Administration Of Hydrochlorothiazide Research Articles

Angiotensin II related glial cell activation and necroptosis of retinal ganglion cells after systemic hypotension in glaucoma

The purpose of this study was to design an animal model mimicking glaucoma with hemodynamic instability and to identify involvement of angiotensin II (AngII) and associated changes of the retina. Systemic hypotension was induced in Sprague–Dawley rats by oral hydrochlorothiazide administration. Rats were sacrificed at 4, 8, and 12-week time points. AngII and receptor levels were examined in the serum and retina. To examine the relationship between glia activation and associated RGC death, biochemical analysis of GFAP, Iba-1, and necroptosis associated factors such as TNFα, receptor-interacting protein (RIP) 1, 3, and inactive caspase 8 were explored. To investigate the difference in RGC death mechanism, JNK inhibitor or RIP3 inhibitor were given intraperitoneally to rats with ocular hypertension and systemic hypotension both to identify the pathway mainly involved. AngII and receptors were increased in the serum and retina of systemic hypotensive rat. At 4, 8, and 12 weeks after hypotension induction, glial activation was increased as indicated by GFAP and Iba-1 staining. TNFα, RIP3 were elevated. and downregulation of inactive caspase 8 was apparent in the retina of hypotensive rat. Electron microscopy revealed that necroptosis of RGC was gradually increased after systemic hypotension. Following intraperitoneal JNK inhibitor or RIP3 inhibitor administration, RGC loss was attenuated in systemic hypotensive rats but not in ocular hypertensive rats. In conclusion, AngII is involved in glial activation and associated RGC necroptosis following systemic hypotension. This pathway represents a novel and distinct cell death mechanism when compared to that involved in elevated intraocular pressure.

THE VARIETY OF GENETIC DEFECTS EXPLAINS THE PHENOTYPIC HETEROGENEITY AND THE MODE OF TRANSMISSION OF FAMILIAL HYPERKALEMIC HYPERTENSION

Abstract Objective: Familial Hyperkalemic Hypertension (FHHt) is a rare inherited form of arterial hypertension. Four genes are responsible for this disease, interacting together in the regulation of ion transport in the distal renal tubule. Whether the type of variants and mutated gene explains the large phenotypic heterogeneity and the different modes of transmission in FHHt has not been explored yet. We report herein the experience of a referral centre based on 151 molecularly proven FHHt cases (82 probands, 69 relatives). Design and method: Patients with persistent hyperkalemia without renal failure, associated with metabolic acidosis, were genetically explored by Sanger sequencing and by new generation sequencing (NGS)Identified variants were confirmed and classified according to the American College of medical Genetics. Clinical and biological data were analyzed based on “questionnaires” filled out by the prescribing physicians. Statistical analyzes were done using Kruskal-Wallis test and post hoc Dunn's multiple comparison tests using Prism V6. Results: We identified 16 families with 12 different CUL3 splice-site variants, 48 families with 37KLHL3 variants (13 in recessive form, 24 in dominant form), 4 families with 4 different WNK1 intron 1 deletions, 11 families with 6 variants in the WNK1 acidic motif and 4 families with 4 different variants in the WNK4 acidic and basic motifs (figure 1). De novo cases were mainly observed in the CUL3-related cases (9 out of 16), recessive cases were only observed in few KLHL3-related cases (13 out 48), whereas all others variants were transmitted in an autosomal dominant manner. The more severe and earlier cases were caused by KLHL3 homozygous variants and CUL3 heterozygous variants in this case associated with growth retardation. Patients with WNK1 acidic motif variants had a typical biological phenotype without hypertension conversely to WNK4 mutations affecting the same motif. Molecular familial screening of relatives allowed us to detect 69 positive cases. Whatever the causing gene, administration of hydrochlorothiazide was effective. Conclusions: This study reinforces the interest of a genetic screening in case of suspicion of FHHt to better orientate the medical care of the patient and his family

Relação do uso prolongado de hidroclorotiazida com o melanoma: uma revisão de literatura

