Treatment of hypertension complicated with hyperuricemia / 中国临床药理学与治疗学

Hypertension and hyperuricemia often coexist, and have a high incidence and often incur great harm. The current guidelines recommend active control of uric acid and blood pressure levels. But patients with high uric acid and high blood pressure still need detailed guidelines to standardize the treatment to avoid incurring more drug-related side effects. This article reviews the epidemiology and clinical harm, the therapeutic target value, the consensus and controversy on therapeutic treatment of high blood pressure combined with high uric acid.

A hipopotassemia como efeito adverso dos diuréticos tiazídicos / Hypopotasemia as an adverse effect of thizide diuretics

O potássio tem função fisiológica fundamental no volume intracelular e na manutenção funcional de nervos e músculos. Distúrbios do potássio são comuns e estão associados a aumento na mortalidade nos portadores de doenças cardiovasculares, entre elas a hipertensão arterial. Assim a manutenção de um equilíbrio entre o potássio intra e extracelular é de fundamental importância para nervos, músculos e o sistema cardiovascular. Há décadas os diuréticos tiazídicos são uma das principais drogas utilizadas no tratamento da hipertensão arterial. Entre suas principais reações adversas relacionam-se os distúrbios eletrolíticos e metabólicos, os quais se tornaram menos frequentes com o uso de doses menores do que as habitualmente empregadas no seu início. Neste artigo os principais efeitos adversos do uso crônico dos diuréticos tiazídicos bem como suas consequências serão discutidos.

Potassium has a fundamental physiological function without intracellular volume and in the functional maintenance of nerves and muscles. Potassium disorders are common and are associated with increased mortality in patients with cardiovascular diseases, including hypertension. Thus, maintaining a balance between intracellular and extracellular potassium is of fundamental importance for the nerves, muscles and cardiovascular system. Thiazide diuretics have been one of the main drugs used in the treatment of hypertension for decades. Among its main adverse reactions are related electrolyte and metabolic disturbances, which become less frequent with the use of lower doses than those usually used at the beginning. In this article, the main adverse effects of the chronic use of thiazide diuretics as well as their consequences will be discussed.

A case of Gitelman syndrome: our experience with a patient treated in clinical practice on a local island / Journal of Rural Medicine

Background: Gitelman syndrome (GS) is an autosomal recessive salt-losing renal tubulopathy resulting from mutations in the thiazide-sensitive Na-Cl cotransporter (NCC) gene. Notably, lack of awareness regarding GS and difficulty with prompt diagnosis are observed in clinical practice, particularly in rural settings.Case presentation: We report a case of a 48-year-old man with GS who presented to a local clinic on a remote island. Occasional laboratory investigations incidentally revealed a reduced serum potassium level of 2.6 mmol/L. A careful medical interview revealed episodes of intermittent paralysis of the lower extremities and muscular weakness for >30 years. Subsequent laboratory investigations revealed hypomagnesemia, hypocalciuria, and hypokalemic metabolic alkalosis. Based on the patient’s history, clinical presentation, and laboratory investigations, we suspected GS. Genetic testing revealed a rare homozygous in-frame 18 base insertion in the NCC gene that might have resulted from the founder effect, consequent to his topographically isolated circumstances.Conclusion: More case studies similar to our study need to be added to the literature to gain a deeper understanding of the functional consequences of this mutation and to establish optimal management strategies for this condition, particularly in rural clinical settings.

3D-QSAR of Thiazide 11β-Hydroxyl Steroid Dehydrogenase Inhibitors / 中国药师

Objective:To establish a three-dimensional quantitative structure-activity relationship (3D-QSAR) model for thiazide 11β-hydroxy steroid dehydrogenase ( HSD) inhibitors in order to perform structure modification and find thiazide 11β-HSD inhibitors with more activity. Methods: The 3D-QSAR model of thiazine derivatives was constructed by the method of comparative molecular force field analysis, and the model was validated by using a molecular docking method. Results:An accurate 3D-QSAR model of 11β-HSD inhibitors was obtained (CoMFA:q2 =0. 346, r2 =0. 850, where q2 was the cross-validation coefficient and r2 was the non-cross validation coefficient) . Conclusion:The results provide important theoretical basis for the rational design of novel thiazide 11β-HSD inhibitors.

