Potential low toxic alternative for Na-Cl cotransporter inhibition: A diuretic effect and mechanism study of Pyrrosia petiolosa.

BACKGROUND: Hydrochlorothiazide, a diuretic commonly used for the treatment of hypertension, is often associated with serious metabolic side effects. Pyrrosia petiolosa (Christ) Ching is a traditional Chinese medicine that possesses diuretic properties, without any obvious side effects. AIM: To evaluate the diuretic effect of P. petiolosa (Christ) Ching and to elucidate its underlying mechanism of action. METHODS: Extracts obtained from different polar components of P. petiolosa (Christ) Ching were analyzed for toxicity in a Kunming mouse model. The diuretic effects of the extracts were compared to that of hydrochlorothiazide in rats. In addition, compound isolation procedures, cell assays of Na-Cl cotransporter inhibition and rat diuretic test of monomeric compounds were conducted to identify the active ingredients in the extract. Subsequently, homology modeling and molecular docking were performed to explain the reason behind the diuretic activity observed. Finally, LC-MS analysis was used to elucidate the underlying mechanism of action of P. petiolosa (Christ) Ching. RESULTS: No toxicity was observed in mice administered P. petiolosa (Christ) Ching extracts. The ethyl acetate fraction showed the most significant diuretic effect. Similar results were obtained during the analysis for Na+ content in rat urine. Further separation of P. petiolosa (Christ) Ching components led to the isolation of methyl chlorogenate, 2',3'-dihydroxy propyl pentadecanoate, and ß-carotene. Results from cell assays showed that the Na-Cl cotransporter inhibitory activity of methyl chlorogenate was greater than that of hydrochlorothiazide. This result was again confirmed by the diuresis tests of monomeric compounds in rats. The molecular simulations explain the stronger interactions between the methyl chlorogenate and Na-Cl cotransporter. Of the compounds determined using LC-MS analysis, 185 were identified to be mostly organic acids. CONCLUSIONS: P. petiolosa possesses significant diuretic activities without any obvious toxicity, with least two possible mechanisms of action. Further study on this herb is warranted.

Enalapril protect human lymphocytes from genotoxicity of Hydrochlorothiazide.

Hydrochlorothiazide (HCTZ) belongs to the thiazide diuretics family that is used for the treatment of hypertension. Enalapril is another drug that is used for the treatment of hypertension. Recently, both drugs were combined in a single medication called vaseretic that showed a strong synergistic effect against hypertension. The aim of this investigation is to examine genotoxicity of HCTZ/enalapril on chromosomal damage by measuring the frequency of sister-chromatid exchanges (SCEs) in cultured human lymphocytes. Findings showed that HCTZ (5µg/mL) significantly increased SCEs frequency (P<0.01) in cultured cells relative to the untreated cells. The levels of SCEs induced by Enalapril (10µg/mL) was similar to the level detected in the untreated cultures (P>0.05). Interestingly, SCEs induced by combined treatment were significantly lower than HCTZ alone (P<0.05). Thus, enalapril seems to protect lymphocytes from genotoxicity induced by HCTZ. Neither HCTZ nor enalapril treatment (alone or in combination) induced changes in the mitotic index and the proliferative index (P>0.05). In conclusion, HCTZ increased SCEs in cultured lymphocytes, and this increase is reduced by enalapril.

An investigation of the mutagenic activity of salamide - a major impurity of hydrochlorothiazide.

Hydrochlorothiazide is a widely used antihypertensive agent and one of its major impurities, salamide (4-amino-6-chlorobenzene-1,3-disulphonamide), has a chemical structure containing a primary amino group, a functional group that has previously been reported to be associated with carcinogenic activity. It is known that hydrochlorothiazide purity is a challenging problem for the pharmaceutical industry. As there were no prior mutagenicity data for the impurity salamide, the aim was to investigate its mutagenicity in this study. Salamide was tested for mutagenic potential in Salmonella typhimurium TA98, TA100, TA 1535, TA 1537, and E. coli WP2 uvrA + E. coli WP2 [pKM101] strains at six different concentrations, the highest concentration being the 5000 µg/plate. In both the presence and absence of the metabolic activation system, no mutagenic activity was observed. Results indicated that salamide should be classified as an ordinary impurity and controlled according to Q3A(R2) and Q3B(R2) guidelines.

Characterization and evaluation of multi-component crystals of hydrochlorothiazide.