Estudos recentes apontam forte relação entre o uso da hidrocloratiazida (droga diurética e anti-hipertensiva) com o risco de desenvolver melanoma devido a sua característica fotossensibilizadora sobre a pele. O objetivo desse trabalho é evidenciar a associação entre o uso de hidrocloratiazida e o aumento do risco de aparecimento do melanoma. A metodologia foi um levantamento bibliográfico com artigos publicados no período de 2016 a 2019 nas bases de dados eletrônicos de confiabilidade científica PubMed, Medline, Science Direct e revistas especializados no assunto. Foram encontrados 4 estudos pertinentes sobre o tema, onde identificou-se que a hidroclorotiazida é classificada como um medicamento carcinogênico pela Agência Internacional de Pesquisa sobre o Câncer. À medida que a exposição à luz ultravioleta aumenta os danos das células da pele, a administração concomitante a longo prazo da hidroclorotiazida conduz a um aumento da probabilidade de malignidade cutânea, incluindo o desenvolvimento de melanoma. A população total do estudo foi de 19.273 casos e 192.730 controles; entre esses, 413 casos (2,1%) e 3.406 controles (1,8%) foram classificados como usuários de altas doses cumulativas de hidroclorotiazida (≥ 50.000 mg), resultando em odds ratio (OR) ajustado de 1,22 para melanoma. Portanto, sugere-se que o uso de hidroclorotiazida está associado ao aparecimento de melanoma. Mais estudos de grandes proporções, principalmente nacionais, são necessários para confirmar os achados. Portanto, a indicação de que o uso de hidroclorotiazida aumenta o risco de melanoma pode ter relevância clínica relacionada à escolha medicamentosa, particularmente para pacientes com fatores de risco para melanoma.

Діуретична активність похідного метилксантину фуроксану за одноразового та тривалого застосування на функцію видільної системи щурів на тлі спонтанного діурезу

The study of the effect of furoxane on renal activity under conditions of spontaneous diuresis was performed by the method of Berkhin. Hydrochlorothiazide was chosen as a reference drug. Furoxane and hydrochlorothiazide were administered intragastrically at a dose of 25 mg/kg for 7 days. The content of Na+ and K+in the urine was determined by flame photometry. The concentration of creatinine in the urine was studied by the method of Folin in the modification of Berkhin. The obtained results were calculated using the methods of variation statistics. The analysis of the results shows that under one-time action of furoxane in rats the daily urination increased by 210.4 % (p <0.001), the concentration of Na+ in the urine of rats increased by 51.9 % (p <0.05), and the concentration of K+ in the urine tended to increase by 5.6 %. Natriuresis increased 1.7 times (p <0.05), potassium - 1.23 times (p <0.05). Excretion of endogenous creatinine increased 1.49 times (p <0.05), indicating an improvement in glomerular ultrafiltration. After administration of hydrochlorothiazide there was an increase in diuresis by 92.2 % (p <0.05), urinary Na+ concentration increased by 49% (p <0.05) and increased Na+excretion from urine by 23.3 % (p <0.05). K+ concentration in urine increased by 12.6 %, and K+excretion - by 27.5 % (p <0.05). Thus, a single administration of furoxane at a dose of 25 mg/kg led to an increase in daily diuresis, Na+ and K+ diuresis, which indicates the potential diuretic and saluretic properties of the drug. Long-term (7 days) furoxane administration contributed to the increase of urination in animals. After 3 days diuresis increased by 226,1 % (p <0.001), on 7th day – by 236,3 % (p <0.001). Salures was increased: the excretion of Na+ after 3 days increased by 2.27 times (p <0,05), after 7 days - by 2,38 times (p <0,05), K+ - 1.83 times (p <0.05). The gradual increase in creatinine excretion in the dynamics of the use of furoxane, indicated a possible prolongation of the effect of furoxane. Thus, furoxane, which by its chemical structure belongs to methylxanthine derivatives is a promising pharmacologically active substance for further study of its specific activity and safety in order to create a highly effective diuretic and implementation in clinical practice.

Hydrochlorothiazide ameliorates polyuria caused by tolvaptan treatment of polycystic kidney disease in PCK rats

