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Biomedical subjects

G W James

Publications and source records attributed to G W James.

17 recordsLinked to original sources
PubMed1979

A comparative study of a BCNU containing 4-drug program versus MOPP versus 3-drug combinations in advanced Hodgkin's disease: a cooperative study by the Cancer and Leukemia Group B.

A prospective randomized trial by CALGB examined the relative value of four chemotherapy regimens in 537 patients with stage III B and IV Hodgkin's disease. A new combination BOPP, derived by substitution of BCNU for nitrogen mustard in the MOPP regimen, was compared to MOPP and to two 3-drug regimens, derived by removing the procarbazine in BOPP (BOP) or removing the alkylating agent (OPP). The 4-drug programs gave significantly higher frequency of complete remissions (BOPP 67%, MOPP 63%) than the 3-drug regimens (BOP 40%, OPP 42%), and significantly longer duration of remission and survival. BOPP had a therapeutic activity equal to MOPP, and was accompanied by less toxicity. After 6 cycles of induction chemotherapy, responding patients, both CR and PR, were continued on maintenance chemotherapy for 3 years. No significant difference in relapse rate was demonstrated following maintenance treatment with either vinblastine, chlorambucil, or chlorambucil plus monthly vincristine + prednisone doses. Nor could a reinforcement phase late in the maintenance program be shown to influence the relapse rate. The median survival for all patients entered on the 4-drug programs was 5 years, while the median has not yet been reached at 6 years for those patients, who obtained CR.

Adult↗
PubMed1979

Studies on the absorption, distribution and elimination of 6-o-chlorophenyl-2,4-dihydro-2(N-methyl-piperazin-1-yl)-methylene-8-nitro-1H-imidazo[1,2-a] [1,4]benzodiazepin-1-one methanesulphonate in the male rat and rabbit.

The fate of a novel imidazo-benzodiazepine (I) was studied in male rats and rabbits using 14C and 3H-labelled I. In both species the compound was rapidly and widely absorbed after an oral dose of 5 mg/kg to give peak tissue and plasma levels after 1 hour in the rat and 4 hours in the rabbit. The highest concentrations of radioactivity were present in the liver (rat) and liver, kidney and subcutaneous fat (rabbit). Plasma levels of radioactivity fell to 3% of the maximum value in 24 hours in the rat but 48 hours were required for a similar fall in the rabbit. The main route of elimination of radioactivity was via the bile followed by excretion in the faeces. For the rat the rate of biliary elimination was 16.6% of the administered dose/hour; for the rabbit this rate was 5.6%/hour. Recovery of administered radioactivity during 0-24 hours for urine and faeces respectively was 4.8% and 69% for the rat and 23.2% and 10.9% for the rabbit. Up to 97% of the radioactivity administered to rats could be recovered in the excreta in the 7 days following dosing. Up to 90% of the dose administered to rabbits appeared in the excreta during 10 days. No unchanged (I) could be detected in the urine or bile. The radioactive metabolites were polar products, some of which were in the form of glucuronide conjugates.

Animals↗
PubMed1979

The general pharmacology of a novel antitussive compound RU 20201.

1,2,3,4,4a,9b-Hexahydro-8,9b-dimethyl-4[3-(4-methyl piperazin-1-yl)propionamido] dibenzofuran-3-one dihydrochloride (RU 20201) is an antitussive compound with a potency comparable to that of codeine. Unlike codeine, RU 20201 is devoid of any apparent CNS effects and does not depress the respiratory system. It has no adverse effect on the gastrointestinal tract no has it any analgesic or anti-inflammatory properties. Only at very high doses was a local anaesthetic effect observed.

Analgesics↗
PubMed1979

The pharmacological profile of a potential hypnotic compound RU 31158.

RU 31158, 6-(orthochlorophenyl)-1, 2-dihydro-2 (N-methylpiperazine-1-yl) methylene-8-nitro-IH, 4H-imidazo [1,2-a] [1,4] benzodiazepin-1-one methanesulphonate, demonstrated potent hypnotic activity compared to diazepam when examined in the mouse and rat. RU 31158 potentiated minimal hypnosis in mice induced by both hexobarbital and chlorprothixene with ED50 values of 2.15 (1.53-3.01) and 0.69 (0.46-1.02) mg/kg p.o. respectively; these compared to values for diazepam of 17.00 (11.25-25.67) and 3.60 (2.25-5.76) mg/kg p.o. RU 31158 also potentiated hexobarbital in the rat with an ED50 value of 1.2 (0.7-2.0) mg/kg p.o. as compared to 32.0 (27.5-38.5) mg/kg p.o. for diazepam. Sleep studies in the rat confirmed the hypnotic properties of RU 31158, and also showed that the duration of action at 8.0 and 16.0 mg/kg p.o. was not longer than 9 hours. RU 31158 also showed potent minor tranquilizer, anxiolytic, and anti-convulsant properties in a series of pharmacological tests.

