The R900S mutation in CACNA1S associated with hypokalemic periodic paralysis.

Primary hypokalemic periodic paralysis is an autosomal dominant skeletal muscle channelopathy. In the present study, we investigated the genotype and phenotype of a Chinese hypokalemic periodic paralysis family. We used whole-exome next-generation sequencing to identify a mutation in the calcium channel, voltage-dependent, L type, alpha subunit gene (CACNA1S), R900S, which is a rare mutation associated with hypokalemic periodic paralysis. We first present a clinical description of hypokalemic periodic paralysis patients harboring CACNA1SR900S mutations: they were non-responsive to acetazolamide, but combined treatment with triamterene and potassium supplements decreased the frequency of muscle weakness attacks. All male carriers of the R900S mutation experienced such attacks, but all three female carriers were asymptomatic. This study provides further evidence for the phenotypic variation and pharmacogenomics of hypokalemic periodic paralysis.

Garlic for the prevention of cardiovascular morbidity and mortality in hypertensive patients.

BACKGROUND: Garlic is widely used by patients for its blood pressure lowering effects. A meta-analysis published in 2008 concluded that garlic consumption lowers blood pressure in hypertensive and normotensive patients. Therefore, it is important to review the currently available evidence to determine whether garlic may also have a beneficial role in the reduction of cardiovascular events and mortality rates in patients with hypertension. OBJECTIVES: To determine whether the use of garlic as monotherapy, in hypertensive patients, lowers the risk of cardiovascular morbidity and mortality compared to placebo. SEARCH METHODS: A systematic search for trials was conducted in the Cochrane Hypertension Group Specialised Register, CENTRAL, MEDLINE, EMBASE, AGRICOLA, AMED, and CINAHL up to November 2011. A hand search of reference lists of identified reviews was conducted. Experts in the area were also contacted to identify trials not found in the electronic search. Clinicaltrials.gov was searched for ongoing trials. SELECTION CRITERIA: Randomized, placebo-controlled trials of any garlic preparation versus placebo for the treatment of hypertension were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality using the risk of bias tool. Data synthesis and analysis was performed using RevMan 5. MAIN RESULTS: The search identified two randomized controlled trials for inclusion. One trial included 47 hypertensive patients and showed that garlic significantly reduces mean supine systolic blood pressure by 12 mmHg (95% CI 0.56 to 23.44 mmHg, p=0.04) and mean supine diastolic blood pressure by 9 mmHg (95% CI 2.49 to 15.51 mmHg, p=0.007) versus placebo. The authors state that garlic was "free from side effects" and that no serious side effects were reported. There were 3 cases "where a slight smell of garlic was noted."The second trial could not be meta-analysed as they did not report the number of people randomized to each treatment group. They did report that 200 mg of garlic powder given three times daily, in addition to hydrochlorothiazide-triamterene baseline therapy, produced a mean reduction of systolic blood pressure by 10-11 mmHg and of diastolic blood pressure by 6-8 mmHg versus placebo.Neither trial reported clinical outcomes and insufficient data was provided on adverse events. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine if garlic provides a therapeutic advantage versus placebo in terms of reducing the risk of mortality and cardiovascular morbidity in patients diagnosed with hypertension. There is also insufficient evidence to determine the difference in withdrawals due to adverse events between patients treated with garlic or placebo.Based on 2 trials in 87 hypertensive patients, it appears that garlic reduces mean supine systolic and diastolic blood pressure by approximately 10-12 mmHg and 6-9 mmHg, respectively, over and above the effect of placebo but the confidence intervals for these effect estimates are not precise and this difference in blood pressure reduction falls within the known variability in blood pressure measurements. This makes it difficult to determine the true impact of garlic on lowering blood pressure.

Use of a rhesus Plasmodium cynomolgi model to screen for anti-hypnozoite activity of pharmaceutical substances.

There remains a need for new drugs to prevent relapse of Plasmodium vivax or P. ovale infection. The relapsing primate malaria P. cynomolgi has been used for decades to assess drugs for anti-hypnozoite activity. After sporozoite inoculation and blood-stage cure of initial parasitemia with chloroquine, rhesus macaques were treated on subsequent relapses with chloroquine in conjunction with test regimens of approved drugs. Tested drugs were selected for known liver or blood-stage activity and were tested alone or in conjunction with low-dose primaquine. Tinidazole and pyrazinamide prevented relapse when used in conjunction with chloroquine and low-dose primaquine. Triamterene and tinidazole administered without primaquine achieved radical cure in some animals. All other tested drugs or combinations failed to prevent relapse. The rhesus macaque-P. cynomolgi model remains a useful tool for screening drugs with anti-hypnozoite activity. Tinidazole and pyrazinamide require further investigation as agents to enable dose reduction of primaquine.