Tolvaptan is an effective treatment for polycystic kidney disease (PKD), but also causes unfortunate polyuria. Hydrochlorothiazide (HCTZ) has been shown to reduce urine volume in nephrogenic diabetes insipidus, raising the possibility that HCTZ could also be effective in reducing tolvaptan-induced polyuria. In this study, we examined the combined administration of HCTZ and tolvaptan. Male PCK rats were divided into four groups of normal chow (Cont), normal chow plus tolvaptan, gavage HCTZ treatment, and tolvaptan + HCTZ. Biochemical examinations of the plasma and urine were performed as well as histological and molecular (mRNA and protein expression) analyses. Groups treated with tolvaptan had significantly higher 24h urine excretion, which was significantly reduced in the tolvaptan + HCTZ group after 2weeks. Cyst size, pERK protein expression, and Cyclin D1 mRNA expression were all significantly reduced in both the tolvaptan and tolvaptan + HCTZ groups, indicating that HCTZ did not affect the beneficial functions of tolvaptan. Notably, aquaporin 2 redistribution from the apical to intracellular domains was observed in tolvaptan-treated rats and was partially reversed in the tolvaptan + HCTZ group. The renal glomerular filtration rate was reduced in the tolvaptan + HCTZ group. Significantly lowered mRNA expression of neuronal nitric oxide synthase, prostaglandin E synthase 2 and renin were also found in the medulla, but not in the cortex. HCTZ reduces tolvaptan-induced polyuria without altering its beneficial effects on PKD. This novel therapeutic combination could potentially lead to better PKD treatments and improved quality of life for the affected patients.

Renal sodium and magnesium reabsorption are not coupled in a mouse model of Gordon syndrome.

Active reabsorption of magnesium (Mg2+) in the distal convoluted tubule (DCT) of the kidney is crucial for maintaining Mg2+ homeostasis. Impaired activity of the Na+‐Cl−‐cotransporter (NCC) has been associated with hypermagnesiuria and hypomagnesemia, while increased activity of NCC, as observed in patients with Gordon syndrome, is not associated with alterations in Mg2+ balance. To further elucidate the possible interrelationship between NCC activity and renal Mg2+ handling, plasma Mg2+ levels and urinary excretion of sodium (Na+) and Mg2+ were measured in a mouse model of Gordon syndrome. In this model, DCT1‐specific expression of a constitutively active mutant form of the NCC‐phosphorylating kinase, SPAK (CA‐SPAK), increases NCC activity and hydrochlorothiazide (HCTZ)‐sensitive Na+ reabsorption. These mice were normomagnesemic and HCTZ administration comparably reduced plasma Mg2+ levels in CA‐SPAK mice and control littermates. As inferred by the initial response to HCTZ, CA‐SPAK mice exhibited greater NCC‐dependent Na+ reabsorption together with decreased Mg2+ reabsorption, compared to controls. Following prolonged HCTZ administration (4 days), CA‐SPAK mice exhibited higher urinary Mg2+ excretion, while urinary Na+ excretion decreased to levels observed in control animals. Surprisingly, CA‐SPAK mice had unaltered renal expression of Trpm6, encoding the Mg2+‐permeable channel TRPM6, or other magnesiotropic genes. In conclusion, CA‐SPAK mice exhibit normomagnesemia, despite increased NCC activity and Na+ reabsorption. Thus, Mg2+ reabsorption is not coupled to increased thiazide‐sensitive Na+ reabsorption, suggesting a similar process explains normomagnesemia in Gordon syndrome. Further research is required to unravel the molecular underpinnings of this phenomenon and the more pronounced Mg2+ excretion after prolonged HCTZ administration.

Edema pulmonar agudo no cardiogénico secundario a hidroclorotiazida. Reporte de un caso y revisión de la literatura

Thiazides are drugs often used in management of high arterial blood pressure. Shock and acute pulmonary edema are rarely described as adverse reactions related to this drug. We report the case of a 55 years-old woman admitted at Hospital de Puerto Montt, Chile. Two hours after having her first dose of hydrochlorothiazide she presented dyspnea. Laboratory tests and images support the diagnosis of non-cardiogenic pulmonary edema. Resolution of her clinical picture was observed 48 hours after hydrochlorothiazide administration was discontinued and hemodynamic and non invasive ventilation support were supplied. The patient was discharged without symptoms, 3 days after entering to hospital.

