Bioavailability study of triamterene and xipamide using urinary pharmacokinetic data following single oral dose of each drug or their combination.

An efficient chromatographic method for the simultaneous determination of triamterene (TRI) and xipamide (XIP) in urine samples, based on high performance liquid chromatography with photodiode array detector (HPLC-DAD) has been developed. The HPLC separation was performed on a RP stainless-steel C-18 analytical column (250 mm × 4.6 mm, 5 µm) with a gradient elution system of 0.05 M phosphate buffer adjusted to pH 4.0 and methanol as the mobile phase. The method was used to determine the urinary excretion profile and to calculate different urinary pharmacokinetic parameters following oral dose of their combination compared with single oral doses of each drug and hence comparing their bioavailability. Quantitation was performed using chlorthalidone as internal standard. The calibration graphs of each drug were rectilinear in the range of 0.2-40 µg/mL urine for TRI and 0.2-15 µg/mL urine for XIP. An HPLC-DAD method was also successfully developed for the simultaneous determination of the investigated drugs in pharmaceutical preparations. The methods were validated in terms of linearity, accuracy, precision, selectivity, limits of detection and quantitation and other aspects of analytical validation.

Severe electrolyte disturbances and renal failure in elderly patients with combined diuretic therapy including xipamid.

UNLABELLED: Diuretics are among the most frequently prescribed substances in elderly patients, but they are also associated with the highest incidence of adverse effects in this group of patients. Xipamide is a sulfonamide-like diuretic whose action does not depend on transtubular secretion. This characteristic makes it suitable for situations in which the kidney is highly sodium avid. Because of the potency of this substance the risk of adverse reactions like electrolyte disorders or hypovolemia is increased as well. We report seven patients (age 65-85) admitted to the emergency room of the University Hospital of Innsbruck between 1998 and 2002 who had developed serious adverse reactions upon initiation of treatment with xipamide as an additional diuretic. Six of these patients had received combinations with loop diuretics. The disturbances observed were hyponatremia (lowest value 108 mmol/l), hypokalemia (lowest value 1.5 mmol/l) and prerenal azotemia (highest serum urea 269 mg/dl, highest serum creatinine 5.13). CONCLUSION: With the exception of diuretic resistance in severe heart failure or renal insufficiency a combination therapy of xipamide with a second diuretic appears to be associated with an unnecessarily high risk of serious adverse reactions and thus should be avoided. This is especially true for elderly patients.

Xipamide disposition in liver cirrhosis.

The pharmacokinetics of the sulfonamide-type diuretic xipamide was studied in patients with liver cirrhosis and ascites and compared with healthy control subjects. After oral administration of 40 mg xipamide, the diuretic was rapidly distributed in the blood and the ascites. The ratio of the area under the concentration-time curve (AUC) of plasma and ascitic fluid was 7:2, as was the protein content in the respective compartments. The AUC in plasma of cirrhotic patients was significantly greater than in control subjects (p less than 0.001). The most striking finding was the increase of the amount (Ae) of parent drug and main metabolite excreted into the urine (p less than 0.001). The renal clearance of xipamide was only moderately reduced in patients with liver cirrhosis. Both AUC and Ae were positively correlated to the plasma concentration of direct bilirubin of the patients (p less than 0.05). We concluded that nonrenal drug clearance in patients with liver cirrhosis was reduced as a result of the blockade of hepatobiliary excretion during cholestatic conditions.

Prediction of diuretic mobilization of cirrhotic ascites by pretreatment fractional sodium excretion.

In a randomized prospective study the efficacy and side effects of xipamide versus the combination spironolactone/furosemide in the treatment of cirrhotic ascites were studied. Out of 27 patients four responded to a basic treatment consisting of salt and water restriction and one had to be excluded because of deterioration of kidney function. The remaining 22 patients were randomized to additional treatment with either 20 mg xipamide/day (group I) or 200 mg spironolactone/day combined with 40 mg of furosemide every other day (group II). A response to treatment during the first 4 days was seen in 7 of 11 patients of group I versus only 3 of 11 patients in group II. In the latter group 7 of 11 patients finally responded after 8 days of treatment. Responsiveness to either diuretic treatment strongly depended on pretreatment fractional Na excretion, FENa. The resistance to diuretic treatment can be predicted by a FENa less than 0.2%, and could be overcome by additional strategies known to reduce avid proximal Na reabsorption. Xipamide frequently induced hypokalemia, whereas hyperkalemia was seen following treatment with spironolactone/furosemide. Kidney function remained stable during either diuretic treatment.