Hydrochlorothiazide does not increase furosemide's effects in end-stage renal disease

Diuretic therapy for the treatment of edema in patients with end-stage renal disease (ESRD) is unsatisfactory, and a combination of thiazide and loop diuretics may produce better clinical effects. To evaluate the influence of thiazide on loop diuretic therapy for ESRD, we performed a crossover study of furosemide versus hydrochlorothiazide plus furosemide treatment. The diuretic effects of furosemide (160 mg i.v.) alone versus a combination of hydrochlorothiazide (100 mg p.o.) and furosemide were studied in ten ESRD patients with proteinuria greater than 1 g/day. The diuretic effects were compared for 24 h urine volume and electrolyte excretion. To detect the influence of thiazide that may have been obscured in the widely dispersed data, pharmacodynamic analysis of urine furosemide excretion rate versus fractional excretion of sodium (FeNa) was also performed using mixed-effect modeling. Combination therapy was not significantly different from furosemide monotherapy in terms of 24 h urine volume, chloride, or sodium excretion. Hydrochlorothiazide was not a significant covariate in the furosemide effect for the pharmacodynamic model. In patients with ESRD and severe proteinuria (>1,000 mg/day), the combination of hydrochlorothiazide with furosemide therapy did not increase the diuretic effect of furosemide.

El metabolismo de la glucosa en pacientes con hipertensión arterial / Glucose metabolism in hypertension patients

Thiazide diuretics (TD) are recommended as first-line therapy in uncomplicated hypertension by several professional organizations. However, they also may pose a risk of glucose metabolism abnormalities in certain individuals. Early studies showed TD cause a small increase in fasting glucose. These effects may be related to exacerbation of insulin resistance as insulin blood levels increased. It could be postulated that long-term use may result in a higher risk of developing diabetes. This was not seen in the Systolic Hypertension in the Elderly study which used low doses of chlorthalidone but an increase in the odds of developing diabetes was demonstrated for chlorthalidone in comparison to lisinopril or amlodipine in the ALLHAT study. Nonetheless, in ALLHAT there was no increased risk of adverse cardiovascular outcomes. In addition, use of chlorthalidone in the ALLHAT study in patients with pre-existing diabetes maintained the same advantage in lower stroke rate versus lisinopril and lower heart failure rate versus amlodipine or lisinopril. Other factors that may play a role in thiazide-induced glucose elevation are potassium levels and weight. In a meta-analysis of 59 trials a correlation existed for lower potassium levels and higher fasting glucose. pidemiological studies suggest that elevated BMI and the level of pre-thiazide fasting glucose predict glucose elevation and new onset diabetes after thiazide therapy. Patients with a BMI over 32.3 kg/m2 had a 6.5% risk of developing diabetes. Whether co-administration of a thiazide diuretic with other classes of antihypertensives modulates the glucose alteration remains unknown. Studies suggest combination with valsartan may reduce the effect perhaps by conserving potassium. Practical implications of these observations would suggest reserving thiazide diuretics to later stages in treatment for patients who are obese, particularly if they have fasting blood glucoses in the pre-diabetic range. However, for the majority of patients thiazide diuretics remain an excellent choice given their long track record of safety and beneficial long-term cardiovascular outcomes