Saline-resistant metabolic alkalosis, severe hypokalemia and hypertension in a 74-year-old woman.

The case of a 74-year-old woman with past history of hypertension and cerebrovascular accident admitted with pneumonia, dehydration, hypernatremia and severe hypokalemic alkalosis is presented. After correction of the hypertonic dehydration, the hypokalemia and alkalosis persisted in spite of aggressive potassium supplementation and the patient became hypertensive. Mineralocorticoid excess was suspected and excluded after extensive endocrinological testing. The use of aldactone failed to revert the abnormalities. Triamterene administration corrected the electrolytes and acid base aberrations, and dramatically improved the blood pressure control. This clinical picture is compatible with the diagnosis of Liddle's syndrome. Our patient exemplifies the unique occurrence of hypokalemic metabolic alkalosis in association with volume contraction at the start of the hospitalization and volume expansion later on her course.

Patterns of potassium wasting in response to stepwise combinations of diuretics in nephrotic syndrome.

OBJECTIVE: To study the urinary potassium wasting patterns when the decreasing effectiveness of diuretics during repeated administrations are counterbalanced by stepwise increases of doses and combinations of them. PATIENTS: Eleven patients with renal edema. Seven patients suffered from advanced nephrotic syndrome and 4 patients were "forme fruste". METHODS: Urinary excretions and serum levels of potassium, sodium, creatinine, osmoles were determined; specific renal functions, glomerular filtration rate (GFR) fractional excretion of potassium (FE(K)), transtubular potassium gradient (TTKG) and free water reabsorption (TcH2O) were calculated. Nine different intervention-induced changes were followed daily: furosemide (FSD) alone, FSD with chlorthalidone (CTN), "low dose" and "high dose" potassium sparing drugs (PSD), FSD with CTN and "low dose" or "high dose" PSD, and "no drug" as well as "postdiuretic" periods with or without PSD. RESULTS: TTKG significantly decreased in response to FSD. It elevated during FSD with CTN, but remained lower than the baseline. The normal correlation between urinary potassium excretion (UKV) and TTKG became distorted under FSD. UKV and FE(K) were slightly increased by FSD and more markedly when given FSD together with CTN, probably because "distal volume flow" was elevated. In the "postdiuretic" periods TTKG increased, but this was reversed by PSD. In response to PSD, TTKG and UKV decreased, but both were elevated when combining with FSD + CTN. CONCLUSIONS: FSD caused relatively small potassium loss, because the enhanced "distal volume flow" was counterbalanced by a decrease of TTKG. FSD may have had a potassium secretion inhibitory influence as well. Potassium loss and TTKG were enhanced during coadministration of CTN, and decreased by PSD. "Postdiuretic rebound" increase of TTKG was reversed by PSD.

[The clinical efficacy of Korinfar-retard in combination with Cordanum, triampur and Capoten in patients with arterial hypertension]. / Klinicheskaia éffektivnost' korinfar-retard v sochetanii s kordanumom, triampurom, kapotenom u bol'nykh s arterial'noi gipertoniei.

Corinfar-retard as a base of different combinations with triampur, Cordanum, Capoten were studied in 52 patients with stable arterial hypertension (systolic pressure > 180 mm Hg, diastolic pressure > 105 mm Hg). In the above combinations pharmacokinetics of corinfar-retard did not change. Good response was noted in corinfar-retard combination with Cordanum in patients with moderate hemodynamic changes, hypertonicity of sympathoadrenal system, tachycardia. In patients with impaired myocardial contractility, elevated total peripheral vascular resistance, noticeable hypotensive effects was registered in combination with triampur. The absence of hypotensive effect in the above combination required the addition of Capoten which was absolutely indicated in patients with stable increase in plasma renin activity.

Liddle's syndrome, an underrecognized entity: a report of four cases, including the first report in black individuals.

