No abstract

A 72-year-old woman with renal insufficiency who was taking oral pilsicainide (150 mg/d) complained of feeling faint 3 days after she was prescribed oral cetirizine (20 mg/d). She was found to have a wide QRS wave with bradycardia. Her symptoms were relieved by termination of pilsicainide. The plasma concentrations of both drugs were significantly increased during the coadministration, and the cetirizine concentration decreased on cessation of pilsicainide despite the fact that treatment with cetirizine was continued, which suggested that the fainting was induced by the pharmacokinetic drug interaction. A pharmacokinetic study in 6 healthy male volunteers after a single dose of either cetirizine (20 mg) or pilsicainide (50 mg), or both, found that the renal clearance of each drug was significantly decreased by the coadministration of the drugs (from 475 +/- 101 mL/min to 279 +/- 117 mL/min for pilsicainide and from 189 +/- 37 mL/min to 118 +/- 28 mL/min for cetirizine; P = .008 and .009, respectively). In vitro studies using Xenopus oocytes with microinjected human organic cation transporter 2 and renal cells transfected with human multidrug resistance protein 1 revealed that the transport of the substrates of these transporters was inhibited by either cetirizine or pilsicainide. Thus elevated concentrations of these drugs as a result of a pharmacokinetic drug-drug interaction via either human multidrug resistance protein 1 or human organic cation transporter 2 (or both) in the renal tubular cells might have caused the arrhythmia in our patient. Although cetirizine has less potential for causing arrhythmias than other histamine 1 blockers, such an interaction should be considered, especially in patients with renal insufficiency who are receiving pilsicainide.

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).

Cyclosporine A (CsA) causes distal renal tubular acidosis (dRTA) in humans and rodents. Because mice deficient in nitricoxide (NO) synthase develop acidosis, we examined how NO production modulated H ϩ excretion during acid loading and CsA treatment in a rat model. Rats received CsA, L-arginine (L-Arg), or N -nitro-L-arginine methyl ester (L-NAME), or combinations of CsA and L-NAME or L-Arg, followed by NH 4 Cl (acute acid load). In vehicle-treated rats, NH 4 Cl loading reduced serum and urine (HCO 3 Ϫ ) and urine pH, which was associated with increases in serum [K ϩ ] and [Cl Ϫ ] and urine NH 3 excretion. Similar to CsA (7.5 mg/kg), L-NAME impaired H ϩ excretion of NH 4 Cl-loaded animals. The combination CsA and L-NAME reduced H ϩ excretion to a larger extent than either drug alone. In contrast, administration of L-Arg ameliorated the effect of CsA on H ϩ excretion. Urine pH after NH 4 Cl was 5.80 Ϯ 0.09, 6.11 Ϯ 0.13*, 6.37 Ϯ 0.16*, and 5.77 Ϯ 0.09 in the vehicle, CsA, CsA ϩ L-NAME and CsA ϩ L-Arg groups, respectively (*P Ͻ 0.05). The effect of CsA and alteration of NO synthesis were mediated at least in part by changes in bicarbonate absorption in perfused cortical collecting ducts. CsA or L-NAME reduced net HCO 3 Ϫ absorption, and, when combined, completely inhibited it. CsA ϩ L-Arg restored HCO 3 Ϫ absorption to near control levels. Administration of CsA along with L-NAME reduced NO production to below levels observed with either drug alone. These results suggest that CsA causes dRTA by inhibiting H ϩ pumps in the distal nephron. Inhibition of NO synthesis may be one of the mechanisms underlying the CsA effect.