Synthesis of 1,2,3,triazole modified analogues of hydrochlorothiazide via click chemistry approach and in-vitro α-glucosidase enzyme inhibition studies.

The current study was aimed to discover potent inhibitors of α-glucosidase enzyme. A 25 membered library of new 1,2,3-triazole derivatives of hydrochlorothiazide (1) (HCTZ, a diuretic drug also being used for the treatment of high blood pressure) was synthesized through click chemistry approach. The structures of all derivatives 2-26 were deduced by MS, IR, 1H-NMR, and 13C-NMR spectroscopic techniques. All the compounds were found to be new. Compounds 1-26 were evaluated for α-glucosidase enzyme inhibition activity. Among them, 18 compounds showed potent inhibitory activity against α-glucosidase with IC50 values between 24 and 379 µM. α-Glucosidase inhibitor drug acarbose (IC50 = 875.75 ± 2.08 µM) was used as the standard. Kinetics studies of compounds 6, 9, 11, 12, 15, 20, 23, and 24 revealed that only compound 15 as a mixed-type of inhibitor, while others were non-competitive inhibitors of α-glucosidase enzyme. All the compounds were found to be non-cytotoxic when checked against mouse fibroblast 3T3 cell line.

Diagnostic pitfalls of drug-induced immune hemolytic anemia.

Immune hemolytic anemia (IHA) is a rare complication of drug administration. However, its true incidence remains obscure, as there are a number of factors that may lead to misdiagnosis. The clinical and serologic pictures are variable, and there is a great deal of unawareness that certain drugs can cause IHA. Furthermore, serologic results can be easily misinterpreted, resulting in a wrong diagnosis.

[Chlorthalidone better than hydrochlorothiazide in hypertension]. / Bij hypertensie liever chloortalidon dan hydrochloorthiazide.

Thiazide diuretics have been the cornerstone in the pharmacological treatment of hypertension for more than 5 decades. Hydrochlorothiazide and chlorthalidone have been the 2 most commonly used diuretics in major clinical trials and are considered interchangeable. Nonetheless, hydrochlorothiazide has been much more widely prescribed than chlorthalidone, especially since nearly all available combinations with other antihypertensive drugs contain hydrochlorothiazide. However, whereas chlorthalidone at low doses has been shown repeatedly to reduce cardiovascular morbidity and mortality, such low doses of hydrochlorothiazide have never been shown to do this. Moreover, in direct comparison, chlorthalidone has a more sustained antihypertensive effect than hydrochlorothiazide, probably due to its very long half-life. These beneficial effects on blood pressure and cardiovascular events make chlorthalidone a tenable choice for the treatment of hypertension.

Amlodipine/valsartan/hydrochlorothiazide: fixed-dose combination in hypertension.

Amlodipine/valsartan/hydrochlorothiazide (HCTZ) is a fixed-dose combination of the well established antihypertensive agents amlodipine (a calcium channel antagonist), valsartan (an angiotensin II receptor antagonist), and HCTZ (a thiazide diuretic). In patients with moderate or severe hypertension, triple combination therapy with amlodipine + valsartan + HCTZ produced significantly greater reductions from baseline in mean sitting systolic and diastolic BP (msSBP and msDBP) than either valsartan + HCTZ, amlodipine + HCTZ, or amlodipine + valsartan in a large, 8-week, randomized, double-blind, multinational, phase III trial. Furthermore, the proportion of patients achieving overall BP control at endpoint was significantly greater with the triple combination regimen than with any of the dual regimens, with significantly more triple combination recipients achieving msSBP and msDBP control at each assessment throughout the trial. Subgroup analyses of this study suggested that amlodipine + valsartan + HCTZ was generally more effective in reducing BP and providing overall BP control than the dual combination therapies, irrespective of age, race, gender, ethnicity, or hypertension severity. Several smaller studies provide data that support the efficacy of amlodipine + valsartan + HCTZ in patients whose BP is inadequately controlled with amlodipine + valsartan, amlodipine + HCTZ, or valsartan + HCTZ dual combination therapy. Treatment with amlodipine + valsartan + HCTZ for up to 8 weeks was generally well tolerated in the large, phase III trial, with most adverse events being transient and of mild to moderate severity.

