The aim of this study was to compare the degree of taste disturbance by losartan, an angiotensin II receptor blocker, with that of perindopril, an angiotensin-converting enzyme inhibitor. Perindopril erbumine (2 mg), losartan potassium (25 mg), or vehicle was given to Japanese volunteers (n = 7) for 14 days in a randomized, placebo-controlled, 3-way crossover design with a 14-day washout period. Gustometry by filter-paper test and electrogustometry were performed before and at the end of each trial. Plasma renin activity (PRA) and serum and salivary zinc concentrations were measured. One subject dropped out because of a perindopril-induced dry cough, but no one claimed a taste disturbance. Detection thresholds of 4 basic tastes (sweet, salty, sour, and bitter) by the paper-disc test and electrogustometry were significantly worsened, and plasma renin activity was elevated by the drugs, whereas the deteriorating effects of 2 drugs did not significantly differ. These drugs did not affect zinc concentrations in plasma and saliva. It was concluded that losartan and perindopril similarly alter taste sensitivity during repeated dosing of the drugs.

AimsThere have been case reports of taste disturbance for the angiotensin II receptor blockers losartan and valsartan, but not for candesartan. This study was undertaken to examine whether candesartan causes taste disturbance. Methods Candesartan cilexetil (4 mg day-1 ) or vehicle was given to healthy volunteers ( n = 8) for 7 days in a randomized, double-blind, placebo-controlled, cross-over design with a 2-week washout period. Clinical gustometry using the filter-paper disc test and electrogustometry were sequentially performed before and at the end of each trial. Serum and salivary zinc concentrations were also measured. ResultsDetection thresholds of four basic tastes (sweet, salty, sour and bitter) determined by the paper disc test were significantly ( P < 0.05 in all tests) worsened (i.e. score of test increased) after repeated dosing of the drug, although the subjects did not notice such changes. The mean ± SEM (and 95% CI) scores of the four tastes at just before the seventh dosing of candesartan or vehicle was 3.38 ± 0.32 (3.02, 3.74) and 2.63 ± 0.18 (2.18, 3.08) for sweetness, 3.63 ± 0.38 (4.49, 2.77) and 2.63 ± 0.26 (3.27, 1.98) for salt, 4.01 ± 0.42 (3.04, 4.98) and 2.61 ± 0.32 (3.35, 1.87) for sourness, 4.01 ± 0.38 (3.22, 4.80) and 2.99 ± 0.33 (2.24, 3.74) for bitterness, for candesartan and placebo, respectively. Electrogustometry confirmed the candesartan-related taste disturbance. Serum and salivary zinc concentrations were not influenced by candesartan. ConclusionsThese data suggest that candesartan subclinically reduces taste sensitivity after repeated dosing in healthy subjects. Because similar events are repor ted for losartan and valsartan in case reports, this adverse effect might be a class effect of angiotensin-II receptor blockers (ARBs).

These results suggest that the effects of GFJ on the pharmacodynamics of triazolam are greater than those on quazepam. These GFJ-related different effects are partly explained by the fact that triazolam is presystemically metabolized by CYP3A4, while quazepam is presystemically metabolized by CYP3A4 and CYP2C9.

1. The aims were to attest whether HepG2-GS-3A4, a cell line into which the human CYP3A4 gene was introduced, can be used for a screening of chemicals that will inhibit CYP3A4 activity. 2. The capacity of the cells for metabolizing CYP3A4 substrates in vitro was evaluated. Also determined was the effect of CYP3A4 inhibitors and non-inhibitors on nifedipine hydroxylation. Western blot, immunohistochemostry and determination of beta-nicotinamide adenine dinucleotide phosphate (NADPH)-reductase activity were performed. 3. HepG2-GS-3A4 selectively metabolized substrates of CYP3A4 (diazepam, nordiazepam, lidocaine, atorvastatin, and nifedipine) to a greater degree than control. The metabolites were easily detected in the culture medium. Values of V(max) of HepG2-GS-3A4 were about 30- to 100-fold higher than those of the control, while values of K(m) were comparable. Pre-incubation of cimetidine and ketoconazole significantly inhibited nifedipine hydroxylation, while addition of inhibitors specific to other isoforms of CYPs had no substantial effect. The HepG2-GS-3A4 expressed a higher amount of CYP3A4 protein and mRNA than control. Most NADPH reductase activity was detected in microsomal fractions. 4 In conclusion, HepG2-GS-3A4 sufficiently and selectively metabolize substrates of CYP3A4, and inhibitors of CYP3A4 reduced the metabolism. Because the metabolites were easily detected in the culture medium, this cell might be useful for the new and easy screening of new drugs for the evaluation of CYP3A4-inhibiting activity in vitro.

Dosing-time-dependent changes in the effect and toxicity of morphine were examined in mice housed under alternating 12 h light (07:00 to 19:00 h) and dark (19:00 to 07:00 h) cycles. Morphine (0.5 mg/kg) was injected intraperitoneally (i.p.) in animals to assess its beneficial effect (i.e., protection against the kaolin-induced, bradykinin-mediated, writhing reaction) and its toxicity (i.e., alteration of the hepatic enzymes of aspartate aminotransferase [AST] alanine aminotransferase [ALT], and glutathione [GSH] in separate experiments). The magnitude of the analgesic effect of morphine depended on dosing time, with minimum effect at 02:00 h and maximum effect at 14:00 h. The serum hepatic enzyme levels of AST and ALT increased after dosing morphine (100 mg/kg) at 02:00 and 14:00 h. Time courses of these enzymes did not differ between the two trials. However, hepatic GSH, which is involved in the detoxification of chemical compounds, significantly decreased after i.p. morphine injection at 02:00 but not at 14:00 h. Overall, the results suggest that the analgesic effect of morphine is greater after dosing during the resting than during the activity phase of mice that have been induced with bradykinin-mediated pain. Drug-induced hepatic damage as inferred by GSH alteration, however, may be greater after dosing during the active phase.