[Photosensitivity following enoxacin and xipamide: combined phototoxic and photo-allergic reaction to enoxacin, photo-allergic reaction to xipamide with subsequent transient light reaction]. / Photosensitivität nach Enoxacin und Xipamid: Kombinierte phototoxische und photoallergische Reaktion auf Enoxacin, photoallergische Reaktion auf Xipamid mit nachfolgender transienter Lichtreaktion.

In a 51-year-old female patient, we observed a combined phototoxic and photoallergic reaction to Enoxacin, a photoallergic reaction to Xipamide, as well as increased sensitivity to light after withdrawal of the drugs. This unusual diagnosis was based on the clinical picture, graded radiation with UV-A and UV-B, the irradiated intradermal assay, and histological findings. To the best of our knowledge, this is the first report on a photoallergic reaction to Xipamide associated with a combined phototoxic and photoallergic reaction to Enoxacin.

A log-dose-response study of xipamide and its effect on metabolic parameters.

An extended dose-response study with xipamide, using seven doublings of the dose, from 0.3125 to 40 mg/day at 4-week intervals, was carried out in 12 hypertensive patients. Blood pressure showed a progressive decline with doses from 5 to 20 mg, and 40 mg xipamide produced no greater fall. Some subjects showed a maximum fall in blood pressure with a single dose increase but most showed a declining blood pressure over two or more dose increases. Plasma urea increased with doses of 5-40 mg to a similar extent, but there was no fall in the mean potassium level except with the 40-mg dose. Urinary calcium was reduced (from 4.2 to 1.7 mmol/24 h) on the 40-mg dose and the corrected plasma calcium level rose from 2.28 to 2.32 mmol/l. Triglycerides, very-low-density lipoprotein cholesterol and plasma aldosterone increased at the maximum dose; the cholesterol ratio, however, was unchanged.

Comparison of two combined diuretics in the treatment of essential hypertension.

The efficacy and safety of two combination drugs, consisting of a diuretic + a K-sparing agent, were investigated in the treatment of essential hypertension. A double-blind, randomized, parallel group study design was employed. After randomization, 14 patients were treated with 10 mg xipamide + 30 mg triamterene (A) and 16 with 25 mg hydrochlorothiazide + 50 mg triamterene (B). The patients suffered from essential hypertension with a systolic blood pressure (SBP) at entry of greater than or equal to 150 mmHg and a diastolic blood pressure (DBP) of greater than or equal to 95 mmHg. After 6 weeks, mean decline in DBP was 12% in group A and 9% in group B, respectively. With treatment A, one patient became hypokalemic and with treatment B one patient became hyperkalemic.

Erythrocyte and leucocyte sodium and potassium transport systems during long-term diuretic administration in men.

The effect of xipamide on the intracellular concentration and transmembrane fluxes of Na+ and K+ was studied in 12 normal male subjects, using a double-blind cross-over design. After a run-in period on placebo for 1 week, the subjects were treated with either placebo (n = 6) or xipamide 20 mg once a day (n = 6) for 16 weeks and were then switched to the alternative medication for another 16 weeks. The intra-erythrocyte and intra-leucocyte Na+ concentration was increased by 11 and 7%, respectively, during xipamide administration, while the intracellular K+ concentration was decreased by 3 and 4%, respectively. No significant effect of xipamide could however be demonstrated on the ouabain-sensitive, bumetanide-sensitive or ouabain-bumetanide-resistant 86Rb uptake and on the maximal 3H-ouabain binding in erythrocytes and leucocytes. The red cell Na+-Li+ countertransport was also not changed in the xipamide-treated subjects. Our data suggest that the increased intracellular Na+ concentration and the decreased K+ concentration in red and white blood cells of xipamide-treated subjects cannot be attributed to changes in the activity of the Na+ pump, the Na+-K+ cotransport or Na+-Li+ countertransport system or to changes in the number of active Na+ pump units.

Xipamide. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy.