Trial of Amiloride in Type 2 Diabetes With Proteinuria

IntroductionRenal sodium (Na+) retention and extracellular fluid volume expansion are hallmarks of nephrotic syndrome, which occurs even in the absence of activation of hormones that stimulate renal Na+ transporters. Plasmin-dependent activation of the epithelial Na+ channel has been proposed to have a role in renal Na+ retention in the setting of nephrotic syndrome. We hypothesized that the epithelial Na+ channel inhibitor amiloride would be an effective therapeutic agent in inducing a natriuresis and lowering blood pressure in individuals with macroscopic proteinuria.MethodsWe conducted a pilot double-blind randomized cross-over study comparing the effects of daily administration of either oral amiloride or hydrochlorothiazide to patients with type 2 diabetes and macroscopic proteinuria. Safety and efficacy were assessed by monitoring systolic blood pressure, kidney function, adherence, weight, urinary Na+ excretion, and serum electrolytes. Nine subjects were enrolled in the trial.ResultsNo significant difference in systolic blood pressure or weight was seen between subjects receiving hydrochlorothiazide and those receiving amiloride (P ≥ 0.15). Amiloride induced differences in serum potassium (P < 0.001), with a 0.88 ± 0.30 mmol/l greater acute increase observed. Two subjects developed acute kidney injury and hyperkalemia when treated with amiloride. Four subjects had readily detectable levels of urinary plasminogen plus plasmin, and 5 did not. Changes in systolic blood pressure in response to amiloride did not differ between individuals with versus those without detectable urinary plasminogen plus plasmin.DiscussionIn summary, among patients with type 2 diabetes, normal renal function, and proteinuria, there were reductions in systolic blood pressure in groups treated with hydrochlorothiazide or amiloride. Acute kidney injury and severe hyperkalemia were safety concerns with amiloride.

Multiple Mechanisms are Involved in Salt-Sensitive Hypertension-Induced Renal Injury and Interstitial Fibrosis

Salt-sensitive hypertension (SSHT) leads to kidney interstitial fibrosis. However, the potential mechanisms leading to renal fibrosis have not been well investigated. In present study, Dahl salt-sensitive (DS) rats were divided into three groups: normal salt diet (DSN), high salt diet (DSH) and high salt diet treated with hydrochlorothiazide (HCTZ) (DSH + HCTZ). A significant increase in systolic blood pressure (SBP) was observed 3 weeks after initiating the high salt diet, and marked histological alterations were observed in DSH rats. DSH rats showed obvious podocyte injury, peritubular capillary (PTC) loss, macrophage infiltration, and changes in apoptosis and cell proliferation. Moreover, Wnt/β-catenin signaling was significantly activated in DSH rats. However, HCTZ administration attenuated these changes with decreased SBP. In addition, increased renal and urinary Wnt4 expression was detected with time in DSH rats and was closely correlated with histopathological alterations. Furthermore, these alterations were also confirmed by clinical study. In conclusion, the present study provides novel insight into the mechanisms related to PTC loss, macrophage infiltration and Wnt/β-catenin signaling in SSHT-induced renal injury and fibrosis. Therefore, multi-target therapeutic strategies may be the most effective in preventing these pathological processes. Moreover, urinary Wnt4 may be a noninvasive biomarker for monitoring renal injury after hypertension.

Alibertia edulis (L.C. Rich.) A.C. Rich – A potent diuretic arising from Brazilian indigenous species

Ethnopharmacological relevanceAlthough Alibertia edulis (L.C. Rich.) A.C. Rich decoction is used in Brazilian folk medicine due to its possible antihypertensive effect, this species has never been critically investigated as a hypotensive drug. So, the aim of this study was to evaluate the possible hypotensive and antihypertensive effects of the oral administration of Alibertia edulis aqueous extract (AEAE) in normotensive and hypertensive rats, and evaluate its inter-relation with a possible diuretic activity. Material and methodsDifferent doses of AEAE (20, 65 and 200mg/kg) were tested on the mean arterial pressure (MAP) of normotensive Wistar rats and after induction of renovascular hypertension (two-kidney, one-clip Goldblatt model). In addition, the diuretic effects of AEAE were compared with hydrochlorothiazide (HCTZ) in an acute and repeated-dose treatment for 7 days. Volume, sodium, potassium, chloride, calcium contents, pH and density were estimated in urine samples collected after 8 or 24h. Plasma sodium, potassium, total protein, urea, creatinine, AST and ALT concentrations were measured in samples collected at the end of the experimental period (seventh day). Finally, the antioxidant activity of the AEAE was assessed using the DPPH radical scavenging and ferric ions reducing power assay. ResultsThe intraduodenal administration of the HCTZ and AEAE significantly reduced, in a dose-dependent manner, the MAP in both normotensive and hypertensive rats. Otherwise, the heart rate was not affected by any treatment. Acute and prolonged oral administration of AEAE (200mg/kg) and HCTZ caused a significant increase in volume and urinary concentrations of sodium, potassium and chloride. Moreover, urinary calcium concentration was significantly increased after administration of AEAE (200mg/kg). Finally, AEAE was able to present important in vitro antioxidant properties. ConclusionThe results obtained have shown that AEAE presents potent diuretic activity and significant hypotensive and antihypertensive effect. In addition, this study may confirm part of the pharmacological activity popularly attributed to this species and opens perspective for the future use in various renal and cardiovascular diseases.

