Effect of intermittent hypobaric hypoxia on efficacy & clearance of drugs.

BACKGROUND & OBJECTIVES: People travelling to high altitude for occupational, recreational or religious purposes are mostly healthy and fit but sometimes they use drugs for common ailments like influenza, acute mountain sickness or chronic disease like diabetes. Limitation of oxygen at high altitude may compromise metabolism of drugs. Hence, we undertook this study to assess the effect of hypobaric hypoxia on some commonly used drugs in rats and rabbits. METHODS: Effect of intermittent hypobaric hypoxia on phenotypic expression of anesthetic drugs pentabarbitone, thiopentone and zoxazolamine (sleeping time) was assessed in rats exposed to 282.4 mm Hg equivalent to 25000 feet in a decompression chamber. Plasma clearance of some commonly used drugs was investigated in rabbits exposed to 429 mm Hg equivalent to 15000 feet. Pharmacokinetic parameters were computed by plotting drug concentration versus time curve on semi log scale. RESULTS: A significant delay in regaining rightening reflex was observed in rats exposed to intermittent hypobaric hypoxia in response to zoxazolamine, pentobarbitone and thiopentone sodium. Pharmacokinetics of acetyl salicylic acid, gentamicin, phenobarbitone and acetazolamide showed increase in plasma half life (t 1/2), decrease in elimination rate constant (k el) and hence prolonged residence of these drugs in hypoxic animals. INTERPRETATION & CONCLUSIONS: This experimental study showed that hypoxia altered therapeutic effectiveness and clearance of several drugs, in rats and rabbits exposed to intermittent hypobaric hypoxia. s0 uch studies need to be done in human volunteers to see the effect of hypoxia on pharmacokinetics of some common drugs.

Effect of novel anti-inflammatory ethanolamine derivatives with antioxidant properties on drug metabolising enzymes.

The influence of four ethanolamine derivatives with anti-inflammatory and antioxidant activity on the in vitro aminopyrine N-demethylation was studied. It was found that these compounds inhibit the N-demethylation of aminopyrine. 1-Cyclohexyl-5-(2-hydroxy-ethylamino)-pentan-2-one (compound 4), possessing the highest inhibitory activity and found earlier to be a potent anti-inflammatory agent, is further tested in vivo on zoxazolamine-induced paralysis, after a single administration to rats, and on aminopyrine N-demethylation, rat hepatic total cytochrome P450 and protein (postmitochondrial and microsomal) content, after a prolonged treatment. It was found that the examined compound had no significant influence on the above biotransformations, however, it could decrease the catalytically active hepatic cytochrome P450 content. These results, considered together with some structural and physicochemical properties of the compound, indicate that this compound may act as a CYP2D6 substrate.

3,4,5-Trihydroxy benzoic acid (gallic acid), the hepatoprotective principle in the fruits of Terminalia belerica-bioassay guided activity.

Compound I isolated from fraction TB5 of Terminalia belerica and finally identified as 3,4,5-trihydroxy benzoic acid (gallic acid) was evaluated for its hepatoprotective activity against carbon tetrachloride (CCl4)-induced physiological and biochemical alterations in the liver. The main parameters studied were hexobarbitone-induced sleep, zoxazolamine induced paralysis, serum levels of transaminases and bilirubin. The hepatic markers assessed were lipid peroxidation, drug metabolising enzymes, glucose-6-phosphatase and triglycerides. Administration of Compound I led to significant reversal of majority of the altered parameters. Our results confirm the presence of hepatoprotective activity in altered parameters. Our results confirm the presence of hepatoprotective activity in Compound I.

Structural features and protective activity of dexamethasone and pregnenolone-16 alpha-carbonitrile.

Pretreatment with dexamethasone acetate or pregnenolone-16 alpha-carbonitrile markedly diminished the pharmacological effect of zoxazolamine in rats. This prophylactic action was associated with significantly decreased plasma drug levels, which, in turn, were correlated with enhanced hepatic drug biotransformation, induced by the steroids. Dexamethasone proved to be more active than pregnenolone-16 alpha-carbonitrile in this respect. The A-ring conformation as well as the distances of O-3-O-11, O-11-O-17, and the O-3-mean plane C-5-C-17 may be key factors in glucocorticoid activity, and the longer the distances, the greater the potency. These characteristics have no bearing on catatoxic activity for which the 16 alpha-substituent appears to be a structural prerequisite.