Xipamide is a diuretic derived from salicylic acid and has a structural resemblance to chlorthalidone. Its pharmacodynamic profile shows a diuretic efficacy is similar to that of frusemide (furosemide) at doses up to 40 mg, but the onset and duration of action are comparable to those of hydrochlorothiazide. Xipamide has been studied mostly in the treatment of mild to moderate essential hypertension, with few controlled studies of its use in oedematous states. The efficacy of xipamide 20 to 40 mg once daily in patients with mild to moderate hypertension is comparable to that of bendrofluazide 5 mg, bumetanide 1 mg or hydrochlorothiazide 50 mg when used alone in newly treated or previously treated patients. The addition of xipamide 20 to 40 mg daily to regimens containing beta-blockers, adrenergic neuron-blocking drugs and/or methyldopa has resulted in a further reduction in blood pressure. A few studies in oedematous states suggest that xipamide 40 to 80 mg is comparable in efficacy to equal doses of frusemide, and that the side effects of hypokalaemia, hyperuricaemia and increased blood glucose in diabetics or latent diabetics are similar to those of other diuretics. Thus, xipamide is a suitable alternative to other diuretics in the treatment of mild to moderate hypertension and combines the efficacy of frusemide with a less abrupt action in the treatment of oedema.

Nadolol in combination with indapamide and xipamide in resistant hypertensives.

Twenty-four hypertensive patients have been studied. All had blood pressure recordings greater than 160/95 mmHg on 3 occasions whilst taking a beta blocker and two other antihypertensive agents in therapeutic doses. Compliance was checked by intermittent urine analysis for the relevant beta-blocker. These difficult to control hypertensives were treated with nadolol alone, nadolol plus indapamide and nadolol plus xipamide each for 2 months in random order. The aim was to reduce the blood pressure to below 160/95 mmHg. The supine blood pressure on nadolol alone (167/100 mmHg) was comparable to that on the previous three drug regimens (157/100 mmHg), the other two treatments were more effective (145/90 and 148/93 mmHg respectively). Hypokalaemia (serum potassium below 3.5 mmol/l) occurred in six individuals but occurred more frequently on xipamide than on indapamide.

Xipamide: no advantage over bendrofluazide in hypertension.

In patients with uncontrolled hypertension addition of xipamide 20 mg daily to bendrofluazide 5 mg daily produced no significant additive antihypertensive effect, and the 95% confidence limits excluded a clinically important response. Xipamide treatment worsened hypokalaemia and increased the blood urea concentration significantly.

The magnesiuric effects of several single doses of xipamide in healthy adults.

Common diuretics induce hypermagnesiuria which may lead to somatic magnesium depletion and subsequently to serious cardiac arrhythmias. The objectives of the present study were to determine if low doses of the diuretic xipamide cause hypermagnesiuria and to describe the time course of urinary Mg2+ excretion after xipamide in normal probands. Experiments were carried out on 13 healthy adult volunteers given monodoses of placebo, 5, 10 and 20 mg xipamide on separate days in random order. Urine collected at 3, 6, 12 and 24 h after dosing was analyzed for Mg2+ and other solutes. All doses of xipamide induced significant increases of 24-h urinary volume, and C1-, Na+, K+ and Mg2+ excretion when compared to the placebo. Urinary Mg2+ flow was delayed with respect to Na+ flow for all doses of xipamide. Xipamide administered acutely at low doses to healthy subjects causes hypermagnesiuria. The likelihood exists that this substance may induce somatic magnesium depletion when chronically administered, even at low doses.

Once daily administration of low-dose xipamide: a long-term study in mild to moderate hypertension.

The anti-hypertensive effects of xipamide in doses of 5-20 mg once daily were studied in a multicenter study. Three general practitioners recruited 74 patients with uncomplicated hypertension. After a run-in period, patients entered a dose-ranging study and were followed for an average period of 10.4 months. Supine and standing blood pressures were significantly decreased (22.2/14 and 21/14 mmHg) during xipamide therapy with average daily dose of 12.2 mg. Serum potassium values dropped from 4.43 +/- 0.06 to 3.96 +/- 0.5 mEq/l, and serum uric acid increased from 5.47 +/- 0.06 to 6.04 +/- 0.18 mg%. In a second part 47 patients entered a double-blind, crossover study of placebo. Their optimum xipamide doses confirmed that in the majority of patients with mild to moderate hypertension xipamide in doses lower than 20 mg is effective in lowering blood pressure. The study further confirmed that xipamide exerted its anti-hypertensive effects for at least 24 h.

Clinical trial of xipamide in the treatment of hypertension.

Nine patients with hypertension were given xipamide 40 mg orally as monotherapy on alternate days. An additional seventeen patients had xipamide added to an existing treatment regime of clonidine 450 micrograms per day. Xipamide alone produced a significant fall in blood pressure comparable to that obtained with clonidine alone. However, a significant further reduction was obtained when xipamide was added to the existing clonidine regime.