Abstract 119: Anti-hypertensive Effect of Thiazides Shifts From Salt Excretion to Vasorelaxation During Salt Restriction or Volume Depletion

Thiazide derivatives, including hydrochlorothiazide (HCTZ), are specific inhibitors of the Na+-Cl- Co-transporter (NCC) in the kidney distal tubules, and the most commonly used diuretic for the treatment of mild to moderate hypertension. Both renal (natriuretis) and extra renal (vasorelaxation) mechanisms have been proposed as major mediators of blood pressure reduction by HCTZ but the circumstances under which the renal or extra renal mechanism predominates remain unknown . To address these issues, systemic blood pressure was monitored by intra-arterial catheter and computerized tail cuff in transgenic mice lacking NCC under varying conditions. For comparison, mice with pendrin ablation or double deletion of pendrin and NCC were used to ascertain the compensatory role of pendrin in salt reabsorption in response to HCTZ. Pendrin KO mice were the only group which showed enhanced salt excretion in response to HCTZ, with salt excretion increasing by ~30% in pendrin KO vs. WT mice (p&lt;0.05). In mice lacking NCC, HCTZ significantly reduced the systemic blood pressure only during salt restriction and without enhancing salt excretion. In volume depleted but not in volume resuscitated NCC/pendrin dKO mice, HCTZ caused dramatic reduction in systemic blood pressure, with systolic blood pressure decreasing from 72.13± 5.1 at baseline to 51.06 ± 6.6 mm Hg in dKO mice within 20 minutes of HCTZ administration (p&lt;0.01 vs. baseline) with no significant effect in WT mice (p&gt;0.5 vs. baseline) or in salt resuscitated NCC/pendrin dKO mice. There was no enhancement in salt excretion and no reduction in echocardiography-monitored cardiac output in pendrin/NCC dKO mice in response to HCTZ. The antihypertensive effects of HCTZ were abrogated in the presence of paxilline, a specific blocker of BK channel, which is upregulated in arterial vasculature of volume depleted mutant mice. We propose that thiazides reduce blood pressure predominantly via vasorelaxation during salt restriction/volume depletion; whereas, they enhance salt excretion during salt replete state and specifically in conditions associated with pendrin downregulation/inactivation.

KORELASI ANTARA DEHIDRASI DENGAN FAKTOR-FAKTOR KLINIS PADA ANAK KAMBING KACANG LOKAL (Capra aegagrus hircus)(Correlation between Dehydration and Assessment Clinical Factors in Kacang Goatlings (Capra aegagrus hircus))

The purpose of this study was to determine the dominant factor that clinically influent the occurrence of dehydration in goats aged 10-14 days old, in order to enhance the accuracy in diagnoinge the state of hydration. Ten native kacang goatlings were used as research objects. Kacang goatlings were dehydrated until loss 10% of their bodyweight by inducing diuretics furosemide (2mg/kg body weight every 4 hours) using intramuscularly, orally administration of spironolactone (50 mg every 8 hours) and hydrochlorothiazide (50 mg every 8 hours). Regression analysis was used to verify the correlation between clinical factors that considered potential, which are enopthalmus, skin turgor (back, neck and upper eyelid), capillary refill time, pulsus, breath, and body temperature. The results showed that enopthalmus, skin turgor on back and eye region has close correlation with dehydration occurrence with coefficient determinant R2 are 0.92; 0.90 and 0.81 respectively. It can be concluded that these three parameters can be used as predictor towards dehydration occurrence.

The pharmacokinetic-pharmacodynamic model of telmisartan and hydrochlorothiazide on blood pressure and plasma potassium after long-term administration in spontaneously hypertensive rats.

