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 prolonged stay at high altitude on platelet aggregation and fibrinogen levels.

Increased liability for thrombosis has been suspected at high altitude. Platelet function and fibrinogen levels are known to play a major role in thrombogenic disorders. In order to investigate effect of chronic hypobaric hypoxia on platelet function and fibrinogen concentration, a study was conducted on 40 healthy men at sea level and following 3 and 13 months sojourn at high altitude (4100 m-4500 m). A consistent decline in platelet number was observed in high altitude sojourners during 13 months stay at high altitude. Platelet counts decreased by 12% after 3 months of stay at high altitude and by 31% after 13 months stay in comparison to sea level counts (266.01 +/- 65.10 x 10(3)/microl). Mean platelet volume increased from 9.18 +/- 0.83 fl at sea level to 10.8 +/- 0.98 fl after 3 months stay at high altitude and showed a further increase to 12.15 +/- 1.18 fl following 13 months residency in the hypoxic environment. There was significant reduction in maximal platelet aggregation in response to ADP, epinephrine and collagen, the effect being most pronounced with collagen (75%) and least with ADP (24%). Plasma fibrinogen concentration was 53% higher in sojourners after 3 months stay at high altitude and 61% higher after 13 months stay at high altitude. This implies that increased platelet activity may not be responsible for precipitation of thrombotic phenomenon during prolonged stay at high altitude but increased availability of substrate for coagulation could still favor pro-coagulant tendencies.

Synthesis and pharmacological evaluation of new arylpiperazines N-[4-[4-(aryl) piperazine-1-yl]-phenyl]-amine derivatives: putative role of 5-HT1A receptors.

In an attempt to design novel 5-HT(1A) agonists/partial agonists, based on an arylpiperazine nucleus, a series of N-{4-[4-(aryl)piperazine-1-yl]-phenyl}-amine derivatives were synthesized and biologically tested. The anxiolytic effect of the compounds was investigated employing the Elevated plus Maze (EPM) task. On the basis of in vivo functional test, compound 1c (3mg/kg) and 4c (3mg/kg) induced significant increments in open arm entries and time on EPM as compared to Buspirone. The anxiolytic effects of compounds 1c and 4c were effectively antagonized by WAY-100635, a 5-HT(1A) receptor antagonist (0.5mg/kg). Furthermore, we have also evaluated the concentration of 5-HT in the brain tissue using HPLC with fluorescent detection. Our result showed that serotonin levels were significantly decreased by approximately 38% (p<0.001) and approximately 32% (p<0.001) after acute administration of compounds 1c and 4c, respectively. These findings suggest that the anxiolytic like activity of these new arylpiperazines is mediated via 5-HT(1A) receptors in the brain.

Acetoxy drug: protein transacetylase catalyzed activation of human platelet nitric oxide synthase by polyphenolic peracetates.

An enhanced intracellular level of Nitric oxide (NO) is essential to ameliorate several pathological conditions of heart and vasculature necessitating the activation of NOS. We have projected in this report the acetylation of eNOS by polyphenolic peracetates (PA) catalyzed by the novel enzyme acetoxy drug: protein transacetylase (TAase) discovered in our laboratory as an unambiguous way of activating NOS which results in the manifestation of physiological action. The human platelet was chosen as the experimental system in order to validate the aforementioned proposition. PA caused profound irreversible activation of platelet NADPH cytochrome c reductase mediated by TAase. The convincing biochemical evidences are presented to show that PA could cause acetylation of the reductase domain of NOS leading to the activation of eNOS in tune with their specificities to platelet TAase. As a result, the enhanced level of NO due to activation of platelet eNOS by PA was found to inhibit the ADP-induced platelet aggregation. The present studies highlight for the first time the role of PA as the novel potent agent for enhancing the intracellular NO levels.

Acclimatization to oxidative stress at high altitude.

Hypoxia-mediated oxidative stress has been implicated in the pathophysiology of high altitude maladaptations. To explore whether prolonged exposure to high altitude can trigger an adaptive response to oxidative stress and restore redox homeostasis in the body, the study was conducted to evaluate biochemical variables related to oxidative stress and antioxidant status in humans at sea level (190 m) and following 3- and 13- month sojourns at altitude (4,500 m). After 3 months at altitude, whole-blood thiobarbituric acid reactive substances (TBARS) were significantly higher (65.6%), nonenzymatic antioxidants like ascorbic acid and caeruloplasmin were significantly lower (41% and 22%, respectively) and plasma total antioxidant status (TAS), glutathione levels, and superoxide dismutase activity were marginally altered as compared to their basal values. After 13 months at altitude, TBARS levels regressed back to preexposure levels. Plasma total antioxidant status (TAS) improved by 21%, glutathione levels by 32.8%, and plasma bilirubin by 35.8% as compared to sea level. Average concentrations of ascorbic acid and caeruloplasmin were 18% and 37% higher as compared to the subjects studied after a 3-month stay at high altitude. In addition, there was a progressive rise in erythrocytic superoxide dismutase activity and persistent hyperurecemia. The study observed that on prolonged exposure to high altitude humans could mount an effective adaptive response to oxidative stress by activating the antioxidant defense. Hence, strengthening the antioxidant defense could be an effective strategy to prevent free-radical-mediated pathophysiological alterations and quicken acclimatization to oxidative stress.