PURPOSE: The present work aims at improving the physicochemical properties of hydrochlorothiazide, a poorly water soluble antihypertensive drug by preparing its multi-component crystals with nicotinic acid (HCT-NA) and 2-picolinic acid (HCT-PIC). METHODS: The crystals prepared by solution crystallization were investigated by thermoanalytical techniques. The crystal structures of HCT-NA (1) and HCT-PIC (2) were determined by the single crystal X-ray diffraction and were assessed for their aqueous solubility, antihypertensive activity and acute toxicity in rats. RESULTS: Both 1 and 2 crystallized in the orthorhombic space group P212121 and formation of salts were confirmed. The solubility profiles of 1 and 2 in basic media showed a maximum release of 2.5 mg/ml and 1.9 mg/ml, respectively, in comparison to the drug (0.82 mg/ml). The in-vivo antihypertensive activity of 1 in deoxycorticosterone acetate salt induced hypertensive rats showed 1.5 fold improvement. No increase in the signs of toxicity were revealed in rats during the acute toxicity studies even at doses of 2,000 mg/kg by body weight in comparison to the free drug. Histopathological findings supported the safety of these multi-component crystals. CONCLUSIONS: The new solid phases exhibit potential to be explored for the oral drug delivery of HCT with improved solubility and therapeutic outcome.

Penfigoide ampolloso inducido por hidroclorotiazida / Hydrochlorothiazide induced bullous pemphigoid

Presentamos el caso de un varón de 55 años, que acude a consulta por presentar lesiones ampollosas pruriginosas en tronco, manos y cuero cabelludo de 3 meses de evolución. Después de descartar diversas enfermedades que justificaran el cuadro descrito, se pensó que la causa podría ser farmacológica. El paciente llevaba varios años en tratamiento con hidroclorotiazida por hipertensión arterial. Con la retirada del tratamiento diurético y la instauración de corticoides orales, las lesiones mejoraron (AU)

We report the case of a 55 year-old man who consulted for pruritic bullous lesions of three months onset located on the body, hands and scalp. After ruling out various illnesses to justify the situation described, it was thought that the cause could be pharmacological. The patient had been on treatment with hydrochlorothiazide for several years due to hypertension. The lesions improved with the withdrawal of diuretic therapy, and the introduction of oral corticosteroids (AU)

Effect of combined treatment with diuretics and gabapentin on convulsive threshold in mice.

Research data show that diuretics can have anticonvulsant properties. This study examined effects of ethacrynic acid, a loop diuretic, and hydrochlorothiazide, a thiazide-type diuretic, on the anticonvulsant activity of gabapentin, a newer antiepileptic drug, in the maximal electroshock seizure threshold test in mice. Diuretics were administered intraperitoneally (ip.) both acutely (single dose) and chronically (once daily for seven days). Electroconvulsions were produced by an alternating current (50 Hz, 500 V, 0.2 s stimulus duration) delivered via ear-clip electrodes by a generator. Additionally, the influence of combined treatment with the diuretics and gabapentin on motor performance in the chimney test has been assessed. In the current study, ethacrynic acid at the chronic dose of 12.5 mg/kg and the single dose of 100 mg/kg did not affect the anticonvulsant activity of gabapentin. Similarly, hydrochlorothiazide (100 mg/kg), both in acute and chronic experiments, had no effect on the gabapentin action. On the other hand, in the chimney test, the combined treatment with ethacrynic acid (100 mg/kg) and gabapentin (50 mg/kg) significantly impaired motor performance in mice. Based on the current preclinical findings, it can be suggested that the diuretics should not affect the anticonvulsant action of gabapentin in epileptic patients. However, the combination of ethacrynic acid with gabapentin may cause neurotoxicity.

[Hyponatremia--should it be ignored or diagnosed?--Case 8/2011]. / Hyponatriämie--ignorieren oder diagnostizieren?--Fall 8/2011.

