Inhibition of theophylline metabolism by interferon.

1 day after a single intramuscular injection of recombinant human interferon alpha A in 5 patients with stable chronic active hepatitis B and 4 healthy controls theophylline clearance was significantly reduced and theophylline elimination half-life was significantly increased. There was a clear relation between pre-treatment and post-treatment theophylline clearance rates, indicating that the greatest effect of interferon was in subjects who were fast metabolisers of theophylline. These observations support the contention that the actions of endogenous interferon may account for the effects of immunisations and viral infections on hepatic drug metabolism. Moreover, treatment with interferon may cause clinically important drug interactions.

The management of epilepsy: patients' perceptions and expectations.

An anonymous questionnaire, which was designed to obtain information on satisfaction with medical management, personal attitudes and experiences, and patients' knowledge about epilepsy, was sent to a systematic sample of persons on the membership lists of various Epilepsy Associations across Australia. Comments regarding doctors' attitudes towards persons with epilepsy and the inadequacy of informational exchanges between doctors and patients reflected many respondents' dissatisfaction with their medical management. The problems that are perceived by patients in regard to the management of their epilepsy may be addressed through improved education of these patients and of the community in general. Continuing education of medical practitioners, especially in relation to current management trends, patient education skills and the importance of a positive attitude towards epilepsy, may help to improve patients' perceptions of their medical treatment.

Halogenated pyrrolopyrimidine analogues of adenosine from marine organisms: pharmacological activities and potent inhibition of adenosine kinase.

Two novel halogenated pyrrolopyrimidine analogues of adenosine, isolated from marine sources, have been examined for pharmacological and biochemical activities. 4-Amino-5-bromo-pyrrolo[2,3-d]pyrimidine, from a sponge of the genus Echinodictyum, had bronchodilator activity at least as potent as theophylline but with a different biochemical profile; unlike theophylline it had no antagonist activity at CNS adenosine receptors and it was quite a potent inhibitor of adenosine uptake and adenosine kinase in brain tissue. 5'-Deoxy-5-iodotubercidin, isolated from the red alga Hypnea valentiae, caused potent muscle relaxation and hypothermia when injected into mice. This compound was a very potent inhibitor of adenosine uptake into rat and guinea-pig brain slices and an extremely potent inhibitor of adenosine kinase from guinea-pig brain and rat brain and liver. Neither of these two pyrrolopyrimidine analogues was a substrate for, or an inhibitor of, adenosine deaminase. Neither compound appeared to have any direct agonist activity on guinea-pig brain adenosine-stimulated adenylate cyclase (A2 adenosine receptors). 5'-Deoxy-5-iodotubercidin is unique in two respects: it appears to be the first naturally-occurring example of a 5'-deoxyribosyl nucleoside and is the first example of a specifically iodinated nucleoside from natural sources. It may be the most potent adenosine kinase inhibitor yet described and, by virtue of its structure, may prove to be the most specific.

Synthesis and pharmacological evaluation of a series of analogues of 1-methylisoguanosine.

A series of analogues of the pharmacologically active marine natural product 1-methylisoguanosine (1) was evaluated for biological activity in muscle relaxant, cardiovascular, antiinflammatory, and antiallergic tests. Modifications at the 1 position produced the ethyl, n-butyl, n-octyl, and phenyl derivatives 3-6, respectively. Substitutions at the 8 position provided the bromo, hydrazino and amino compounds 9-11. Modification at the 5' position yielded the deoxy, iodo, and phosphate derivatives 15, 13, and 16, as well as the cyclic 3',5'-phosphate 17. The synthesis of the C-nucleoside analogue 19 was achieved from the beta-D-ribofuranosylcarboximidic ester 20. The acyclic analogue 29 and the beta-D-arabinofuranosyl derivative 35 were both synthesized by reaction of methyl isocyanate with the appropriately protected aminocyanoimidazole precursors 28 and 32. 1-Methylxanthosine (12), isoguanosine (7), and 2-methoxyadenosine (18) were also synthesized. At doses up to 100 mg/kg po, the 5'-phosphate 16, cyclic 3',5'-phosphate 17, and the O-methylated analogue 2-methoxyadenosine 18 were active in producing muscle relaxation and hypothermia. These compounds possessed antiallergic activity and produced dose-dependent falls in mean blood pressure and heart rate as did the 1-ethyl (3) and 1-n-butyl (4) analogues. In general, antiinflammatory activity paralleled the other results, except that the cyclic 3',5'-phosphate 17 was inactive at the dose tested, while the 3,5'-anhydronucleoside 14 was weakly active and displayed antiallergic effects.

Methylaplysinopsin and other marine natural products affecting neurotransmission.

Methylaplysinopsin is a novel marine natural product that, after oral administration, prevented the effects of tetrabenazine in mice and rats. Methylaplysinopsin was a short-acting inhibitor of monoamine oxidase activity with greatest potency when serotonin was the substrate studied. The brain concentration of serotonin in the mouse was increased by methylaplysinopsin over the same time course as monoamine oxidase inhibition ex vivo. Methylaplysinopsin was also a weak inhibitor of the neuronal uptake of [3H]serotonin and a potentiator of the K+-induced release of [3H]serotonin from prelabeled synaptosomes. The predicted potentiation of serotonergic neurotransmission was supported by initial neurophysiological studies in an identified serotonergic pathway in the central nervous system of Aplysia. Two other studies on the pharmacology of marine natural products are reviewed. The majority of polyhalogenated monoterpenes isolated from red algae had central nervous system depressant properties. The exception is plocamadiene A, which caused, in mice, a reversible spastic paresis lasting up to 72 hours after oral administration. The severe muscle spasm was antagonized by diazepam. The final study discussed is the effect of a variety of marine natural products on the synthesis, neuronal uptake, and metabolism of GABA. Their selectivity is discussed with regard to the effects on metabolic respiration, and the correlation of neurochemical and neurophysiological effects on these marine substances.