Animals↗
PubMed1979

The antitussive activity of a novel compound RU 20201.

A novel compound, 1,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-4-[3-(4-methylpiperazin-1-yl)propionamido]dibenzofuran-3-one dihydrochloride (RU 20201), has been shown to have comparable antitussive activity to that of codeine phosphate in animal experiments after oral administration. RU 20201 was also shown to have local antitussive activity when given by aerosol. This effect took place immediately. Initial observations suggest that RU 20201 is an antitussive compound that exerts its activity in the lungs, probably by direct inhibition of superficial receptors in the respiratory tract.

Aerosols↗
PubMed1978

The effect of various topical antibiotic and antibacterial agents on the middle and inner ear of the guinea-pig.

The topical application of antibiotics and anti-inflammatory agents is used to reduce inflammation of the middle ear mucosa and irradicate infection. Many of the antibiotic and anti-inflammatory preparations so used contain compounds known to be or are potentially ototoxic. Eighteen antibiotic, antibacterial, antifungal and anti-inflammatory compounds and four commonly used solvents were screened for the absence of ototoxicity and inflammation to the middle ear mucosa. All compounds were injected intra-tympanically and sensory hair cells loss recorded graphically. Inflammation of the middle ear mucosa was assessed macroscopically. Of the 18 compounds only three, penicillin, carbenicillin and nystatin were free of hair cell toxicity and inflammatory effects on the middle ear mucosa. Only one of the commonly used solvents was free of side effects.

Animals↗
PubMed1978

The physiological disposition of the anti-tussive agent, 1,2,3,4a,9b-hexahydro-8,9b-dimethyl-4-[3-(4-methylpiperazin-1-yl)propionamido]dibenzofuran-3-one dihydrochloride Azipranone, in man, rat, dog and baboon.

1. The absorption, tissue distrigution, elimination and biotransformation of the anti-tussive agent Azipranone labelled with 14C have been investigated after oral dosing to rat, dog, baboon and man and parenteral administration to rat and baboon. 2. Levels of radioactivity in plasma were maximal within 20 min of dosing in the rat and after 1-2 h in the remaining species. The concn. declined thereafter with a half-life estimated at 1, 3-4 and 18-24 h for rat, dog, and baboon and man respectively. 3. Three human volunteers excreted 53, 62 and 70% of the radioactivity in the urine in 96 h while the remaining species excreted 50-70% of the dose in the faeces in the same period. 4. Radioactivity was rapidly and extensively eliminated in the bile of both rat and baboon after administration of [14C]Azipranone. 5. The 24 h urine samples from all species contained ten major and a similar number of minor radioactive components. 6. In hepatic microsomal preparations, biotransformations of Azipranone are catalysed by enzymes requiring both NADPH2 and cytochrome-P450.

Administration, Oral↗
PubMed1978

Inhibition of experimental immediate hypersensitivity reactions by a novel xanthone, RU 31156.

RU 31156, the tris-(hydroxymethyl)-aminomethane salt of 7-(S-methylsulphonimidoyl)-5-(n-hexyl)-xanthen-9-one-2-carboxylic acid has been found to be a potent inhibitor of experimental immediate hypersensitivity reactions in vivo. In the IgE-mediated rat PCA test, RU 31156 had an ED50 of 0.0046 (00037--0.0057) mg/kg which compared to a figure of 1.21 (1.04--1.42) mg/kg for disocium cromoglycate (DSCG), both compounds being administered intravenously. RU 31156 was also active when administered orally, having an ED50 of 0.19 (0.07--0.30) mg/kg when given 10 min before antigen. RU 31156 partially inhibited an IgG-mediated PCA reaction in the rat. Both RU 31156 and DSCG inhibited anaphylactic bronchoconstriction in the rat, giving bell-shaped dose-response curves. From the upward part of the curves, approximate ED30 values of 0.02 and 2.0 mg/kg were obtained for RU 31156 AND DSCG respectively. Anaphylactic bronchoconstriction in the guinea-pig was not affected by RU 31156 and pinnal anaphylaxis was inhibited at only relatively high doses of 1--10 mg/kg i.v. The effects of both histamine and 5-hydroxytryptamine in the mouse pinna were not affected by RU 31156. In PCA experiments, RU 31156 showed self-tachyphylaxis following both intravenous and oral administration. It also showed cross-tachyphylaxis with DSCG, indicating that these compounds are likely to share a similar mode of action.