Los diuréticos tiazídicos (DT) se recomiendan como tratamiento de primera línea para la hipertensión no complicada, por varias organizaciones profesionales. Sin embargo, también pueden suponer un riesgo de alteraciones del metabolismo de la glucosa en ciertos individuos. Los primeros estudios mostraron que los DT causan un pequeño aumento de la glucemia en ayunas. Estos efectos pueden estar relacionados con la exacerbación de la resistencia a la insulina y los niveles de insulina plasmáticos están incrementados. Se podría postular que el uso a largo plazo puede resultar en un mayor riesgo de presentar diabetes. Esto no se observó en el estudio Systolic Hypertension in the Elderly, realizado con adultos mayores que utilizaban bajas dosis de clortalidona; sin embargo, un aumento en las probabilidades de contraer diabetes fue demostrado por el uso de clortalidona en comparación con lisinopril y amlodipina en el estudio ALLHAT. No obstante, en el ALLHAT no hubo mayor riesgo de eventos cardiovasculares adversos. Además, el uso de clortalidona en el estudio ALLHAT en pacientes con diabetes preexistente mantuvo la misma ventaja en la baja tasa de accidentes cerebrovasculares, en comparación con lisinopril, y la menor tasa de paro cardíaco, en comparación con amlodipina o lisinopril. Otros factores que pueden desempeñar un papel en la elevación de la glucosa inducida por tiazidas son los niveles de potasio y el peso del paciente. En un metanálisis de 59 ensayos se encontró una correlación entre los niveles de potasio más bajos y los niveles más elevados de glucemia en ayunas. Los estudios epidemiológicos sugieren que el índice de masa corporal (IMC) elevado y el nivel de la glucemia previo al tratamiento con tiazidas pueden predecir la elevación de la glucosa y la diabetes de nueva aparición después de la terapia con tiazidas. Los pacientes con un IMC superior a 32.3 kg/m2 tenían un riesgo de 6.5% de presentar diabetes. Se desconoce aún si la administración de un diurético tiazídico con otras clases de antihipertensivos modula la alteración de la glucosa. Los estudios sugieren que la combinación con valsartán puede reducir el efecto, quizá mediante la conservación del potasio. Las repercusiones prácticas de estas observaciones sugieren reservar los diuréticos tiazídicos para etapas posteriores del tratamiento para los pacientes que son obesos, sobre todo si han presentado glucemia en ayunas en el rango de prediabetes. Sin embargo, para la mayoría de los pacientes, los diuréticos tiazídicos siguen siendo una excelente opción dado su largo historial de seguridad y los resultados cardiovasculares beneficiosos a largo plazo

Effect of Saccharum spontaneum Linn. on Lysosomal enzymes of Uro-lithiatic rats.

The ethanolic root extract of Saccharum spontaneum of family Poaceae was used to treatthe urolithiasis induced by glycolic acid On this course, the extract also repairs the changesthat happened in the lysosomal enzymes like β-D-glucuronidase, xanthine oxidase in liver and kidney and n-acetyl _-d-glucosaminidase in serum, liver, kidney and urine of the urolithiatic rats. The ethanolic root extract (200 and 300 / kg b.w.) elevated the levels of reduced β-D-glucuronidasein liver and n-acetyl _-d-glucosaminidase in liver and kidney and reduced the level of xanthineoxidase in liver and kidney and n-acetyl _-d-glucosaminidase in serum and urine significantly (p<0.05) when compared with the toxic groups. The results shown by the ethanolic root extract (200 and 300 mg / kg b.w.) was compared to standard thiazide drug treated group, showing no significantdifference (p<0.05) and thus it proves that the ethanolic root extract of S.spontaneum exhibits potent antiurolithiatic activity.

Gitelman Syndrome with Normal Serum Magnesium

Gitelman syndrome is an autosomal recessive renal tubular disorder characterized by hypokalemic metabolic alkalosis, and it is distinguished from Batter syndrome by hypomagnesemia and hypocalciuria. This disorder is caused by mutation in SLC12A3 gene which encodes thiazide-sensitive Na(+)-Cl(-)cotransporter (NCCT) which is expressed in the apical membrane of cells, lining distal convoluted tubule. A 8-year old boy who presented with Rolandic epilepsy, and horseshoe kidney accidentally showed clinical features of metabolic alkalosis, hypokalemia, hypocalciuria without hypomagnesemia. So we identified a heterozygote mutation and an abnormal splicing in the SLC12A3 gene, encoding NCCT. The mutation was detected in the exon 15 and 22 of SLC12A3 gene.