Liddle's syndrome, a rare cause of hypokalemic hypertension, is characterized by a renal tubular sodium channel defect resulting in excessive sodium absorption and concomitant potassium wasting. In this disorder, although the clinical manifestations resemble primary aldosteronism, serum and urine aldosterone are suppressed. The syndrome is transmitted in an autosomal dominant pattern. It has been reported previously in white and oriental populations but not in the black individuals. We identified four patients (two of whom are black) in our nephrology clinic, with severe hypokalemic hypertension not correctly diagnosed for several years. All patients underwent an extensive work-up for secondary hypertension because of persistent severe hypertension (average blood pressure, 210/130 mm Hg) despite high-dose multi-drug therapy. Primary aldosteronism was excluded because of low serum aldosterone. Cushing's syndrome, pheochromocytoma, renal artery stenosis, and enzymatic deficiencies of cortisol synthesis (11 beta-hydroxylase, 17 alpha-hydroxylase, 5 beta-reductase, and 11 beta-hydroxysteroid dehydrogenase) were ruled out with extensive endocrine and radiologic studies. Once the diagnosis of Liddle's syndrome was suspected, all patients were treated with either triamterene or ameloride, with resolution of hypokalemia and correction of hypertension occurring within 5 to 7 days. Our findings suggest that Liddle's syndrome can occur in the black population. Although the actual incidence of this syndrome remains unknown, it may be significantly more common than we are led to believe since it is inherited in a Mendelian pattern. Whether there is a subset of low-renin, salt-sensitive black hypertensive patients who have the same or similar sodium channel defect remains to be elucidated.

[Effects of potassium chloride and triamterene on kaliuresis, natriuresis and diuresis in congestive heart failure]. / Vliianie khloristogo kaliia i triamterena na kaliurez, natriiurez i diurez pri zastoinoi serdechnoi nedostatochnosti.

KCl and triamterene were given to 52 patients (27 males and 25 females with CHF) aged 21-82 years. Large-dose KCl (6 g daily) apparently stimulate kaliuresis, natriuresis and diuresis. As a rule, this is associated with a rise or a fall of plasma potassium concentrations. In the latter case potassium elimination runs more actively and may involve both introduced and body's potassium. As low and moderate doses of KCl (1-4 g daily) showed neither natriuretic nor diuretic effects while enhanced kaliuresis occurred in half of the patients only, did not lower potassium concentrations in plasma they are preferable. Daily treatment with triamterene is characterized by inhibition of its K-retaining action on administration day 2-3. Within first 2 days of triamterene discontinuation all the retained K eliminates from the body. Diuretics-induced metabolic alkalosis decreased intensification of natriuresis and diuresis resultant from large-dose KCl treatment.

Interaction of biofeedback-assisted relaxation and diuretic in treatment of essential hypertension.

Thirty patients with essential hypertension participated in a study designed to compare two treatments: diuretic medication alone (n = 10) and biofeedback assisted relaxation combined with diuretic (n = 20). One of 10 patients lowered BP with diuretic alone and 11 of 20 patients lowered BP with diuretic combined with biofeedback-assisted relaxation. The addition of the behavioral intervention to the diuretic therapy produced a decrease in blood pressure beyond that associated with the diuretic alone. The decrease in BP mediated by diuretic were related to high entry levels of BP, low anxiety, forehead muscle tension, anger expression and plasma renin activity. The BP decrease mediated by combined diuretic and biofeedback-assisted relaxation was associated with high pretreatment BP, anger controlled, low finger temperature and high/normal plasma renin activity.

Acute and long-term renal and metabolic effects of piretanide in congestive cardiac failure.

1. The renal and metabolic effects of the sulphamoylbenzoic acid diuretic, piretanide, have been studied, under controlled dietary conditions, in 39 patients with congestive cardiac failure. 2. In acute studies, peak saluresis occurred within 4 h of oral piretanide administration; saluresis was complete within 6 h, after which a significant antidiuretic effect was observed. Addition of triamterene, 50 mg, blunted the 0-6 h kaliuretic effect of piretanide. Over 24 h, piretanide, alone, caused insignificant urinary losses of potassium when compared with control. 3. In comparative studies, the piretanide dose-response curve was found to be parallel to that of frusemide over the dose range studied. The 0-6 h saluretic responses of piretanide, 6, 12 and 18 mg, were found to be equivalent to frusemide, 40, 80 and 120 mg respectively. The collective mean ratios of all the saluretic responses to each dose of piretanide with the corresponding dose of frusemide was observed to be 0.99 +/- 0.12, over 0-6 h period, and 0.86 +/- 0.09 over the 24 h period. The relative potency of piretanide, when compared with frusemide was found to be 6.18 (95% confidence limits 4.87-8.33), over the 0-6 h period, and 4.73 (95% confidence limits 3.65-6.14), over 24 h period. 4. In 15 patients in severe cardiac failure, urinary recovery of piretanide, over first 6 h, at the start of treatment was 21.2 +/- 2.1% while efficiency of the diuretic (mmol Na/mg drug) was 47.3 +/- 4.1. Long-term piretanide therapy was continued in the same group for up to and in some cases over 3 years. No other diuretics or potassium supplements were given. Piretanide dosage ranged from 6 to 24 mg day-1 according to clinical need. Plasma potassium fell significantly at 12 and 24 months, though remaining within the normal range. At these same times, significant elevations in both plasma urate and total fasting cholesterol were observed. Two patients developed overt gout on high dose piretanide therapy (24 mg day-1). Piretanide was well tolerated, and effective in the management of congestive cardiac failure without any other recognized metabolic or electrolyte changes.

