Synthesis and Antimicrobial Activity of a Dihydroampicillin and a Dihydrocephalexin

A dihydroampicillin ( 3 ) and a dihydrocephalexin ( 4 ) have been synthesized by condensing α-(cyclohexa-1,3-dienyl)glycyl chloride with 6-aminopenicillanic acid ( 1 ) and 7-deacetoxycephalo-sporanic acid ( 2 ) respectively. The two antibiotics obtained show enhanced antimicrobial activity towards certain bacterial strains compared with ampicillin and cephalexin.     

Absorption and disposition of a tripeptoid and a tetrapeptide in the rat

The present study is concerned with the absorption and disposition of a tripeptoid (N-substituted glycine derivative) and a tetrapeptide in the rat. The two compounds have similar backbone structures but differ with respect to the presence or absence of peptide bond. [3H]tripeptoid and [3H]tetrapeptide were administered orally (30 mg kg(-1)) and intravenously (i.v.) (30 or 3 mg kg(-1)) to Sprague Dawley rats. Blood, urine and feces were collected at designated times for radioactivity and parent drug analysis. The intestinal absorptive clearances of the tripeptoid and tetrapeptide were studied using an in situ rat intestinal perfusion model. The octanol/water partition coefficient of these two compounds was also determined. The results showed that the peptoid and peptide have similar absorptive clearance and octanol/water partitioning, but different in vivo absorption and disposition characteristics. The absorptive clearances of the tripeptoid and tetrapeptide were 6.7 and 4.8 x 10(-4) mL min(-1) cm(-1), respectively, and the corresponding octanol/water partition coefficients were 0.39 and 0.30. The extent of oral absorption of the tripeptoid was only 3-8%, consistent with its low absorptive clearance. In contrast, the apparent absorption of the tetrapeptide was > 75% of the radioactive dose. The peptide was completely metabolized within 2 h after an i.v. dose, whereas the peptoid was stable in blood and was primarily eliminated in feces as intact drug. In conclusion, the difference in in vivo absorption and disposition between the peptoid and peptide was apparently due to the presence or absence of a peptide bond. The tetrapeptide was subject to rapid metabolism in the body. Its relatively high absorption appeared to represent the absorption of metabolized radioactive fragments. The peptoid appears to have advantages over the peptide in term of metabolic stability, but its low oral absorption and rapid biliary excretion present additional challenges in the selection of an optimal drug candidate.     

Synthesis of a psilocin hapten and a protein-hapten conjugate

Derivatives of psilocin with omega-functionalized alkyl spacers in position 1 of the indole ring were synthesized as haptens for use in a radioimmunoassay. Whereas the psilocin analogues with a 3-aminopropyl and a 4-aminobutyl moiety at the indole nitrogen decomposed during synthesis, the analogous 3-carboxypropyl psilocin derivative proved to be stable. This compound was coupled to bovine serum albumin (BSA) using the N-hydroxysuccinimide ester-mediated conjugation. The protein-hapten conjugate was characterized by matrix-assisted laser desorption ionization mass spectrometry. The mass spectrometry data indicated an average incorporation ratio of 4-5 molecules of psilocin hapten per molecule of BSA.     

Podophyllum toxicity: a report of a fatal case and a review of the literature

A 59-yr-old male ingested 10 g of podophyllum in a fatal suicide attempt. Previously unreported nuclear and cytoplasmic changes were observed in circulating leukocytes. Symptoms did not occur until 10 h after ingestion with loss of reflexes, coma, and a marked lactic acidosis. Despite hemoperfusion, the patient expired 39 h after ingestion. The literature on podophyllum toxicity is reviewed.     

Actions of a mixture of amphetamine and a barbiturate in man

The effects in man of a mixture of amphetamine and a barbiturate (15 mg of amphetamine sulphate and 300 mg of cyclobarbitone) and of each of the constituents separately were assessed on the performance of simple mental and motor tasks, on the pulse rate and on subjective reports. The mixture produced a pattern of effects which was different from that produced by either drug separately. It impaired the efficiency of the performance of tasks much less than did the barbiturate drug alone; it produced almost as big a rise in the pulse rate as did amphetamine alone; and it produced reports of feeling “elated” from many more subjects than did either drug separately, though there was no corresponding increase in reports of other feelings and sensations.     