Inequalities in prescription of hydrochlorothiazide for diabetic hypertensive patients in Colombia / Desigualdades en la prescripción de hidroclorotiazida en pacientes hipertensos diabéticos en Colombia

Objective Evaluating differences in the suitable prescription of thiazides in hypertense patients, according to affiliation regime. Materials and methods This was an analytical cross-sectional study. The database from a previous study was used regarding two groups of hypertense patients (subsidised regime and contributory regime) who had attended out-patient consultation between 01-09-2007 and 29-02-2008. Ideal therapy was evaluated in both groups. Univariate and multivariate analysis was carried out. Results 136 patients (contributory: 41.9 percent; subsidised: 58.1 percent). Subsidised regime patients were older (mean=68.8±10) than those from the contributory regime (mean=64.1±11.1) (t-test, p=0.0110). Prescribing antihypertensive drugs was ideal in 49/136 of the patients (36.0 percent). Ideal prescription accounted for 24/79 (30 percent) of the patients in the subsidised regime and 25/57 (43.8 percent) in the contributory one (OR=1.79; 95 percent CI:0.88-3.64). Older people (aged ≥ 65yo) were at risk of receiving a non-ideal prescription (OR=2.12; 95 percentCI:1.02-4.38) whilst this was not so in the subsidised regime (OR=1.62; 95 percent CI:0.78-3.35). Conclusions Ideal prescription of antihypertensive drugs was low in the population being studied. There were differences regarding age ideal prescription but not concerning affiliation regime. It is suggested that a longitudinal study be carried out in the future.

Objetivo Evaluar las diferencias en la adecuada prescripción de tiazidas en pacientes hipertensos, según régimen de afiliación. Materiales y métodos Estudio de corte transversal analítico. Se utilizó la base de datos de un estudio previo, dos grupos de pacientes hipertensos: régimen subsidiado y régimen contributivo que asistieron a consulta externa entre el 01-09-2007 y el 29-02-2008. Se evaluó terapia ideal en los dos grupos. Se realizó análisis univariado y multivariado. Resultados Se estudiaron 136 pacientes (contributivo: 41,9 por ciento; subsidiado: 58,1 por ciento). Los pacientes del régimen subsidiado fueron mayores (promedio= 68,8±10) que los del contributivo (promedio=64,1±11.1) (t-test, p=0,0110). La prescripción de antihipertensivos fue ideal en 49/136 (36,0 por ciento). En el régimen subsidiado la prescripción fue ideal en 24/79 (30 por ciento) y en el contributivo en 25/57 (43,8 por ciento) (OR: 1,79 IC95 por ciento (0,88-3,64)). La edad ≥65años fue riesgo de prescripción no ideal (OR: 2.12, IC95 por ciento(1,02-4,38)), mientras que no lo fue estar en el régimen subsidiado (OR=1,62, IC95 por ciento(0,78-3,35). Conclusiones La prescripción ideal de antihipertensivos es baja. Hay diferencias en la edad, en la prescripción ideal, mas no por régimen de afiliación. Se sugiere un estudio longitudinal en el futuro.

Direct Vascular Actions of Indapamide in Aorta from Renal Hypertensive Rats / 대한신장학회지

PURPOSE: Thiazide diuretics exert their hypotensive efficacy through a combined vasodilator and diuretic effect. The present study was conducted to assess the inhibitory effect of thiazide diuretic, hydrochlorothiazide, and the thiazide-like diuretics, indapamide and chlorthalidone on contractile responses to norepinephrine and arginine vasopressin in aortic rings from 2K1C renal hypertensive and sham-clipped normotensive rats. METHODS: 2K1C hypertension was made by clipping the left renal artery and age-matched control rats received a sham treatment. Changes in the tension of aortic ring preparations were measured isometrically. RESULTS: Indapamide inhibits the contractile responses to norepinephrine and vasopressin in aortic rings from 2K1C rats, while it did not modify in control rats. The inhibitory effect of indapamide was abolished by endothelium removal. Hydrochlorothiazide or chlorthalidone did not affect the vasoconstriction induced by norepinephrine and vasopressin either in sham or in 2K1C hypertensive rats. CONCLUSION: These results suggest that indapamide inhibits the contractile responses to norepinephrine and vasopressin via an endothelium-dependent mechanism in 2K1C renal hypertension.

Acquired Gitelman Syndrome

Acquired renal tubular disorder can be observed in various disease processes, especially autoimmune diseases. Gitelman syndrome is an autosomal recessive disease characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. This disorder is caused by mutation in the SLC12A3 gene, which encodes the thiazide - ensitive NaCl cotransporter (NCCT). Acquired Gitelman syndrome has been reported and the majority has been associated with Sjogren's syndrome. The presence of circulating auto - antibodies to NCCT was suggested as a mechanism of acquired Gitelman syndrome. Treatment of acquired Gitelman syndrome was done with supplements of potassium and magnesium and prednisone was effective in some cases. Acquired Gitelman syndrome should be included in the differential diagnosis of renal involvement in patients with autoimmune diseases, especially Sjogren's syndrome.