Maintenance of potassium balance during long-term diuretic therapy in chronic heart failure patients with thiazide-induced hypokalemia: comparison of potassium supplementation with potassium chloride and potassium-sparing agents, amiloride and triamterene.

The relative efficacy of potassium chloride, amiloride and triamterene in maintaining potassium and magnesium balance was evaluated in 23 hypokalemic (S-K less than or equal to 3.5 mmol/l) patients with chronic heart failure receiving diuretic therapy. Amiloride and triamterene were administered in a randomized, crossover manner, followed by potassium chloride in an open manner. During a 5-month treatment with hydrochlorothiazide 50 mg twice/day, potassium chloride 1 g twice/day was not as effective as amiloride 5 mg or triamterene 75 mg twice/day in maintaining serum potassium and magnesium and total-body potassium, while amiloride and triamterene seemed to be equally effective. During all three supplementations, a decrease in serum potassium to a hypokalemic level was observed in some patients. The need for higher doses of potassium chloride, amiloride and triamterene was clearly concentrated to the same patients, and correction was easily reached by increasing the respective doses.

Clinical trial of gossypol as a male contraceptive drug. Part II. Hypokalemia study.

A randomized controlled study was designed to evaluate the merit of whether ingesting potassium salt or potassium (K) blocking agent while using gossypol contraceptive drug could alleviate the symptom of hypokalemia. Results indicate that K salt supplementation did not reverse the gossypol-related hypokalemia and that the blocking agent triamterene did not prevent loss of or enhance the retention of serum K.

PIP: A randomized, controlled study was designed to determine whether ingestion of potassium salt or a potassium blocking agent in conjunction with use of the male contraceptive gossypol could alleviate the symptom of hypokalemia noted in an earlier study. The 120 male volunteers were randomly assigned to 1 of 4 groups: gossypol 20 mg/day, gossypol 20 mg/day with potassium chloride 1.5 gm, gossypol 20 mg/day with triamterene 50 mg, and a control group. No pregnancies occurred among the wives of volunteers in the 3 gossypol-treated groups during the 12-month study period. A general trend of declining blood pressure by the end of the treatment period was noted in the 3 gossypol-treated groups. The serum potassium decline persisted until the end of the 1st treatment year for the 3 study groups but not for controls. Gossypol itself produced the least decline in serum potassium, followed by the gossypol-potassium chloride group and finally by the gossypol-triamterene regimen. This may be an indication that gossypol alone causes renal impairment, and therefore potassium supplementation and a blocking agent may have no effect on the restoration of potassium to normal levels.

Serum magnesium and potassium levels in hypertensive patients after a therapeutic switch from hydrochlorothiazide plus a potassium supplement to maxzide.

Determinations of serum magnesium and potassium levels and blood pressure were made in 40 hypertensive patients in whom daily therapy with 50 mg of hydrochlorothiazide plus potassium supplements was switched to a once-daily regimen of 50 mg of hydrochlorothiazide plus 75 mg of triamterene (Maxzide). Patients showed no clinically significant changes in blood pressure or in serum magnesium or serum potassium values following the switch. It is concluded that therapy in patients receiving hydrochlorothiazide and up to 60 meq of potassium can be safely switched to Maxzide without adversely affecting serum magnesium levels, serum potassium levels, or blood pressure control.

[Effect of diuretics on the course of experimental arrhythmias]. / Vliianie diuretikov na techenie éksperimental'nykh aritmii.

The protective effect of triamterene was demonstrated on aconitine (rats) and strophanthin (cats) models of arrhythmias. Furosemide potentiates the antiarrhythmic effects of calcium chloride (rats) and strophanthin, ethacrynic acid potentiates the arrhythmogenic action of all agents used.

Plasma electrolytes in elderly patients taking fixed combination diuretics.

Plasma potassium and sodium concentrations were measured in a group of elderly patients taking maintenance thiazide diuretic therapy alone, with a potassium supplement or in combination with a potassium sparing diuretic. Fixed dose combinations of a thiazide and potassium sparing diuretic did not significantly reduce the prevalence of hypokalaemia and the combination of amiloride-hydrochlorothiazide was associated with a disproportionate number of cases of hyponatraemia. The desirability of the current widespread use of fixed dose combination diuretics over less expensive single agents is questioned.

