A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule.
(33/496)
PURPOSE: Sodium phenylbutyrate (PB) demonstrates potent differentiating capacity in multiple hematopoietic and solid tumor cell lines. We conducted a Phase I and pharmacokinetic study of PB by continuous infusion to characterize the maximum tolerated dose, toxicities, pharmacokinetics, and antitumor effects in patients with refractory solid tumors. PATIENTS AND METHODS: Patients were treated with a 120-h PB infusion every 21 days. The dose was escalated from 150 to 515 mg/kg/day. Pharmacokinetics were performed during and after the first infusion period using a validated high-performance liquid chromatographic assay and single compartmental pharmacokinetic model for PB and its principal metabolite, phenylacetate. RESULTS: A total of 24 patients were enrolled on study, with hormone refractory prostate cancer being the predominant tumor type. All patients were evaluable for toxicity and response. A total of 89 cycles were administered. The dose-limiting toxicity (DLT) was neuro-cortical, exemplified by excessive somnolence and confusion and accompanied by clinically significant hypokalemia, hyponatremia, and hyperuricemia. One patient at 515 mg/kg/day and another at 345 mg/kg/day experienced this DLT. Toxicity resolved < or =12 h of discontinuing the infusion. Other toxicities were mild, including fatigue and nausea. The maximum tolerated dose was 410 mg/kg/day for 5 days. Pharmacokinetics demonstrated that plasma clearance of PB increased in a continuous fashion beginning 24 h into the infusion. In individuals whose V(max) for drug elimination was less than their drug-dosing rate, the active metabolite phenylacetate accumulated progressively. Plasma PB concentrations (at 410 mg/kg/day) remained above the targeted therapeutic threshold of 500 micromol/liter required for in vitro activity. CONCLUSION: The DLT in this Phase I study for infusional PB given for 5 days every 21 days is neuro-cortical in nature. The recommended Phase II dose is 410 mg/kg/day for 120 h. (+info)
Toluene induced hypokalaemia: case report and literature review.
(34/496)
Generalised weakness is a common complaint. A case is presented of toluene induced hypokalaemia in a 22 year old woman who presented with generalised weakness. The effect of toluene and causes of weakness and hypokalaemia in this setting are discussed. (+info)
Hypokalaemia and hyperkalaemia.
(35/496)
Disturbances in potassium homoeostasis presenting as low or high serum potassium are common, especially among hospitalised patients. Given the fact that untreated hypokalaemia or hyperkalaemia is associated with high morbidity and mortality, it is critical to recognise and treat these disorders promptly. In this article, normal potassium homoeostasis is reviewed initially and then a pathophysiological approach to work-up and management of hypokalaemia and hyperkalaemia is presented. Recent advances with respect to the role of kidney in handling of the potassium, the regulation of renal ion transporters in hypokalaemia, and treatment of hypokalaemia and hyperkalaemia will be discussed. (+info)
In rat inner medullary collecting duct, NH uptake by the Na,K-ATPase is increased during hypokalemia.
(36/496)
In rat terminal inner medullary collecting duct (tIMCD), the Na,K-ATPase mediates NH uptake, which increases secretion of net H(+) equivalents. K(+) and NH compete for a common binding site on the Na,K-ATPase. Therefore, NH uptake should increase during hypokalemia because interstitial K(+) concentration is reduced. We asked whether upregulation of the Na,K-ATPase during hypokalemia also increases basolateral NH uptake. To induce hypokalemia, rats ate a diet with a low K(+) content. In tIMCD tubules from rats given 3 days of dietary K(+) restriction, Na,K-ATPase beta(1)-subunit (NK-beta(1)) protein expression increased although NK-alpha(1) protein expression and Na,K-ATPase activity were unchanged relative to K(+)-replete controls. However, after 7 days of K(+) restriction, both NK-alpha(1) and NK-beta(1) subunit protein expression and Na,K-ATPase activity increased. The magnitude of Na,K-ATPase-mediated NH uptake across the basolateral membrane (J) was determined in tIMCD tubules perfused in vitro from rats after 3 days of a normal or a K(+)-restricted diet. J was the same in tubules from rats on either diet when measured at the same extracellular K(+) concentration. However, in either treatment group, increasing K(+) concentration from 10 to 30 mM reduced J >60%. In conclusion, with 3 days of K(+) restriction, NH uptake by Na,K-ATPase is increased in the tIMCD primarily from the reduced interstitial K(+) concentration. (+info)
Correlation between decrease of 11beta-hydroxysteroid dehydrogenase activity and hypokalemia induced by furosemide in rats.