Anaphylaxis↗
PubMed1978

Hyperalgesia after treatment of mice with prostaglandins and arachidonic acid and its antagonism by anti-inflammatory-analgesic compounds.

Prostaglandin E1 (PGE1), prostaglandin E2 (PGE2) and arachidonic acid have been demonstrated to potentiate the peritoneal writhing response in the mouse induced by benzoquinone. The resultant dose-response relationships were bell shaped with a maximum activity of 10 ng/kg i.p. of potentiating agent. Floctafenine, indometacin and acetylsalicylic acid (ASA) blocked the potentiation induced by arachidonic acid but not that induced by PGE2. This suggests that it is prostaglandin that causes the potentiation and that the mechanism of action of ASA-like drugs against hyperalgesia associated with inflammation is blockade of prostaglandin synthesis. Morphine reduced the potentiation by PGE2 and arachidonic acid but the bell shaped hyperalgesia was still evident using both agonists. These results indicate that morphine does not inhibit prostaglandin synthetase but may modify the effect of prostaglandin. This method may be useful to distinguish between ASA-like and morphine-like analgesic compounds using a pain response in vivo.

Animals↗
PubMed1977

Measurement of free-circulating cis-dichlorodiammineplatinum(II) in plasma.

Dichlorodiammineplatinum(II) is an anti-neoplastic agent that is currently undergoing clinical evaluation. We describe an analytical method for monitoring the free drug (or its breakdown products) in plasma. The method is able to distinguish between free and protein-bound drug. Plasma samples are deproteinized by centrifugal ultrafiltration. The platinum in the ultrafiltrate is converted to a cationic species by reaction with ethylenediamine and then collected on paper impregnated with cation-exchange resin. This process concentrates the samples, increases the stability of the platinum compounds (by removing the compound from solution), and places the sample in a uniform matrix of minimum thickness, which maximizes detection capabilities. Platinum was measured directly on the ion-exchange disks by X-ray fluorescence. The detection limit for free drug is 240 microgram/liter of plasma at the 3s level and fluorescence intensity is linearly related to drug concentration in the range from 570 to 5700 microgram/liter.

Chromatography, Ion Exchange↗
PubMed1976

Preliminary studies on the absorption, distribution and excretion of N-(2-hydroxyethyl)-maleopimarimidyl morpholide (3H-RU 18492) in the female rat and dog.

Following the oral administration of 3H-labelled N-(2-hydroxyethyl)-maleopimarimidyl morpholide (3H-RU 18 492) to rats and dogs, radioactivity was detected in plasma and the various tissues examined. However, the major fraction of the dose remained unabsorbed and the highest concentrations of radioactivity were found in the liver. In both species the major route of excretion of radioactivity was via the bile.

Animals↗
PubMed1976

The protective effect of a novel compound RU 18492, on galactosamine-induced hepatotoxicity in the rat.

A novel compound N-(2-hydroxyethyl)-maleopimarimidyl morpholide (RU 18 492), was investigated for its effect against galactosamine induced hepatitis in rats. It was found to be active in reducing both serum transaminase levels and morphological changes due to the hepatotoxin. The protection was shown to be dose related and a significant reduction in liver damage was seen at doses of 50-400 mg/kg p.o. RU 18 492 was ineffective against carbon tetrachloride induced hepatitis in rats. It was suggested that the protective effect of RU 18 492 was due to its ability to stimulate the smooth endoplasmic reticulum thus inducing a more rapid detoxification of galactosamine.

Animals↗
PubMed1975

An investigation and some parameters that affect the galactosamine model of hepatitis in the rat.

1. The effect of d-galactosamine hydrochloride on the livers of rats was observed by measuring serum transaminase levels and histological examination. 2. Galactosamine caused dose related liver cell damage when given i.p. and s.c. but was ineffective when given orally. 3. The time of maximum effect was 24--48 h after administration. 4. The liver cell damage was modified by the oestrus cycle in female rats. 5. Galactosamine when given in proportion to body weight tended to be less effective as body weight increased.

Administration, Oral↗