Altered Renal Sodium Transporter Expression in an Animal Model of Type 2 Diabetes Mellitus

Hemodynamic factors play an important role in the development and/or progression of diabetic nephropathy. We hypothesized that renal sodium transporter dysregulation might contribute to the hemodynamic alterations in diabetic nephropathy. Otsuka Long Evans Tokushima Fatty (OLETF) rats were used as an animal model for type 2 diabetes. Long Evans Tokushima (LETO) rats were used as controls. Renal sodium transporter regulation was investigated by semiquantitative immunoblotting and immunohistochemistry of the kidneys of 40-week-old animals. The mean serum glucose level in OLETF rats was increased to 235+/-25 mg/dL at 25 weeks, and the hyperglycemia continued up to the end of 40 weeks. Urine protein/ creatinine ratios were 10 times higher in OLETF rats than in LETO rats. At 40th week, the abundance of the epithelial sodium channel (ENaC) beta-subunit was increased in OLETF rats, but the abundance of the ENaC gamma-subunit was decreased. No significant differences were observed in the ENaC alpha-subunit or other major sodium transporters. Immunohistochemistry for the ENaC beta-subunit showed increased immunoreactivity in OLETF rats, whereas the ENaC gamma-subunit showed reduced immunoreactivity in these rats. In OLETF rats, ENaC beta-subunit upregulation and ENaC gamma-subunit downregulation after the development of diabetic nephropathy may reflect an abnormal sodium balance.

SIADH Caused by the Synergistic Effect of S-1 and Thiazide

Hyponatremia is a dangerous electrolyte disturbance in patients on chemotherapy and may cause sudden death if not detected early. SIADH (syndrome of inappropriate antidiuretic hormone) is one of the known causes of hyponatremia in patients undergoing chemotherapy. Few chemotherapeutic agents, however, are reported to cause SIADH. The current study reports that SIADH developed in a 55 year old woman on S-1 (80 mg/m2) and cisplatin (60 mg/m2) chemotherapy for the peritoneal metastasis of gastric cancer. The patient underwent a total gastrectomy, a splenectomy, and a segmental resection of the transverse colon for gastric cancer. She had used thiazide and betablocker to treat hypertension for 12 years. She admitted to our hospital with complaining of general weakness, dysarthria, loss of appetite, and urinary discomfort. The serum level of sodium and potassium were 94 mEq/L and 2.2 mEq/L respectively. The hyponatremia completely resolved uneventfully after 3% saline infusion, which led to normalized electrolyte balance. The patient was discharged on the 13th hospital day.

Cardiovascular Disease in the Elderly

No abstract available.

Relationship of the Change of RAAS Activity with Plasma Glucose after Long Term Therapy of Hydrochlorothiazide / 中国药房

OBJECTIVE:To investigate the relationship between the change of RAAS activity and plasma glucose after one year therapy of hydrochlorothiazide. METHODS:A total of 119 hypertensive patients were enrolled in this study. The activity of RAAS and plasma glucose level were measured at baseline. Patients were given 12.5 mg hydrochlorothiazide once a day for one year. Then the relationship between activity change of RAAS and the level of plasma glucose were analyzed. RESULTS:After one year treatment,the decrease of plasma glucose in PRA elevated group and PRA unelevated group were(-0.26?0.26)mmol?L-1 and(-1.36?0.23)mmol?L-1respectively,and there was statistical significance in difference(P

Two Cases of Allopurinol Hypersensitivity Syndrome in Patients Receiving Thiazide Therapy due to Hypertension / 대한피부과학회지

Allopurinol hypersensitiviy syndrome (AHS) is a rare immunologic response to allopurinol, characterized by multiple findings such as skin rash, fever, hepatic dysfunction, decreased renal function, leukocytosis and eosinophilia. The risk developing AHS tends to increase in patients receiving thiazide therapy or in those who have a pre-existing renal disease. We report two cases of AHS in patients who were taking thiazide medication due to hypertension and underlying renal disease. They developed an erythematous skin rash, fever, renal dysfunction, and eosinophilia after allopurionol therapy.

