Elementary, my dear Dr. Allen: the case of barium toxicity and Pa Ping.

OBJECTIVE: We aimed to review the English and Chinese literature on Pa Ping and to confirm by personal interview the story of how its pathogenesis was uncovered. BACKGROUND: In 1930, Dr. Alexander Stewart Allen noticed a pattern of illness arising in the region of Kiating, China. Area residents began presenting to local hospitals with nausea, vomiting, and diarrhea, and what emerged was a clinical picture of a gradual ascending paralysis that could result in death, termed Pa Ping. All 3 patients observed by Dr. Allen were male, had no family history of the disease, and had recently eaten before the onset of paralysis. Pa Ping developed in Dr. Allen himself, but he survived. METHODS: Medical literature was reviewed for primary sources. Interviews of living descendants and friends of the doctors in China and North America were conducted and information was corroborated by written records. RESULTS: Dr. Huang, with the National Central University College of Medicine, noticed a striking similarity between Pa Ping and familial periodic paralysis in 12 patients and reported 2 patients with Pa Ping treated with potassium citrate who experienced a reversal of the paralysis. Dr. K.T. Du analyzed meals of patients with Pa Ping seen by Dr. Zhe Tung and found barium in concentrations as high as 25.7%. This finding was confirmed by administering barium chloride to animals, which recapitulated the human syndrome. CONCLUSIONS: Although Dr. Huang had correctly noticed an underlying potassium depletion in patients with Pa Ping, the observations of Dr. Zhe Tung and Dr. K.T. Du ultimately established barium-induced hypokalemia as the underlying cause.

Diuretic-induced potassium depletion and glucose intolerance are not related to hyperactivity of the renin-angiotensin-aldosterone system in hypertensive patients with the metabolic syndrome.

The metabolic syndrome (MS) has been associated with hyperactivity of the renin-angiotensin-aldosterone system (RAAS). To assess the hypothesis that diuretic therapy in MS patients through further stimulation of RAAS would elicit greater potassium (K) depletion, two groups of hypertensive patients with (MS group [MSG]; n=20) and without (control group [CG]; n=19) MS were studied. Plasma renin activity (PRA), aldosterone (PA), and K levels were determined and an oral glucose tolerance test with plasma insulin determinations for calculation of homeostasis model assessment of insulin resistance (HOMA-IR), sensitivity (ISI), and secretion (HOMA-beta) was performed, both before and 12 weeks after hydrochlorothiazide (HCT; 25 mg/d) therapy. At baseline, higher HOMA IR and HOMA-beta and lower ISI and plasma K were found in the MSG than in the CG, with no differences in PA and PRA between groups. With therapy, PRA increased similarly in both groups while PA increased only in the MSG. However, greater reduction in plasma K occurred in the CG, and the 2 groups reached similar final K values. Impairment in glucose tolerance occurred in both groups, with no change in HOMA-beta in the CG and reduction in the MSG, suggesting that diuretic therapy increases insulin resistance and impairs insulin secretion independent of abdominal obesity. These alterations could not be attributed to hyperactivity of RAAS.

Effects of hydration with salt repletion on renal toxicity of conventional amphotericin B empirical therapy: a prospective study in patients with hematological malignancies.

OBJECTIVE: Several studies have suggested that hydration and sodium load might reduce nephrotoxicity related to amphotericin B-deoxycholate (AmB-d). However, a schedule of these nephroprotective measures has not been standardized until now. A protocol of hydration and electrolyte supplementation was used prospectively in patients with hematological malignancies receiving empirical AmB-d treatment to evaluate its effect on AmB-d-related renal toxicity. PATIENTS AND METHODS: A total of 77 consecutive patients received AmB-d (1 mg/kg per day) in association with an initial intravenous hydration of at least 1 l/m2 body surface, containing at least 1 l of 0.9% saline daily. Hydration was increased when serum creatinine levels showed a 20% increase from baseline. Serum electrolytes were replaced when indicated. RESULTS: The median duration of AmB-d therapy was 14 days. The mean intravenous hydration and the mean diuresis were 1530 and 1970 ml/m2 of body surface per day, respectively. Overall, 55 patients (71.4%) received a mean of 18.5 days of therapy without dose-limiting adverse events. Despite significant increases in mean creatinine serum levels and decreases in mean creatinine clearance observed early in the whole population, in only six patients (7.8%) was therapy discontinued due to renal failure, which always recovered after treatment discontinuation. In eight patients (10.4%) therapy was stopped due to infusion-related side effects. Seven patients died while under antifungal therapy without relevant signs of AmB-d-associated toxicity. CONCLUSIONS: Our prospective experience confirms that adequate hydration (about 1500 ml/m2 of body surface) and careful electrolyte supplementation are simple measures able to contain nephrotoxicity and to permit adequate antifungal therapy at least in the empirical setting.

