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Biomedical subjects

J F Howes

Publications and source records attributed to J F Howes.

At least 37 records · Page 2Linked to original sources
PubMed1981

Analgesic narcotic antagonists. 9. 6-Methylene-8 beta-alkyl-N-(cycloalkylmethyl)-3-hydroxy- or -methoxymorphinans.

Series of N-(cyclopropylmethyl) (P series) or N-(cyclobutylmethyl) (B series) 3-methoxy (1) or 3-hydroxy (2) morphinan-6-ones with hydrogen (a), methyl (b), or ethyl (c) groups in the 8 beta position were converted to the 6-methylene compounds 3 or 4 by reaction with Ph3P = CH2. One member of this new series, N-(cyclobutylmethyl)-8 beta-methyl-6-methylenemorphinan-3-ol (4Bb), had potent mixed agonist-narcotic antagonist properties and, in contrast to the previously studied 6-oxo compound 2Bb, did not substitute for morphine in dependent rats or monkeys.

Analgesics↗
PubMed1980

Physical dependence and tolerance development after chronic exposure to low levels of morphine in the rat.

A sustained-release delivery system containing 14C-morphine was implanted subcutaneously in rats. Measurement of urinary excretion of 14C suggested a steady state release of approximately 640 micrograms 14C morphine/day during a 10-day test period. Tolerance developed rapidly to the analgetic effects produced by an injected ED95 dose of morphine sulfate in implanted rats tested on the hot-plate. Physical dependence, determined by naloxone-precipitated abstinence behavior, was evident in rats at 24 hr. Morphine dosage was estimated to be as low as 2.5 mg/kg/day. Peak abstinence behavior was observed on Day 4. However, naloxone-precipitated withdrawal signs were markedly diminished by Day 6 and essentially absent by Day 8. These results are discussed with reference to the suggestion that metabolic changes, occcurring during chronic exposure to morphine, may explain the lack of abstinence behavior during a time when maximal concentrations of urinary morphine were observed and a high degree of tolerance was manifest.

Analgesics↗
PubMed1980

Analgesic narcotic antagonists. 2. 8-Alkymorphinan-6-ones.

A series of 8-alkyl-3-methoxy-17-methylmorphinan-6-ones (3C) and -isomorphinan-6-ones (3T) were prepared by conjugate addition of lithium dialkylcuprates to the corresponding 7,8-didehydro-6-ones 2C and 2T. These 17-methyl compounds were potent analgesics and were converted to mixed narcotic agonists-antagonists 7-10, by replacement of the 17-methyl groups with cycloalkylmethyl moieties. The 8 substituent modified the type of activity observed. One of these compounds, 17-(cyclobutylmethyl)-3-hydroxy-8 beta-methylmorphinan-6-one (10Ca), had an agonist-antagonist ratio of 0.1. Compound 10Ca did not support or cause dependence in rats. This compound, however, appeared to be a typical narcotic agent in morphine-dependent monkeys.

Acetates↗
PubMed1978

Drugs derived from cannabinoids. 7. Tachycardia and analgesia structure-activity relationships in delta9-tetrahydrocannabinol and some synthetic analogues.

delta9-Tetrahydrocannabinol (delta9-THC) and eight other synthetic analogues were found to induce a dose-related increase in heart rate in the conscious Wistar rat. Ina comparison of tachycardia with analgesic activity (mouse hot-plate and antiwrithing tests) it was found that the water-soluble ester derivatives of 2a, 1-hydroxy-3-(3-methyl-2-octyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo(b,d)pyran (DMHP), had the least potency for tachycardia and the greatest potency for analgesia. These findings suggest that these compounds may have promise as therapeutic agents.

Analgesics↗
PubMed1978

Sustained release of sulphadiazine.

An implantable system was developed which released sulphadiazine in mice over an extended period of time efficacious against infective challenges by Plasmodium berghei. The most successful preparation was a copolymer of L(+)-lactic acid + (+/-)-lactic acid (90 and 10% by weight, respectively) with a molecular weight of 150 000, with which sulphadiazine was mixed at 33.3% of the total weight, in a formulation as beads of 1.5 mm diameter. This preparation released sulphadiazine at a nearly constant rate over three months as measured by the appearance in urine of mice of radioactivity from [35S] sulphadiazine in transplanted material. When implanted in mice, the beads gave effective protection against repetitive (weekly) infective challenges with P. berghei by implanted beads at dosages equivalent to 57 mg kg(-1) sulphadiazine and greater over 21 weeks.