A Case of Gitelman Syndrome Presented with Epileptic Seizure

Both Gitelman syndrome and Bartter syndrome are autosomal recessively inherited renal tubular disorders characterized by hypokalemic metabolic alkalosis, salt wasting and normal to low blood pressure. Gitelman syndrome is caused by mutations in the thiazide-sensitive Na- Cl cotransporter (NCCT) and distinguished from Bartter syndrome, which is associated with mutations of several genes, by the presence of hypomagnesemia and hypocalciuria. In most of the patients with Gitelman syndrome, the disease manifests with transient episodes of muscular weakness and tetany in the adult period, but, often, is asymptomatic. We report here an 11 years-old female with Gitelman syndrome who presented with aggravation of epileptic seizure. The diagnostic work-up showed typical clinical features of metabolic alkalosis, hypokalemia, hypomagnesemia and hypocalciuria. We also identified a heterozygote mutation(642CGC(Arg)>TGC(Cys)) and an abnormal splicing in the SLC12A3 gene encoding NCCT.

Altered expression of sodium transporters in the excretory duct-ligated submandibular gland in rat

Effects of Oral Administration of Citrate, Thiazide, Allopurinol and Magnesium on Renal Calcium Oxalate Crystal Formation and Osteopontin Expression in a Rat Urolithiasis Model / 대한비뇨기과학회지

PURPOSE: It has previously been reported that citrate, thiazide, allopurinol and magnesium (CTAM) have inhibitory effects on calcium oxalate crystallization, but the effects of CTAM on the matrix proteins of stones in vivo has not been studied. Using an ethylene glycol-induced urolithiasis model, we investigated the effects of CTAM on renal crystallization and the expression of osteopontin (OPN), which is an important stone matrix protein. MATERIALS AND METHODS: Adult Sprague-Dawley rats (200-250gm) were divided randomly into 6 groups of 10 rats. Group 1 was left untreated, and served as a control. Group 2 (CID group) was fed 0.8% ethylene glycol and 1% ammonium chloride (crystal-inducing diet, CID) in drinking water for 4 weeks. Groups 3, 4, 5 and 6 (CTAM groups) were fed the same CID as group 2, but were also treated with either potassium citrate or hydrochlorothiazide or allopurinol or magnesium hydroxide, for 4 weeks, respectively. We biochemically analyzed the 24-hour urine and serum samples. The renal calcium content was measured by atomic absorption. The kidneys were histologically examined for crystal deposit with HandE staining, and for OPN expression with immunohistochemical staining. RESULTS: The grade of calcium oxalate crystal deposits, and renal calcium content, were significantly decreased in the CTAM groups compared to the CID group, which also correlated with the decreased expression of OPN proteins in the kidneys of the CTAM-treated rats. CTAM were all effective in preventing calcium oxalate crystal formation, and decreasing the expression of OPN in rat kidneys. CONCLUSIONS: Our results suggest that CTAM are effective in preventing calcium oxalate stone formation, and that OPN plays an important role in calcium oxalate nephrolithiasis.

Efficacy of combination of multiple drugs in the management of hypertension in elderly patients with type 2 diabetes mellitus / 中华老年医学杂志

Objective To work out a proper treatment regimen for hypertension in elderly patients with type 2 diabetes mellitus. Methods Sixty-five elderly patients 〔aged (68.3?4.4) yrs old〕 with hypertension and type 2 diabetes were randomized into three arms of antihypertensive treatment: arm A, n=20, treated with nifedipine in long-acting gastrointestinal-transport system (nifedipine-GITS) 60 mg/d; arm B, n=22, treated with nifedipine-GITS 30 mg/d and valsartan (angiotensin Ⅱ receptor blocker, ARB) 80mg/d; and arm C, n=23, treated with nifedipine-GITS 30mg/d, Valsartan 80mg/d and sustained-releasing indapamide (diuretics)1.5 mg/d. Results Eight weeks later, both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were decreased significantly in all of the patients ( P