Inhibition of p38 kinase mimics survival signal-linked protection against apoptosis in rat cerebellar granule neurons.

The mitogen-activated protein kinase (MAPK) cascades are thought to be important mediators in the transduction of extracellular signals into cellular responses. The p38 kinase, a member of the MAPK superfamily, is activated by a wide variety of extracellular stimuli and has been implicated in neuronal apoptosis induced by glutamate. In this study we have examined the role of p38 kinase in the potassium deprivation model of apoptosis in rat cerebellar granule neurons (CGN). An increase in p38 kinase activity was observed with a 15-minute potassium deprivation when compared to the basal level. We also found that SB203580 and PD169316, specific p38 kinase inhibitors, significantly attenuated apoptosis in potassium-deprived cells in a dose dependent manner. A decrease in caspase-3 mediated DEVD-MCA, substrate hydrolysis and the appearance of the 120 kDa-spectrin breakdown product in cells treated with SB203580 further suggests that the p38 kinase acts upstream of caspase-3 in the apoptosis cascade. The data provides evidence for an essential role of p38 kinase in mediating apoptotic cell death in CGN and the inhibition of p38 kinase mimics the suppression of apoptosis provided by natural survival signals.

[Potassium-sparing diuretics (spironolactone, triamterene, amylorid)]. / Káliummegtakarító diureticumok (spironolacton, triamteren, amilorid).

The group of drugs, so-called "potassium sparing diuretics" represent an important part of our modern therapeutic arsenal. Their "weak diuretic" properties are especially beneficial in cirrhotic patients with ascites, when highly effective loop diuretics may be hazardous. Potassium sparing diuretics have not only the advantage of avoiding potassium loss, but can potentiate the effects of diuretics acting in distal tubules and Henle's loop also. They may be combined by each other or ACE inhibitors too, taking the necessary precautions and laboratory monitoring. Their indications include the hypertension and special diseases as Conn's, Bartter's, Liddle syndromes and hirsutism. The broad clinical usefulness justifies the drug inventory ambition to develop new, more effective potassium sparing compounds without side effects. Authors overview their main clinicofarmacological properties, therapeutical indications alone or in combinations and their potential side effects.

Magnesium and potassium deficiency. Its diagnosis, occurrence and treatment in diuretic therapy and its consequences for growth, protein synthesis and growth factors.

Thiazides and loop diuretics facilitate the loss of K and Mg through the kidneys leading to deficiencies that may require treatment with supplements. These losses may be overlooked, however, because serum concentrations may remain normal even when the muscle concentrations are appreciably reduced. In 76 patients who had received diuretics for 1-17 years, the mean concentrations of K, Mg and Na,K-pumps in skeletal muscle biopsies were significantly lower than in those from an age- and sexmatched control group, and muscle Mg and K concentrations were significantly correlated. The serum concentrations, however, were only below the control range in a few patients. The fact that Mg,K deficiencies may often be overlooked emphasises the need for data on the contents of skeletal muscle. A recently developed simple biopsy needle procedure permitted the detection of disorders of electrolytes during long-term diuretic treatment despite normal serum concentrations. With the same technique it was possible to detect repletion of the muscle electrolytes after a Mg supplementation period. Oral Mg supplementation could reestablish normal Mg as well as K status in patients in long-term diuretic therapy, provided that the supplementation was maintained for 6 months. Moreover, the normalization of muscle Mg and K was accompanied by a restoration of the concentration of Na,K-pumps measured as the [3H]ouabain binding site capacity in skeletal muscle. Mg and K contents were closely correlated in human muscle biopsies from patients on diuretic treatment, but also in rat muscle which had been moderately Mg depleted in vivo or in vitro. In isolated soleus muscle, which had been moderately Mg-depleted in vitro, reduction in cellular K could not be ascribed to reduced Na,K-pump mediated K-influx. The reduced K content might rather be related to increased K efflux from the muscles. In rats, insufficient dietary supplies of K, Mg and Zn were characterized by inhibition of growth and protein synthesis. These effects could not readily be related to the loss of these elements from muscle tissue, but rather should be seen as a response to a general deficiency. The most marked evidence of deficiency was seen in the serum levels, which pointed to the serum concentration as a possible mediator for the regulation of tissue growth. IGF-I is a low molecular weight peptide possessing growth promoting properties in many tissues probably as an interplay of both autocrine/paracrine and endocrine actions. In both animals and man insufficient supplies of energy and protein are accompanied by growth retardation and a decrease in serum IGF-I.(ABSTRACT TRUNCATED AT 400 WORDS)