Successful control of intractable hypoglycemia using rapamycin in an 86-year-old man with a pancreatic insulin-secreting islet cell tumor and metastases.

CONTEXT: Insulinomas are rare tumors of the pancreatic islet cells that produce insulin. Approximately 5 to 10% of these tumors are cancerous, and control of insulin secretion and hypoglycemia may be difficult in these patients. Malignant insulinomas generally respond poorly to traditional chemotherapeutic agent regimens. At present, streptozotocin is the only approved drug for the treatment of pancreatic islet cell tumors. SETTING AND PATIENT: This report describes a case of an elderly gentleman with a metastatic pancreatic insulinoma and severe hypoglycemia. A continuous infusion of octreotide lowered the blood glucose levels further. He required diazoxide, a thiazide diuretic, phenytoin, and a constant infusion of glucose to control the hypoglycemia and elevated insulin levels. INTERVENTION: Rapamycin was administered at an oral dose of 2 mg/d. RESULTS: On the mTOR (mammalian target of rapamycin) agent rapamycin, he was weaned off all drugs except for the thiazide diuretic and maintained euglycemia with a reduction of circulating insulin levels. He remained euglycemic for the past year with no evidence of tumor progression based on Octreoscan. His quality of life is excellent, and he remains active having recently completed a triathlon. CONCLUSIONS: Rapamycin may provide a useful means of abrogating tumor growth and controlling hypoglycemia in malignant insulinomas by reducing the malignant beta-cell growth and proliferation as well as inhibiting insulin production.

Renal and vascular glutathione S-transferase mu is not affected by pharmacological intervention to reduce systolic blood pressure.

BACKGROUND: Our previous studies demonstrated reduced rat glutathione S-transferase mu type 1 (Gstm1) expression in stroke-prone spontaneously hypertensive rats (SHRSPs), when compared with the normotensive Wistar-Kyoto rat. METHODS: This study investigated the effects of angiotensin II type 1 receptor blocker (ARB) and a diuretic/vasodilator combination on the expression levels of rat Gstm1 and other Gstm isoforms. RESULTS: Antihypertensive treatments of young and mature SHRSPs with an ARB and a diuretic/vasodilator combination improved SBP but did not affect the expression levels of Gstm1. Although Gstm1 is a member of a family of highly homologous genes, with the exception of Gstm2, there was no evidence for compensatory increase in expression of other Gstm isoforms. In contrast, we observed reduced expression of several other Gstm isoforms in untreated SHRSPs. Untreated SHRSPs demonstrated increased renal and vascular oxidative stress, both of which were not significantly affected by the antihypertensive treatments. Untreated SHRSPs scored significantly higher when assessed for renal histopathological damage, and this was improved by antihypertensive treatments. CONCLUSION: These results suggest that reduced Gstm1 expression in SHRSPs is due to strain-dependent genetic abnormalities, playing a causative role in the development of hypertension, probably through oxidative stress pathway. Renal changes occur as a consequence of increased blood pressure and can be improved when treated with antihypertensive drugs. In silico comparative genome analysis combined with expression studies in rat and human vascular tissue revealed that there are possible four human homologues (GSTM1, GSTM2, GSTM4 and GSTM5) for rat Gstm1.

LC and LC-MS methods for the investigation of polypills for the treatment of cardiovascular diseases. Part 1. Separation of active components and classification of their interaction/degradation products.