Clinical efficacy and safety of long-term diuretic treatment in renal parenchymal hypertension.

In 48 patients with early stage renal disease and mild to moderate hypertension, control of high blood pressure and metabolic alterations during long-term diuretic treatment (mean duration, 71 months) were assessed. Compared to the untreated state, administration of thiazide-potassium sparing diuretics, a single table per day, supplemented by dietary sodium restriction, led to normalization of high blood pressure. Renal function was preserved. Gross abnormalities in electrolyte metabolism did not occur. Deterioration of glucose tolerance was noted in 3 patients. Preexisting hyperlipidemia was aggravated by the diuretics in men and postmenopausal women, but premenopausal women were protected. Long-term diuretic treatment was well tolerated, and caused remarkably few significant untoward reactions. The unfavorable metabolic response to diuretic treatment may, however, cancel part of the potential benefit of blood pressure control in certain patients. During long-term diuretic treatment of renal patients, attention should be given to monitoring of metabolic parameters and the introduction of specific dietary treatment may become the cornerstone of patient management.

Effects of muzolimine and of a combination of hydrochlorothiazide/triamterene in healthy subjects and in nephrotic patients.

The diuretic effects of 30 mg muzolimine and 25 mg hydrochlorothiazide/50 mg triamterene were comparable in healthy subjects and nephrotic patients (serum albumin less than 32 g/l, creatinine clearance greater than 50 ml/min/1.73 m2). A single daily dose of 30 mg muzolimine or 25 mg hydrochlorothiazide/50 mg triamterene was sufficient in the majority of the investigated nephrotic patients. The different diuretic effects which were observed in nephrotic patients were not related to the severity of hypalbuminemia, but rather to differences in preceding diuretic treatment. Plasma levels and urinary excretion of unchanged muzolimine were comparable in healthy subjects and nephrotic patients after one day of diuretic treatment; after seven days of treatment plasma levels of muzolimine were significantly lower and urinary excretion significantly higher in nephrotic patients than in control subjects.

Early changes in plasma and urinary potassium in diuretic-treated patients with systemic hypertension.

Two groups of patients with uncomplicated systemic hypertension were studied. Group 1 included 11 patients who had overt hypokalemia with diuretic drug treatment, and group 2 included 11 patients who remained normokalemic. After baseline studies without treatment were performed, both groups received hydrochlorothiazide, 50 mg twice daily. Plasma potassium (PK) was significantly reduced within the first day of treatment and stabilized by day 7 in both groups. The average decrease in PK was 1.0 +/- 0.1 mEq/liter (p less than 0.01) in the first group and 0.6 +/- 0.2 mEq/liter (p less than 0.01) in the second group. Cumulative losses of K were approximately 200 mEq in the hypokalemic group and were minimal in the normokalemic group as assessed by 24-hour urinary collections. Patients in the hypokalemic group also had a greater reduction in body weight and blood pressure. Supplementation with KCl, 96 mEq/day, or triamterene, 200 mg/day, in 9 hypokalemic patients resulted in an increase of PK to approximately 3.5 mEq/liter leveling off by day 7, and a cumulative K retention of approximately 200 mEq. Thus, overt thiazide-induced hypokalemia was associated with small and biologically unimportant losses of K from body stores. With replacement therapy the estimated amount of retained K was also small.

Female preponderance in diuretic-associated hypokalemia: a retrospective study in seven long-term care facilities.

A retrospective review of the medical records of 161 geriatric nursing-home patients receiving diuretics alone or in combination with potassium supplements or potassium sparing-diuretics revealed a 13.7 per cent overall prevalence of hypokalemia. The prevalence of hypokalemia in patients receiving diuretics alone, diuretics with potassium supplements, and potassium-sparing diuretics with kaliuretic diuretics were similar. However, there was a significantly higher prevalence of hypokalemia in women (16.4 per cent) compared with men (3.0 per cent), P less than 0.05. In patients taking non-chloride salts of potassium, there was a significantly higher prevalence of hypokalemia than in those taking the chloride salt (3.6 per cent vs. 8 per cent, P less than 0.025). Seven per cent of patients taking diuretics with potassium supplements and 11.5 per cent of patients taking potassium-sparing diuretics had hyperkalemia. Thus, although many elderly women taking diuretics may have hypokalemia routine potassium supplementation for all non-digitalized geriatric patients receiving diuretics does not seem to be indicated.