Animals↗
PubMed1978

Production of cyclochlorotine and a new metabolite, simatoxin, by Penicillium islandicum Sopp.

Production of the hepatotoxin cyclochlorotine by Penicillium islandicum was studied under a variety of fermentation conditions. The best system for production was agitated red wheat. A thin-layer chromatographic method was developed for the detection of this cyclic polypeptide. These experiments have resulted in the isolation of a new toxic metabolite, which we call simatoxin.

Animals↗
PubMed1976

Drugs derived from cannabinoids. 3. Sulfur analogs, thiopyranobenzopyrans and thienobenzopyrans.

Sulfur analogs of cannabinoids corresponding to DMHP (1) were prepared utilizing the Pechmann condensation between the appropriate keto ester and (5-(1,2-dimethylheptyl)resorcinol, followed by Grignard reaction. Compounds of various structural types (2-6), which had different ring size and position of the sulfur atom substituted in the alicyclic ring, were found to be active CNS agents in pharmacological tests in mice, rats, and dogs. They showed profiles qualitatively similar to those of the nitrogen and carbocyclic analogs. Basic esters of the most interesting parent phenols 2 and 4 were also prepared and tested.

Aggression↗
PubMed1976

Drugs derived from cannabinoids. 4. Effect of alkyl substitution in sulfur and carbocyclic analogs.

Various CNS-active cannabinoids in which the alicyclic ring was thiopheno, cyclopenteno, or cyclohexeno with the alkyl substituent in various positions (structural types 1-6) were synthesized by procedures described previously. These compounds were compared in selected pharmacological tests in mice, rats, dogs, and cats. The results suggested that methyl substitution in the close proximity of the phenolic hydroxyl group strongly influenced the activity of some cannabinoids, particularly of those which had a planar five-membered alicyclic ring rather than a six-membered ring.

Acoustic Stimulation↗
PubMed1976

Hashish. Unsaturated side-chain analogues of delta8-tetrahydrocannabinol with potent biological activity.

Two delta8-THC derivatives, 4a and 4b, with functionalized side chains were synthesized. Treatment of (+)-trans-p-mentha-2,8-dien-1-ol with the resorcinal 2b followed by removal of the dithiol group with HgO--BF3-Et2O gave the aldehyde 3b. A Wittig reaction of dimethyl (2-oxoheptyl)phosphate with 3b furnished 4a, which was reduced to 4b. Compounds 4a and 4b showed potent cannabinoid-like activity in mice.

Animals↗
PubMed1976

Development of polylactic/glycolic acid delivery systems for use in treatment of narcotic addiction.

Implantable polylactic/glycolic acid matrix systems have successfully provided the sustained release of naltrexone to mice for periods of up to 200 days. In vitro and in vivo release rates have been determined by measuring chemical concentrations in pH 7 buffer solution and urine, respectively, and in vivo efficacy has been measured by direct challenge with morphine (Dewey-Harris mouse tail-flick test). Dosage forms of small implantable cylinders, 1/16'' diameter, (25 mg/rod, one rod/mouse) containing 33% by weight naltrexone pamoate in 90 L(+)/10 polylactic/glycolic acid have sustained the delivery of chemical for 20 days. Delivery of chemical from dosage forms of 1/16'' diameter spherical beads (3 mg/bead, 3 beads/mouse) containing 33% by weight naltrexone base in 90 L(+)/10 polylactic/glycolic acid was sustained for 60 days. Earlier a similar bead type dosage form of 75 L(+)/25 polylactic/glycolic acid containing 50% by weight naltrexone base and coated with the pure polymer provided controlled release for 25 days. Polymerization conditions which incorporate the use of pharmacologically suitable catalysts and yield products reproducibly have have been delineated. Techniques for sterilization of the final implant have been screened.

Animals↗