"Polypill" is a fixed-dose combination (FDC) containing three or more drugs in a single pill. The same is under development for the treatment and prevention of cardiovascular diseases. In the present study, gradient LC methods were developed for simultaneous determination of the possible components of a polypill, i.e., lisinopril, aspirin and one each among atenolol/hydrochlorothiazide and atorvastatin/simvastatin/pravastatin, in the presence of a total of 13 major interaction/degradation products. The drugs and the products were well separated using a reversed-phase (C-8) column and a mobile phase comprising of acetonitrile: phosphate buffer (pH 2.3). Other HPLC parameters were flow rate, 1 ml/min; detection wavelength, 210 nm; column oven temperature, 60 degrees C; and injection volume, 5 microl. The methods were validated for linearity, precision, accuracy, and specificity. These were further modified to make them compatible for LC-MS studies by removal of the phosphate buffer and adjustment of pH by formic acid. The suitability of the methods for LC-MS studies was established by matching the theoretical mass values of the drugs with those obtained experimentally. These methods were used to determine mass values of the major interaction/degradation products, which helped to know the source of their origin.

A case of gain-of-function mutation in calcium-sensing receptor: supplemental hydration is required for renal protection.

AIMS: The calcium-sensing receptor (CaSR) regulates the extracellular calcium level, mainly by controlling parathyroid hormon secretion and renal calcium reabsorption. In gain-of-function CaSR mutations, the genetic abnormalities increase CaSR activity leading to the development of such clinical manifestations as hypercalciuric hypocalcemia and hypoparathyroidism. We report a Japanese case of CaSR gain-of-function mutation and represent a therapeutic intervention based on the functional characteristics of CaSR in renal tubule. METHODS AND RESULTS (CASE): DNA sequence analysis revealed a heterozygous G to T mutation identified in a 12-year-old Japanese girl presenting with sporadic onset of hypercalciuric hypocalcemia and hypoparathyroidism. The mutation is located in the N-terminal extracellular domain of the CaSR gene, one of the most important parts for the three-dimensional construction of the receptor, resulting in the substitution of phenylalanine for cysteine at amino acid 131 (C131F) in exon 3. Based on the diagnosis of the gain-of-function mutation in the CaSR, oral hydrochlorothiazide administration and supplemental hydration were started in addition to calcium supplementation. The combination therapy of thiazide and supplemental hydration markedly reduced both renal calcium excretion and urinary calcium concentration from 0.4-0.7 to less than 0.1 mg/mg (urinary calcium/creatinine ratio) and from 10-15 to 3-5 mg/dl (urinary calcium concentration), respectively. This therapy stopped the progression of renal calcification during the follow-up period. CONCLUSION: Supplemental hydration should be considered essential for the following reasons: (1) calcium supplementation activates the CaSR in the kidney and suppresses renal urinary concentrating ability, (2) the thiazide has a diuretic effect, (3) as calcium supplementation increases renal calcium excretion, the supplemental hydration decreases urinary calcium concentration by increasing urinary volume, thereby diminishing the risk of intratubular crystallization of calcium ion.

[Anxiodepressive and neuromediatory disorders in hypertensive patients. Effects of cypramil therapy].

AIM: To investigate psychic status and characteristics of neuromediatory metabolism in hypertensive patients, efficacy of antihypertensive therapy with lisinopril and hydrochlorthiaside with adjuvant citalopram (cipramil) which is a selective inhibitor of serotonin reuptake. MATERIAL AND METHODS: Fifty patients with hypertension stage II (37 females, 13 males, mean age 48 years, mean duration of the disease 10.6 years) have undergone psychometric examination, estimation of evoked potentials P-300, 24-h monitoring of blood pressure. Plasma levels of epinephrine and norepinephrine, plasma and platelet levels of serotonin and 5-OIAA were measured at high-performance liquid chromatography. RESULTS: Hypertensive patients were found to have high levels of depression, reactive and personality anxiety, subnormal quality of life. Blood pressure lowered more in patients given adjuvant cipramil. CONCLUSION: Hypertensive patients have anxiodepressive disorders accompanied by monoamines disbolism. Cipramil effectively corrects these disorders.

Phototoxicity to sulphonamide-derived oral antidiabetics and diuretics: investigations in hairless mice.