Renal papillary cytoplasmic granularity and potassium depletion induced by carbonic anhydrase inhibitors in rats.

Renal papillary cytoplasmic granularity (RPCG) induced by carbonic anhydrase inhibitors (CAIs) in rats is characterized by the accumulation of dense secondary lysosomes in epithelial, endothelial, and interstitial cells and may be related to drug-induced potassium depletion. Female Sprague-Dawley rats were given the CAI, acetazolamide, by gavage. Half were supplemented with 1% potassium chloride in the drinking water. Two treated groups were allowed to recover for 1 or 2 mo. Potassium supplementation inhibited RPCG by 80% but produced little amelioration of the mild 13% decrease in serum potassium induced by 200 mg/kg/day acetazolamide for 28 days. Acetazolamide-induced RPCG is reversible because 1- and 2-mo recovery periods decreased the incidence by 75% and 80%, respectively. The results support the hypothesis that RPCG is related to potassium depletion secondary to carbonic anhydrase inhibition. Because supplementation of potassium chloride had little effect on serum potassium, these data suggest that depletion of renal medullary potassium content is important in the pathogenesis of RPCG as previously suggested by others. Other types of diuretics that produce hypokalemia as a side effect may not deplete medullary potassium since RPCG has not been reported in humans or animals given these drugs.

Furosemide-induced electrolyte depletion associated with echinocytosis in horses.

Echinocytes have been incriminated in the pathogenesis of exertional diseases in horses. To evaluate the hypothesis that echinocytes are dehydrated erythrocytes, we decreased blood sodium and potassium concentrations in 4 horses by administering furosemide (1.0 mg/kg of body weight, q 12 h) for 2 days and we monitored CBC, serum and erythrocyte sodium and potassium concentrations, and echinocyte numbers. Serum sodium concentration decreased progressively over the 48 hours of furosemide administration, then returned to near baseline concentration at 168 hours. A statistically significant decrease (P < 0.05) in serum potassium concentration was observed at 24, 48, and 72 hours after initial furosemide administration, and remained less than the baseline value at the end of the study. Mean erythrocyte potassium concentration decreased rapidly and remained low at the end of the study. Minimal changes were observed in erythrocyte sodium concentration during the first 72 hours after furosemide administration, but the value was significantly (P < 0.05) increased at 168 hours. Type-I and type-II echinocyte numbers increased by 4 hours after furosemide administration and persisted throughout the study. Type-III echinocytes were not seen in baseline samples, but numbers increased only modestly after furosemide administration. Administration of epinephrine to well-hydrated horses increased echinocyte numbers only minimally, indicating that splenic contraction was not the likely cause for the furosemide-associated increase. To determine whether the decrease in erythrocyte potassium concentration and increase in sodium concentration was caused by furosemide acting directly on the erythrocyte membrane, we quantified erythrocyte potassium and sodium concentrations before and after incubation with furosemide in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

[Comparative study of potassium-sparing effects of triamterene and amiloride in the treatment with hydrochlorothiazide]. / Sravnitel'noe izuchenie kaliisberegaiushchego éffekta triamterena i amilorida pri lechenii gidrokhlortiazidom.