UNLABELLED: HISTORY, CLINICAL FINDINGS: A 72-year-old dehydrated female was admitted to our emergency department. She presented with a decreased level of consciousness and had experienced a fall. Her medication included hydrochlorothiazide and amiloride. DIAGNOSTIC: Laboratory findings showed a severe hyponatremia with a serum sodium concentration of 107 mmol/l and a reduced serum osmolality. Urine sodium and potassium excretion were > 30 mmol/l. A CT scan of the head did not show any signs of trauma. DIAGNOSIS, THERAPY AND CLINICAL COURSE: Using a diagnostic algorithm, the diagnosis of a hypotonic hypovolemic hyponatremia due to the intake of diuretics was confirmed. By intravenous infusion of physiological sodium chloride solution and cessation of diuretics, serum sodium concentration was raised gradually. Hereby, the patient`s state of consciousness completely normalized. CONCLUSIONS: Hyponatremia represents the most frequent electrolyte disturbance of hospitalized patients. It correlates with neurological deficits, proneness to falling and intrahospital mortality. Due to diagnostic insecurity of many physicians, the finding of a hyponatremia is often ignored or misclassified. Standardized approaches using diagnostic algorithms improve diagnostic accuracy. The here presented algorithm is based on only few parameters: serum and urine osmolality, urine sodium and potassium. Besides gradual raise of serum sodium, therapy of the underlying cause is essential, for example cessation of diuretics. For patients with syndrome of inadequate secretion of antidiuretic hormone (SIADH; hypotonic isovolemic hyponatremia), selective arginin-vasopressin-receptor 2-antagonists (vaptans) are a new therapeutic option. However, due to high costs, we only see an indication for patients with SIADH who are not able to consequently comply with fluid restriction.

Retinal phototoxicity induced by hydrochlorothiazide after exposure to a UV tanning device.

UV radiation is known to cause acute and chronic eye and skin damage. The present case report describes the occurrence of hydrochlorothiazide-induced retinal phototoxicity immediately after exposure to UV light emanated from a sunbed in a 40-year-old myopic woman. During the tanning session she had always worn UV protective eyewear, except for a few minutes when she took the protective goggles off to put her spectacles on to locate and turn the timer switch off. At baseline her visual acuity was 10/25 in OD and 10/80 in OS. Fundus examination revealed the presence of retinal lesions in both eyes. More specific tests confirmed the presence of a phototoxic macular damage. Hydrochlorothiazide was discontinued, and she was recommended to wear UV filtering glasses. Over the follow-up period (12 months), a slow and progressive visual acuity recovery in both eyes occurred. At the last check the visual acuity improvement was of about 60% from baseline in both eyes. Fundus examination showed only a juxtafoveal flat pigmented scar of the retinal pigment epithelium in both eyes, milder in OD. The constant rise in the number of sunbed users makes the knowledge of UV-related side effects a problem that cannot be postponed further. Awareness of the general public about the harmful effects of UV exposure must represent one of the leading preventive health strategies. Therefore, a careful analysis of the medical history before the admission to a sunbed session throughout a questionnaire could represent an economic and effective measure to avoid further cases of a phototoxic macular damage in patients taking photosensitizing compounds.

Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia.

Hydrochlorothiazide (HCTZ) is used to manage hypertension and heart failure; however, its side effects include mild hypokalemia, metabolic abnormalities, and volume depletion, which might have deleterious effects on renal and endothelial function. We studied whether HCTZ cause renal injury and/or altered vasoreactivity and if these changes are hypokalemia-dependent. Rats were given a normal diet or a diet moderately low in potassium K+ with or without HCTZ. Animals fed either a low K+ diet alone or HCTZ developed mild hypokalemia. There was no significant difference in systolic blood pressure in the different treatment groups. All three groups with hypokalemia had mild proteinuria; low K(+)-HCTZ rats had reduced creatinine clearance. HCTZ-treated rats displayed hypomagnesemia, hypertriglyceridemia, hyperglycemia, insulin resistance, and hyperaldosteronism. No renal injury was observed in the groups without HCTZ; however, increased kidney weight, glomerular ischemia, medullary injury, and cortical oxidative stress were seen with HCTZ treatment. Endothelium-dependent vasorelaxation was reduced in all hypokalemic groups and correlated with reduced serum K+, serum, and urine nitric oxide. Our results show that HCTZ is associated with greater renal injury for the same degree of hypokalemia as the low K+ diet, suggesting that factors such as chronic ischemia and hyperaldosteronism due to volume depletion may be responsible agents. We also found impaired endothelium-dependent vasorelaxation was linked to mild hypokalemia.

Human renal organic anion transporter 4 operates as an asymmetric urate transporter.