A pharmacokinetic-pharmacodynamic model was developed to describe the time course of blood pressure and plasma potassium after long-term telmisartan and/or hydrochlorothiazide administration in spontaneously hypertensive rats. The spontaneously hypertensive rats were administered once daily for 6 weeks. The drug concentration, blood pressure and plasma potassium were monitored for several points. The time courses of blood pressure and plasma potassium were described by indirect response pharmacokinetic-pharmacodynamic model. The synergistic antihypertensive pharmacodynamic interaction between telmisartan and hydrochlorothiazide was observed, which was simulated by the inhibitory function of telmisartan and stimulatory function of hydrochlorothiazide after co-administration of the two drugs. For plasma potassium, when hydrochlorothiazide administrated alone, the plasma potassium reached to a low steady-state level at 4.64 mmol/L for 6 weeks. The plasma potassium increased to a steady-state level at 4.84 mmol/L after co-administration of telmisartan. The time courses of plasma potassium were successfully characterized by indirect response pharmacokinetic-pharmacodynamic model after long-term administration of telmisartan and/or hydrochlorothiazide. The model captured turnovers of blood pressure and plasma potassium in the different time phases and dose conditions.

Thiazide-induced hyponatraemia is associated with increased water intake and impaired urea-mediated water excretion at low plasma antidiuretic hormone and urine aquaporin-2

Hyponatraemia is a common, potentially life-threatening, complication of thiazide diuretics. The mechanism of thiazide-induced hyponatraemia is incompletely understood. Previous experiments have suggested a direct effect of thiazide diuretics on the plasma membrane expression of aquaporin (AQP)2. We examined the effects of a single re-exposure to hydrochlorothiazide (HCTZ) 50 mg on water balance, renal sodium handling and osmoregulation in 15 elderly hypertensive patients with a history of thiazide-induced hyponatraemia and 15 matched hypertensive controls using thiazide diuretics without previous hyponatraemia. Patients with thiazide-induced hyponatraemia had significantly lower body weight and lower plasma sodium and osmolality at baseline. After HCTZ administration, plasma sodium and osmolality significantly decreased and remained lower in patients compared with controls (P < 0.001). Plasma antidiuretic hormone (ADH) and urine AQP2 were low or suppressed in patients, whereas solute and electrolyte-free water clearance was significantly increased compared with controls. Ad libitum water intake was significantly higher in patients (2543 ± 925 ml) than in controls (1828 ± 624 ml, P < 0.05), whereas urinary sodium excretion did not differ. In contrast, urea excretion remained significantly lower in patients (263 ± 69 mmol per 24 h) compared with controls (333 ± 97 mmol per 24 h, P < 0.05) and predicted the decrease in plasma sodium following HCTZ administration. Thiazide diuretics are associated with markedly impaired free water excretion at low ADH and AQP2 in elderly patients. The higher water intake and lower urea excretion in patients points to an important role for polydipsia and urea-mediated water excretion in the pathogenesis of thiazide-induced hyponatraemia.

Modeling of the pharmacokinetic/pharmacodynamic interaction between irbesartan and hydrochlorothiazide in normotensive subjects.

To investigate the pharmacokinetic/pharmacodynamic (PK/PD) interaction between irbesartan (IRB) and hydrochlorothiazide (HCT) in normotensive subjects. A three-way crossover study was used. Serial drug concentrations and drug effects, including systolic and diastolic blood pressure and heart rate were monitored after administration of irbesartan and hydrochlorothiazide alone and in combination. The data were fitted to a PK/PD model and the parameters for irbesartan and hydrochlorothiazide when administered alone and in combination were compared. The plasma profiles for irbesartan and hydrochlorothiazide followed the two-compartment model after a single dose. The PK parameters of irbesartan were not affected by hydrochlorothiazide; however irbesartan decreased the hydrochlorothiazide AUC by 25% and increased its clearance by 25%. There were no significant changes in heart rate after each drug alone or in combination. Irbesartan plus hydrochlorothiazide had a greater blood pressure lowering effect compared with irbesartan alone, despite the unchanged irbesartan PK. The relationship between irbesartan plasma concentration and its effects plotted in chronological order showed anticlockwise hysteresis. The PD parameter estimates for the effect of irbesartan on systolic blood pressure, when administered with hydrochlorothiazide were significantly different from those when irbesartan was administered alone. This was manifested by a 25% increase in Emax , and a 40% decrease in EC50 , suggesting a synergistic blood pressure lowering effect for the combination. While parameter estimates for the effect of irbesartan on diastolic blood pressure were changed by hydrochlorothiazide, the differences were only significant for EC50 . A limited potential for clinically significant interactions between irbesartan and hydrochlorothiazide at the given doses were observed; therefore, no dosage adjustments were recommended for either drug when used together. (ClinicalTrials.gov Identifier NCT01858610)

Bartter and Gitelman syndromes: Spectrum of clinical manifestations caused by different mutations.