The oral antidiabetics glibenclamide, glipizide, glymidine, tolazamide and tolbutamide and the diuretics bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, furosemide, hydrochlorothiazide, hydroflumethiazide and trichlormethiazide were investigated for phototoxic effects in hairless mice. The back of the animals (hr/hr-c3H/TifBom) was covered with Duoderm dressing, and at the site of two punched out holes 0.05 ml of the test substances at 0.25 mol/l concentration and the solvent alone as control were injected intradermally, respectively. Both test and control sites were irradiated with 6-12 J/cm2 of longwave UVA light from a "Bluelight 2000" apparatus (Hönle, Martinsried, Germany). Skin reactions were read at 24 and 48 h. Compared to the solvent alone, all of the test substances induced reactions (necrosis or oedema)--most frequently seen by macroscopic and histologic investigation and by measurements with a thickness gage. Injection of the test substance or solvent alone without or with subsequent UVA irradiation, as well as UVA alone, did not induce measurable skin changes in this model. Three oral antidiabetics and four diuretics, not yet described to induce photosensitivity in vitro nor in vivo, were detected as potential photosensitizers using our animal model.

Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure.

It is commonly assumed that thiazide diuretics are ineffective in patients with advanced renal failure (GFR < 30 ml/min/1.73 m2). Thiazides act on the nephron segment distal to the ascending thick loop of Henle, that is, the site of action of loop diuretics. Blockade of sodium reabsorption in the thiazide-sensitive segment should therefore obliterate the compensatory increase in sodium reabsorption seen after administration of loop diuretics and thus potentiate the natriuretic efficacy of loop diuretics even in advanced renal failure. In a single-blind, randomized, placebo controlled crossover study we compared the natriuretic and chloruretic effect of the loop diuretic, torasemide, given alone or in combination with the thiazide diuretic, butizid, in 10 patients with advanced renal failure (mean CIn 13.1 +/- 5.9 ml/min/1.73 m2). For two weeks patients adhered to a diet containing a standardized amount of Na+ and K+. On the 6th and 13th study days, two sham infusions were given to patients in order to assess basal 24-hour urinary electrolyte excretion. On the 7th and 14th days they were randomly allocated to receive either 50 mg i.v. torasemide in combination with a sham infusion or torasemide in combination with 20 mg i.v. butizid. Administration of torasemide alone significantly (P < 0.01) increased mean cumulative 24-hour excretion of sodium (from 154 +/- 30 to 232 +/- 59 mmol/24 hr) and chloride (from 128 +/- 21 to 233 +/- 84 mmol/24 hr) as compared with baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

[Potassium canrenoate and the combination of potassium canrenoate-butizide in the therapy of light to moderate arterial hypertension]. / Il canrenoato di potassio e l'associazione canrenoato di potassio-butizide nella terapia dell'ipertensione arteriosa di grado lieve-moderato.

The aim of the study was to evaluate the antihypertensive effect of K-canrenoate, alone or in combination with butizide, in mild to moderate essential hypertensives. Fifteen patients (supine diastolic blood pressure ranging from 95 to 114 mmHg) received K-canrenoate 50mg/die (step 1). In patients with supine diastolic blood pressure greater than 90 mmHg therapeutic regimen was modified at two-week intervals according to the following design: K-canrenoate 100 mg/die (step 2), K-canrenoate 50 mg + butizide 5 mg/die (step 3), K-canrenoate 100 mg + butizide 10 mg/die (step 4). Blood pressure control was achieved in 2 patients treated with K-canrenoate alone (step 2) and in 8 patients on a combined regimen (step 3), and it was maintained throughout the whole trial period (12 weeks); step 4 did not achieve the goal of therapy in the remaining 5 subjects. A statistically significant increase in triglyceridemia (123.2 +/- 42.1 vs 158.3 +/- 62 mg/dl) and uricemia (4.6 +/- 0.9 vs 5 +/- 0.9 mg/dl) was observed at the end of the follow-up period. Serum potassium levels remained stable in all patients. Therefore, K-canrenoate in combination with butizide is an effective and well tolerated drug in the treatment of mild to moderate essential hypertension.

In vitro aldose reductase inhibitory activity of N-aryl-glycine derivatives and their thioisosters.