(37/496)
AIM: To investigate the correlation between decrease of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity and hypokalemia induced by furosemide (Fur) in rats. METHODS: SD rats were given single dose or successive doses of Fur by gavage. The activity of 11beta-HSD was evaluated by measuring the ratio of 11-dehydrocorticosterone (A) and corticosterone (B) in urine and conversion rate of B to A in renal cortex microsome preparation was determined with HPLC. RESULTS: After giving single dose of Fur (40, 100, and 250 mg/kg) or multiple doses of Fur (10, 20, and 100 mg/kg, bid x 20 d), the ratio of A/B was reduced by 29.0 %, 58.6 %, and 60.9 % at 0 - 2 h; 14.4 %, 36.0 %, and 44.9 %, respectively; the conversion rate of B to A was decreased by 29 %, 33 %, and 37 %; 6 %, 17 %, and 23 %, respectively. The serum potassium was significantly reduced by multiple doses of Fur (20 and 100 mg/kg, bid x 20 d) (P < 0.01). The reduction in serum potassium was positively correlated with the lowering of A/B ratio and the conversion of B to A (P < 0.01). CONCLUSION: The inhibition of renal 11beta-HSD activity may be another new biochemical mechanism for hypokalemia induced by Fur. (+info)
Recognising signs of danger: ECG changes resulting from an abnormal serum potassium concentration.
(38/496)
A number of metabolic insults can result in changes to the serum potassium concentration. Potassium is predominantly an intracellular cation, and it has an important role in determining the resting membrane potential of cells. Disruption of the potassium gradient across the cell membrane can result in impaired cellular functioning. This may affect a number of organs including the cardiovascular and central nervous systems, resulting in various neurological symptoms and cardiac arrhythmias. Though laboratory tests are the gold standard test for diagnosing changes in the serum electrolyte concentration, there may be delays in obtaining the results. The electrocardiogram (ECG) may be a useful diagnostic tool, if the clinician is aware of the possible changes resulting from abnormalities in the serum potassium concentration. This article presents three cases that highlight the ECG changes resulting from an abnormal serum potassium concentration and will briefly look at the treatment options to reduce the risk of life threatening arrhythmias occurring. (+info)
Transient global amnesia associated with cardiac arrhythmia and digitalis intoxication.
(39/496)
A 54-year-old woman with transient global amnesia (TGA) was found to have digitalis-induced bradyarrhythmia with atrioventricular dissociation. The amnesia cleared only upon resolution of the arrhythmia. Cardiac arrhythmia has been postulated as a cause, but TGA in the setting of cardiac arrhythmia has not been documented previously. Cardiac arrhythmia should be excluded in patients with TGA, and TGA, a syndrome diagnosed on clinical grounds alone, must be recognized as one possible manifestation of treatable, potentially serious cardiac or cerebrovascular disease. (+info)
Normokalemic hyperaldosteronism in patients with resistant hypertension.
(40/496)
BACKGROUND: Primary aldosteronism is a common cause of non-renal secondary hypertension. A correct diagnosis results in curing the hypertension or targeting appropriate pharmacotherapy. In patients with low renin resistant hypertension (after treatment with three or more different anti-hypertensive drugs the blood pressure remains above 140/90 mmHg), screening for aldosteronism is mandatory. OBJECTIVES: To demonstrate that normal blood levels of potassium in resistant hypertensive patients do not exclude the possible presence of hyperaldosteronism, and to suggest the use of the plasma aldosterone concentration (ng/dl)/plasma renin activity (ng/ml/hour) ratio in screening for hyperaldosteronism. METHODS: Blood tests, suppression and stimulation tests (2 L normal saline i.v./4 hours and 20 mg furosemide i.v. for 60 minutes in a standing position) were systematically performed in 20 low renin normokalemic resistant hypertensive patients. None had renal disorders, known endocrine abnormalities or heart failure. They did not receive anti-hypertensive drugs affecting PAC or PRA. Basal PRA and PAC were measured twice: PAC after saline infusion and PAC/PRA after stimulation. RESULTS: PAC/PRA above 50 was used to denote hyperaldosteronism. Serum K was 4 +/- 0.07 mM/L, PAC 22.8 +/- 1.8 ng/dl, PRA 0.13 +/- 0.02 ng/ml/hour, PAC/PRA 190 +/- 22 (above 100 in 17). After suppression PAC decreased from 25 +/- 1.8 to 11 +/- 1 ng/dl (normal < 5 ng/dl). Stimulation did not affect PRA and PAC/PRA. Abdominal computed tomography scan revealed normal adrenal glands in 15 patients. Spironolactone (116 +/- 60 mg/day) normalized blood pressure in all patients; it was used as a single therapy in 8, and in association with only one anti-hypertensive drug in the remaining 12 patients. In one patient the treatment was discontinued due to the presence of hyperkalemia. CONCLUSIONS: Low renin resistant hypertension associated with normokalemia may be due to hyperaldosteronism. Normal aldosterone levels in the basal condition do not exclude the possibility of hyperaldosteronism. Using a PAC/PRA ratio above 50 as a screening test can aid the physician in deciding when to perform dynamic tests, thus increasing the sensitivity of the diagnosis of hyperaldosteronism. CT scan is frequently normal. Targeted pharmacotherapy leads to a normalization of blood values. (+info)