Synthesis and evaluation of novel prodrugs of foscarnet and dideoxycytidine with a universal carrier compound comprising a chemiluminescent and a photochromic conjugate

To facilitate intracellular delivery of hydrophilic drugs, a general lipophilic carrier molecule was designed and synthesized. The carrier comprised a chemiluminescent-photochromic conjugate that potentiates diffusion across cell membranes to enhance intracellular uptake of the drug. The designed mechanism involves activation of the chemiluminescent moiety by intracellular oxygen free radicals and intermolecular energy transfer of the excited state energy to the photochromic moiety to result in release of the drug to allow the desired pharmacological effect to occur. Prodrugs of foscarnet and dideoxycytidine with several carriers caused suppression of a human immunodeficiency virus infection in human cultured macrophages that was up to five times more effective than the drug alone. Successful in vivo efficacy testing of prodrug has been accomplished by demonstrating the suppression of a retroviral infection of Friend leukemia virus in mice. Acute toxicity studies of the carrier indicated that it was nontoxic.     

Amelioration of sulfur mustard skin injury following a topical treatment with a mixture of a steroid and a NSAID

The ability to ameliorate sulfur mustard (HD)-induced oedema by treatment with anti-inflammatory drugs was reported previously after screening four steroids and four non-steroidal anti-inflammatory drugs (NSAIDs) using the mouse ear vesicant model. Following the screening study, one steroid and one NSAID (Adexone and Voltaren) were selected as the most effective, and a mixture of the two was chosen for the present more extensive research. The effect of the combined treatment on clinical, biochemical and histopathological parameters following HD insult was studied. Mice ears were exposed to 0.2 micro l of HD for 10 min to produce a moderate skin injury. Oedema development peaked ca. 48 h following exposure, as determined by weighing ear biopsies. Histological observations at that time exhibited damage to the epidermis and dermis. An increase in prostaglandin E (PGE) was measured in skin homogenates, starting 8 h following exposure and lasting at least up to 48 h post-exposure. A topical treatment using the above anti-inflammatory mixture significantly reduced inflammatory parameters when applied up to 4 h following exposure. These parameters included extent of oedema, levels of PGE, area of clinical damage and extent of cytotoxic injury (vesications and damaged epithelial cells). Thus, a combination of a steroid and NSAID was found to be effective in reducing the intensity of HD skin injury and possibly shortening the time to full recovery. The treatment, however, did not prevent completely the ensuing cytotoxic processes in the epithelial layer.     

Treatment of dyslipidaemia with a simple low fat diet and with a combination of a low fat diet and a formulation containing soybean protein

The first approach to treatment of dyslipidaemia is with diet. Currently, modified soybean protein is often included in the diet. A study was made of 32 patients with types IIa and IIb dyslipidaemia to see what changes in blood lipids could be induced by a simple low fat diet and a diet with modified soybean protein substituted for part of the animal protein. After six weeks on the initial low fat diet, all of the patients had lower total cholesterol and triglyceride levels, but there were no significant changes in the high density lipoprotein-cholesterol levels. The same diet was continued for eight weeks by 19 of the patients, who continued to improve. The 13 patients who had shown the least response to the initial simple low protein diet were given a diet in which the animal protein was partially replaced with modified soybean protein. This diet further decreased the total cholesterol.     

Comparative efficacy and bioequivalence of a brand-name and a generic triamterene-hydrochlorothiazide combination product

The clinical efficacy, safety, and bioavailability of a generic triamterene-hydrochlorothiazide product were compared with those of Dyazide. Thirty patients who had a diagnosis of nonlabile essential hypertension and who were receiving Dyazide (triamterene 50 mg and hydrochlorothiazide 25 mg) were continued on Dyazide maintenance for 16 days to determine the stability of blood pressure control and serum chemistry values. After this baseline period, the subjects were randomized to receive either Dyazide or a generic version for 21 days. They were then crossed over to receive the opposite product for another 21 days. Blood pressures were monitored throughout the study period, and blood samples were taken for measurement of serum electrolytes and of serum triamterene and its major metabolite, hydroxytriamterene sulfate. Hydrochlorothiazide was assayed in 24-hour urine samples. There were no statistically significant differences between regimens in recumbent and standing mean diastolic blood pressures or in mean concentrations of serum potassium, chloride, glucose, creatinine, and uric acid. Area under the concentration-time curve from 0 to 24 hours after drug administration, maximum concentration in serum, and time to achieve maximum concentration in serum did not differ significantly between regimens for triamterene and hydroxytriamterene sulfate. Similarly, there were no significant differences in excretion, maximum rate of excretion, and time to achieve maximum rate of excretion for urinary hydrochlorothiazide. Patients treated with a brand-name fixed-combination product containing triamterene 50 mg and hydrochlorothiazide 25 mg were given a generic formulation without loss of therapeutic efficacy or development of toxicity.     