Bartter and Gitelman syndromes (BS and GS) are inherited disorders resulting in defects in renal tubular handling of sodium, potassium and chloride. Previously considered as genotypic and phenotypic heterogeneous diseases, recent evidence suggests that they constitute a spectrum of disease caused by different genetic mutations with the molecular defects of chloride reabsorption originating at different sites of the nephron in each condition. Although they share some characteristic metabolic abnormalities such as hypokalemia, metabolic alkalosis, hyperplasia of the juxtaglomerular apparatus with hyperreninemia, hyperaldosteronism, the clinical and laboratory manifestations may not always allow distinction between them. Diuretics tests, measuring the changes in urinary fractional excretion of chloride from baseline after administration of either hydrochlorothiazide or furosemide show very little change (< 2.3%) in the fractional excretion of chloride from baseline in GS when compared with BS, except when BS is associated with KCNJ1 mutations where a good response to both diuretics exists. The diuretic test is not recommended for infants or young children with suspected BS because of a higher risk of volume depletion in such children. Clinical symptoms and biochemical markers of GS and classic form of BS (type III) may overlap and thus genetic analysis may specify the real cause of symptoms. However, although genetic analysis is available, its use remains limited because of limited availability, large gene dimensions, lack of hot-spot mutations, heavy workup time and costs involved. Furthermore, considerable overlap exists between the different genotypes and phenotypes. Although BS and GS usually have distinct presentations and are associated with specific gene mutations, there remains considerable overlap between their phenotypes and genotypes. Thus, they are better described as a spectrum of clinical manifestations caused by different gene mutations.

Pharmacokinetic-pharmacodynamic model of the antihypertensive interaction between telmisartan and hydrochlorothiazide in spontaneously hypertensive rats

The goal of this study was to establish an integrated indirect response pharmacokinetic-pharmacodynamic model between telmisartan and hydrochlorothiazide to describe the antihypertensive interaction of these two drugs in spontaneously hypertensive rats. The blood pressure and plasma concentrations were measured by the tail-cuff test and high performance liquid chromatography-mass spectrometry, respectively, in spontaneously hypertensive rats. The current pharmacokinetic-pharmacodynamic model was based on the non-competitive pharmacodynamic interaction of two drugs acting on different physiological processes. This model was able to acquire the temporal changes in drug concentration and blood pressure after administration of telmisartan or hydrochlorothiazide. The noncompetitive pharmacodynamic interaction assumed that the decreased blood pressure was attributed to the inhibitory function of telmisartan and stimulatory function of hydrochlorothiazide after administration of these two drugs. There was no significant pharmacokinetic change of telmisartan and hydrochlorothiazide in the different groups tested. The model predicted a synergistic pharmacodynamic interaction when telmisartan was administered in combination with hydrochlorothiazide, which was notably stronger than if the effects were additive. The results showed that the presented pharmacokinetic-pharmacodynamic model was suitable for describing the antihypertensive interaction between telmisartan and hydrochlorothiazide.

Acute inhibition of NCC does not activate distal electrogenic Na+reabsorption or kaliuresis

Na+ reabsorption from the distal renal tubule involves electroneutral and electrogenic pathways, with the latter promoting K+ excretion. The relative activities of these two pathways are tightly controlled, participating in the minute-to-minute regulation of systemic K+ balance. The pathways are interdependent: the activity of the NaCl cotransporter (NCC) in the distal convoluted tubule influences the activity of the epithelial Na+ channel (ENaC) downstream. This effect might be mediated by changes in distal Na+ delivery per se or by molecular and structural adaptations in the connecting tubule and collecting ducts. We hypothesized that acute inhibition of NCC activity would cause an immediate increase in Na+ flux through ENaC, with a concomitant increase in renal K+ excretion. We tested this using renal clearance methodology in anesthetized mice, by the administration of hydrochlorothiazide (HCTZ) and/or benzamil (BZM) to exert specific blockade of NCC and ENaC, respectively. Bolus HCTZ elicited a natriuresis that was sustained for up to 110 min; urinary K+ excretion was not affected. Furthermore, the magnitude of the natriuresis was no greater during concomitant BZM administration. This suggests that ENaC-mediated Na+ reabsorption was not normally limited by Na+ delivery, accounting for the absence of thiazide-induced kaliuresis. After dietary Na+ restriction, HCTZ elicited a kaliuresis, but the natiuretic effect of HCTZ was not enhanced by BZM. Our findings support a model in which inhibition of NCC activity does not increase Na+ reabsorption through ENaC solely by increasing distal Na+ delivery but rather by inducing a molecular and structural adaptation in downstream nephron segments.

