I. 46,474) Part II: In Female Patients

Abstract

1. The metabolism of orally administered [¹⁴C]tamoxifen was investigated in four women. Most of the ¹⁴C was slowly excreted in the faeces, only small amounts appearing in the urine.

2. The labelled material in the faeces was present mainly as conjugates. Unchanged drug and hydroxylated metabolites accounted for less than 30% of the faecal radioactivity.

3. Blood levels of total radioactivity following oral doses of about 0·3 mg/kg reached peak values of 0·06–0·14 μg/ml 4–7 h after dosing. At this time only 20–30% of the radioactive material was present as tamoxifen.

4. The prolongation of blood levels and faecal excretion is thought to be due to enterohepatic circulation.     

Incorporation into endogenous metabolic pathways of small fragments derived from I.C.I, 58,834(vioxazine).

1. Metabolic degradation of the tetrahydro-oxazine ring of 2-(2-ethoxyphenoxymethyl)-2,3,5,6-tetrahydro-1,4-oxazine (I.C.I. 58,834) gives rise to one- or two-carbon fragments which are utilized by endogenous metabolic pathways. 2. Evidence of this in dogs is shown by the 14C-labelled residues in tissues, 14C-labelled material in blood which has a half-life of three weeks, and elimination of [14C]urea in urine. 3. The same phenomenon occurs in rat, mouse and man, but to a smaller extent than in the dog. 4. Intravenous administration of [14C]ethanolamine to a dog gave rise to residual 14C blood levels with a half-life comparable to that produced by metabolic incorporation of 14C from 14C-I.C.I. 58,834.     

Some aspects in the pharmacology of diclonium bromide (2-(3,2-dichloroanilino)quinolizinium bromide). Part I: Antispasmodic action.

Diclonium bromide (EU-2972; 2-(3,4-dichloroanilino)quinolizinium bromide) was demonstrated to possess an effective, prolonged inhibitory action on contractions in response to stimuli or propulsive movements in the lower bowel of the dog. The compound's antagonism to contractile activity was greater in the distal colon than in the duodenum or upper bowel. Diclonium bromide was a nonselective antispasmodic but, unlike papaverine, caused profound antagonism against smooth muscle contractile responses to intrinsic motor neural excitation. The drug had weak specific anticholinergic action, but its lack of antagonistic effect on other cholinergic responses in this study indicates that the anticholinergic action contributes very little, if at all, to its overall antispasmodic effect. The compound has potential application in the treatment of spastic-colon disease.     

The bioavailability of Tamoplex (tamoxifen). Part 1. A pilot study

Tamoxifen and N-desmethyltamoxifen plasma concentrations were found to be similar after a first single dose and during two months therapy with Tamoplex or Nolvadex in groups of 6 and 8 patients, respectively. Single dose absorption results in 10 healthy male volunteers demonstrated bioequivalence of Tamoplex and Nolvadex 10 mg tablets. A large interindividual variation in tamoxifen absorption data was observed, probably related to the dominating metabolic clearance of tamoxifen.     

Oxidation and degradation products of papaverine. Part I: Gadamer and Schulemann's papaverinol synthesis revisited

In 1915 Gadamer published in this journal [1] a procedure for the synthesis of papaverinol 2 from papaverine 1 in excellent yield. However, he did not investigate the formation of a violet fluorescence produced upon crystallization of papaverinol 2 from ethanol. The compound responsible for this fluorescence was isolated and identified as the yet unknown quaternary ammonium ion 4, a 6a, 12a-diazadibenzo-[a, g]fluorenylium derivative. The isolation of 4 and its structure determination by spectroscopic methods are described. However, its formation mechanism is unknown.     

The investigations into the interferon-like activity of Polygonum L. genus

The interferon inducing abilities of eleven ethanolic extracts obtained from nine taxons of Polygonum L. genus, were tested in the cell culture of monkey kidney. The extracts from the herb of Polygonum amphibium L. and the rhizome and fruit of Polygonum bistorta L. induced a substance showing an interferon-like activity. Biological activity studies showed that the protective titre (the highest dilution which protected cells by 50% against virus infection) of the interferon-like materials was 1:10-1:15.     

Practitioners' assessment of the externship experience: a retrospective analysis. Part I.

This study examines the externship experience of participants in the first four years of Illinois' mandatory externship program. A questionnaire was developed and mailed to a sample of 300 pharmacists resulting in a 60 percent response rate. Analysis of the data suggest a generally positive attitude toward externship and this was especially true for more recent graduates. It was also found that preceptors were perceived as positive role models, that externship had only slightly positive impact on preparing the respondents for practice and their perceived development of self confidence, and had virtually no influence on their ultimate choice of practice environment. These findings hold important implications for future refinements of externship programs.