Hydrochlorothiazide (HCT), 25 or 50 mg a day, alone and in combination with triamterene (T), 50 and 100 mg, respectively, or amiloride (A), 2.5 and 5 mg, respectively, was examined for effects on daily urinary potassium and sodium excretion. Daily sodium excretion was increased 1.5-2-fold with a double dose of the combined drugs as compared with their single dose. T and A produced additive effects on the natriuretic action of HCT. Lower doses of HCT and T failed to prevent urinary potassium loss, but their potassium-sparing effect was shown with their double dose. This effect was largely displayed by A given in a single or double dose. Lower serum potassium levels were seen with all the drugs, but this was less marked with HCT combined with T or A than with HCT monotherapy. Their double dose reduced serum potassium levels to an insignificantly greater extent. In some cases, the elderly patients developed hyperkalemia during the combined therapy. Thus, with the routine dose ratios, A showed a slightly higher potassium-sparing effect than did T. Some patients taking HCT in combination with T showed reddish-brown crystals and casts in the urinary sediment, which may indicate its tubular interstitial damaging action. Consequently, use of the combined drugs is more preferable than HCT monotherapy, and HCT in combination with A is likely to be more preferable than that with T.

[Magnesium and long-term diuretic therapy]. / Magnesium og langvarig diuretikabehandling.

Thiazides and loop diuretics, facilitate the loss of Mg and K resulting in increased excretion in the urine. Although serum-K and serum-Mg values in patients receiving long-term treatment for hypertension or incompensated heart disease usually are normal, muscle-Mg and muscle-K contents are reduced in around 50% of these patients. Mg deficiency increases K loss and K/Mg deficiencies are frequently observed simultaneously. K repletion is often difficult if the accompanying Mg deficiency is not corrected simultaneously. The K/Mg loss from the muscles is accompanied by reduced concentration of Na,K-pumps. These disturbances may produce muscle symptoms, increased sensitivity to digitalis, inhibition of growth and possibly arrhythmias. Evaluation of the K and Mg status during diuretic treatment should be preferentially based on tissue determinations. The muscle biopsy method is rapid, reliable and may reveal conditions of deficiency. In several cases, oral supplements of Mg have proved to be adequate to restore the normal K/Mg status.

[Hypotensive and metabolic effects of small doses of hydrochlorothiazide in the long-term treatment of elderly patients with systolic arterial hypertension]. / Hipotensyjne i metaboliczne dzialanie malych dawek hydrochlorotiazydu stosowanego przewlekle u osób wieku podeszlym, chorych na nadcisnienie tetnicze skurczowe.

In a group of elderly patients with systolic hypertension the hypotensive efficacy and adverse effects were studied of hydrochlorothiazide given in daily doses of 25 mg in a year. A fall of systolic and diastolic arterial blood pressure was obtained in 86% of these patients. Adverse effects included reduced concentration of potassium and magnesium ions in the serum and lymphocytes, but this reduction was small and appeared mainly in the serum. The used doses of hydrochlorothiazide had no effect on plasma renin activity, and on the serum levels of aldosterone, glucose, uric acid, cholesterol and triglycerides.

Comparison of potassium alone and potassium-magnesium supplementation in patients with heart failure using hydrochlorothiazide.

Supplementation of potassium alone and in combination with magnesium was compared in 10 patients with chronic compensated heart failure receiving hydrochlorothiazide 50 mg twice daily for the whole trial. After a 3-week run-in period, the patients were randomized to receive active supplementation for 6 weeks in a double-blind cross-over manner. A 3-week wash-out period was kept in between. Addition of 2 g potassium chloride daily (27 mmol K+) did not efficiently correct the serum potassium concentration. After the combined supplementation of 2 g potassium and 1 g magnesium (27 mmol K+ and 17 mmol Mg2+ daily), both serum potassium and magnesium concentrations increased statistically significantly during the first 2 weeks of treatment. After a longer treatment of 6 weeks, the effect of combined supplementation was less clear, even though a trend toward a better maintenance of serum potassium was still evident.