Pharmacokinetic Interactions of Valsartan and Hydrochlorothiazide: An Open-Label, Randomized, 4-Period Crossover Study in Healthy Egyptian Male Volunteers

BackgroundCo-administration of valsartan (VAL) and hydrochlorothiazide (HCT) has been used to regulate blood pressure. Compliance with a multiple medication regimen can be difficult for some patients; therefore, a combination of VAL + HCT tablets may be a suitable alternative. ObjectiveThis study was conducted to compare the rate and extent of absorption of VAL and HCT after oral administration as a fixed-dose combination (FDC) tablet and concomitant administration of the individual drugs under fasting conditions in healthy Egyptian subjects. The study was extended to investigate any potential interaction between VAL and HCT. MethodsThis study was conducted as an open-label, randomized study with 2 parts (parts I and II), with each part consisting of 4 single-dose treatment periods with a crossover design and 2-week washout periods. Blood samples were collected up to 48 hours postdose, and plasma was analyzed for VAL and HCT concentrations by using HPLC. The pharmacokinetic properties of each drug after co-administration of VAL and HCT were compared with those of each drug administered alone. Tolerability was assessed by physical examination and verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects were recorded in adverse-event forms. ResultsForty-eight healthy subjects were enrolled (24 in each part), and all subjects completed the study. None of the participants showed any sign of adverse drug reactions during or after the completion of the study. Statistical analysis confirmed that the 90% CIs for AUC and Cmax of VAL/HCT FDC and VAL + HCT were within the commonly accepted bioequivalence range of 0.8 to 1.25. As a result, from an in vivo pharmacokinetic perspective, 1 FDC tablet could be considered interchangeable in medical practice with the 2 individual reference tablets. However, the 90% CIs between VAL alone and when administered with HCT, either as FDC or concomitantly, indicated the presence of an interaction between VAL and HCT, which would significantly decrease the systemic exposure and intensity of VAL absorption. The co-administration of HCT with VAL decreased the AUC and Cmax of HCT nonsignificantly compared with administration of HCT alone. ConclusionsBoth VAL/HCT FDC and VAL + HCT were well tolerated. The safety/efficacy profile of VAL + HCT co-administration therapy could be extended to the VAL/HCT FDC tablet. The interaction of HCT with other angiotensin-receptor blockers should be investigated to determine whether this interaction is limited to VAL or if other angiotensin-receptor blockers have the same pharmacokinetic interactions. Further studies are necessary to determine the role of efflux and influx transporters on VAL and HCT disposition and pharmacokinetics.

Congenital nephrogenic diabetes insipidus: about a case report

Congenital nephrogenic diabetes insipidus is a rare, hereditary in nature, characterized by an inability of the kidney to concentrate urine, secondary to the manifold resistance to the action of vasopressin. X-linked forms of transmission (90%) are expressed in boys, from the neonatal period in general, by polyuria and polydipsia. Symptomatology in transmissive girls is variable but can sometimes be quite marked. These forms are secondary to mutations in the gene encoding the vasopressin V2 receptor, located at position Xq28, responsible for a loss of function of this receptor. Some of these mutations may cause a partial phenotype, less severe. Forms of autosomal, recessive or dominant are more rare (10%). Treatment is symptomatic, sometimes difficult in infants. It aims to avoid episodes of dehydration. It is based on a conventional diet hypo-osmotic and administration of hydrochlorothiazide and indomethacin. We report here the case of a child with congenital nephrogenic diabetes insipidus hospitalized at Children's Hospital of Rabat and throughout this case we review the pathophysiology and clinical and biological characteristics of the disease and including importance of contribution of clinical biochemistry laboratory in the diagnosis and monitoring of this disease.