A series of N-arylglycine derivatives and their thioisosters (1-10) was synthesized and evaluated as in vitro aldose reductase inhibitors. Among these, (6-chloro-1,2,4-benzothiadiazine-1,1-dioxide-3-yl)-2-propanoic acid (5) shows an inhibitory activity (IC50:5.1 microM) comparable to Alrestatin.

[Effect of captopril therapy on sodium and water excretion in patients with liver cirrhosis and ascites]. / Effekte einer Captopriltherapie auf die Natrium- und Wasserausscheidung bei Patienten mit Leberzirrhose und Aszites.

UNLABELLED: Ascites in patients with cirrhosis of the liver frequently is refractory to diuretic treatment. It was postulated that vasoconstriction of the renal cortex, mediated by activation of the renin-angiotensin-aldosterone-system (RAAS), may be one course of the disturbed sodium- and water-excretion in these patients. We therefore investigated in 14 cirrhotic patients with ascites under constant diuretic treatment the effects of low-dose captopril therapy on urinary sodium- and potassium-excretion, body weight, abdominal girth, serum-sodium, -potassium, creatinine-clearance, plasma-renin-activity (PRA), plasma-aldosterone (PA) and mean arterial pressure (MAP). After a control period of 4 days the patients received 2 x 6.25 mg/d captopril for 5 days and 4 x 6.25 mg/d for further 5 days. Treatment was followed by a second control period without captopril. PRA increased significantly after 2 days of captopril treatment. 2 x 6.25 mg/d captopril induced a significant increase in sodium excretion and a significant decrease of body weight. MAP decreased slightly but significantly without clinical signs of hypotension. 4 x 6.25 mg/d captopril resulted in a further reduction of body weight and a further enhancement of sodium excretion. Three days after withdrawal of captopril sodium output was significantly reduced again. CONCLUSION: In cirrhotic patients low-dose captopril seems to be efficient in the treatment of ascites resistant to diuretics without causing major side effects.

Simultaneous quantitative determination of butizide, potassium canrenoate and canrenone in tablets by high-performance liquid chromatography.

A procedure for the simultaneous quantitative determination and selective identification of potassium canrenoate and butizide is proposed. The amount of canrenone, the degradation product of potassium canrenoate, is also determined. Elution of these compounds is investigated on LiChrosorb RP-18 and RP-8 columns. The analysis time was shorter on a RP-8 column while the specific identification was still possible. Therefore, the LiChrosorb RP-8 column was chosen. The eluent consisted of an acetonitrile--0.05 M phosphate buffer, pH 4 (45:55) mixture. Quantitative determination was performed at the absorption maximum of each compound: 286 nm for potassium canrenoate and for canrenone, 271 nm for butizide. This change in wavelength is performed automatically by the computer that controls the spectrophotometric diode array detector.

[Comparative study of 2 diuretic-containing combination preparations in patients with edematous heart failure]. / Vergleichende Untersuchung zweier diuretikahaltiger Kombinationspräparate bei Patienten mit hydropischer Herzinsuffizienz.

The efficacy and tolerability of two combinations, namely 50 mg spironolactone + 20 mg furosemide (SF) or 50 mg spironolactone + 5 mg butizide (SB), were compared in a randomised intraindividual trial in 22 patients with congestive heart failure. The parameters used were: weight, ankle- and calf-circumference, blood pressure, resting pulse, resting ECG, spirometry and blood chemistry. The physicians' judgement of the success of treatment was also recorded. Clinical symptoms improved clearly in both groups and in most cases there was significant improvement of the various parameters. The trend towards improvement was more apparent with SF. The physicians considered SF to be more effective in 12 cases compared to one case with SB. In all other cases both treatments were considered equally effective. The blood chemistry data showed relevant differences: serum-potassium levels were less scattered with SF and showed a - desirable - shift into the upper normal range. The number of patients with elevated serum-creatinin-levels increased during SB-treatment whereas the opposite was noted with SF. This could be due to furosemide's positive effects on renal functions.