Synthesis and cytogenetic effects of aminoquinone derivatives with a di- and a tripeptide

Quinones are of significant interest due to their important role in specific cellular functions. Quinoproteins are a big class of oxyreductive agents occurring in bacteria and other organisms. In this investigation derivatives of 2-amino-1,4-benzoquinone, 2-amino-1,4-naphthoquinone and 2-amino-5,8-dihydroxy-1,4-naphthoquinone with a di- and a tripeptide were prepared for first time. The effect of the synthesized compounds on sister chomatid exchange (SCE) rates and human lymphocyte proliferation kinetics on a molar basis was studied. Among these coupled products the most effective in inducing SCEs and depressing proliferation rate indices is the coupling product of 2-amino-1,4-naphthoquinone with the tripeptide GHK (10). Next in order of magnitude in inducing cytogenetic effects is 2-amino-1,4-naphthoquinone (2) and its coupling products with glycine and serine (4 and 5), while the rest displayed marginal activity.     

Rapid determination and NMR assignments of antiparallel sheets and helices of a scorpion and a cobra toxin

An NMR method is described which should provide a rapid means for determining and assigning antiparallel sheets and helices in small proteins. It begins by locating apparent NOESY crosspeaks which suggest the presence of the secondary structure; this is followed by searches for MCD patterns (Englander & Wand (1987) Biochemistry 22, 5953) which are characteristic of these structures. As a result, only spin-systems of the amino acids within the secondary structure need to be defined. A triple-stranded, antiparallel sheet and a helix have been found and assigned for both α-cobratoxin and the scorpion toxin AaH III.     

Nomenclature and classification of drug- and alcohol-related problems' a shortened version of a who memorandum

Earlier work in this field is reviewed and present concepts and terminologies are examined in detail. A revised way of dealing with ideas implicit in the terms 'drug abuse' or 'drug misuse' is proposed; the term 'neurodaptive state' is suggested as an alternative to 'physical dependence; a profile is given of the elements that constitute a 'drug dependence syndrome'; and the need to differentiate conceptually between 'dependence' and 'drug related disability' is stressed. A model of dependence is outlined in which dependence is considered as a psycho-physiological-social syndrome determined and kept going by a complex system of reinforcements. The bearing of the foregoing considerations on work towards the revision of relevant classification systems is considered, and, in the final section, several recommendations on nomenclature are brought together and suggestions are made for research that might lead to refinement of classification and diagnostic systems.     

Synthesis and in Vitro Study of a Diglyceride Prodrug of a Peptide

A diglyceride derivative of a pentapeptide renin inhibitor, the 1,3-dipalmitoyl-[Iva-Phe-Nle-Sta-Ala-Sta-acetyl]-glycerol was synthesized and tested in vitro as a potential prodrug for oral administration. The ability of the diglyceride analog to inhibit the renin activity was equivalent to that of the parent peptide after predigestion with pancreatic lipase. Furthermore, the presence of the palmitoyl groups was found to induce, in vitro, an efficient protection of the peptide from gastric and intestinal hydrolysis. During incubation with intestinal and gastric fluids, and with -chymotrypsin and pancreatic lipase, the glycerolipidic derivative was more stable than the peptide alone. These results support the use of glycerolipidic prodrug for oral administration of peptides.     

Enantioselective capillary electrophoretic separation of tryptophane- and tyrosine-methylesters in a dual system with a tetra-oxadiaza-crown-ether derivative and a cyclodextrin

Different dual selector systems containing a cyclodextrin derivative (methyl-beta-cyclodextrin and dimethyl-beta-cyclodextrin) and a new diaza-crown-ether derivative (N-[2-(1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)propanoyl]glycine) were studied in the enantioselective separation of tryptophan-methylester and tyrosine-methylester enantiomers. This paper deals with the systematic study of the effects of changing the composition of the background electrolyte on the resolution of the d- and l- forms using an experimental design approach. It was found that the dual systems allowed a better chiral separation of the amino acid derivatives. The experimental design approach also allowed improving the separation compared to the starting conditions (center point of the design), which were adopted from a previous study.     

Isolation and synthesis of a new chromenochalcone and a new chromene from Orthosiphon glabratus

Chemical investigation on Orthosiphon glabratus afforded 10 compounds, among which a chromenochalcone and a chromene are new. The structures of the new constituents were settled from their 1D- and 2D-NMR spectra. The synthesis of these two compounds and some of their analogues have been accomplished.