Human organic anion transporter 4 (hOAT4) is located at the apical membrane of proximal tubule cells and involved in renal secretion and reabsorption of endogenous substances as well as many drugs and xenobiotics. This study reevaluated the physiologic role, transport mode, and driving forces of hOAT4. 6-Carboxyfluorescein (6-CF) uptake into HEK293 cells that stably expressed hOAT4 was saturable, resulting in a K(m) of 108 muM. 6-CF as well as [(3)H]estrone sulfate ([(3)H]ES) accumulation by HEK293-hOAT4 cells were abolished by ES, dehydroepiandrosterone sulfate, sulfinpyrazone, benzbromarone, and probenecid, whereas several OA, including p-aminohippurate (PAH), lactate, pyrazinoate, nicotinate, glutarate, and the diuretic hydrochlorothiazide (HCTZ) exhibited a slight or a NS inhibitory effect. PAH and glutarate are not taken up by HEK293-hOAT4 cells, but they trans-stimulated 6-CF and [(3)H]ES uptake, indicating an asymmetric interaction of hOAT4 with these substrates. In chloride-free medium, HEK293-hOAT4-mediated [(3)H]PAH efflux was almost abolished, whereas addition of ES restored it comparable to Ringer solution, consistent with a physiologic ES/PAH or PAH/Cl(-) exchange mode of hOAT4. Moreover, an acidification of the uptake medium increased 6-CF as well as [(3)H]ES uptake, which was reduced by nigericin, suggesting that hOAT4 also can operate as an OA/OH(-) exchanger. hOAT4 facilitates substantial uptake of [(14)C]urate, which was elevated 2.6-fold by intracellular HCTZ. Thus, hOAT4 is the long-postulated, low-affinity apical urate anion exchanger that facilitates HCTZ-associated hyperuricemia.

Genotoxicity of hydrochlorothiazide in cultured human lymphocytes. I. Evaluation of chromosome delay and chromosome breakage.

Hypertension is often treated with diuretics, like hydrochlorothiazide (HCTZ). Previous results on the in vitro genotoxicity of HCTZ are equivocal. In the present study, we have evaluated the genotoxicity of HCTZ in cultured human lymphocytes using the Cytokinesis Blocked Micronucleus (CBMN) assay. In addition, micronucleus (MN) induction was analyzed by Fluorescence In Situ Hybridization (FISH) with an alpha-satellite DNA centromeric probe to distinguish between clastogenic and aneugenic effects. Lymphocyte cultures from 32 healthy adults were exposed to 5 and 40 microg/ml HCTZ. Age, gender, and smoking were evaluated as factors affecting the MN analysis. We found that HCTZ increased MN frequencies. FISH analysis revealed that HCTZ exerts its genotoxicity more strongly at the 40 microg/ml concentration, and principally through chromosome delay (aneugenicity). Multiregression analysis of our results confirmed the known effect of age and gender on MN induction in human lymphocytes. Smoking was also a confounding factor for MN induction, especially for centromere-negative MN frequencies. Under the experimental conditions used, only age had a clear positive effect on the response of lymphocytes to HCTZ. These data indicate that HCTZ produces micronuclei in cultured human lymphocytes by a mechanism that involves chromosome delay and to a lesser extent through chromosome breakage.

Hydrochlorothiazide induced hepato-cholestatic liver injury.

Hydrochlorothiazide and other thiazide-like diuretics are considered as a first-line drug for initial therapy in uncomplicated arterial hypertension [1]. There are several reports [2-6] of thiazide-induced cholecystitis, but here we report a case of serious hepatotoxicity associated with hydrochlorothiazide treatment.

Renal effects of 26-week administration of olmesartan medoxomil/hydrochlorothiazide in rats.

The combination of an angiotensin II type 1 receptor blocker (ARB) and a diuretic is effective clinically in treatment of hypertension. As a non-clinical safety evaluation of a combination of the ARB olmesartan medoxomil (OM) and the diuretic hydrochlorothiazide (HCTZ), male and female normotensive rats were administered OM/HCTZ (fixed ratio of 8 : 5) orally by gavage for 26 weeks at dose levels of 0, 4.88, 16.25, 48.75, 162.5, 487.5, or 1625 mg/kg/day. Additional groups were given 1000 mg/ kg/day OM or 625 mg/kg/day HCTZ. Statistically significant and marked decreases in urinary protein excretion were observed in males and females given doses of 16.25 mg/kg/day or higher compared to vehicle-control groups. Increases in blood urinary nitrogen (BUN) were observed in males and females given doses of 16.25 and 162.5 mg/kg/day or higher, respectively. Increased incidence of chronic progressive nephropathy (CPN), a rat-specific spontaneous renal lesion, was observed in males and females given doses of 48.75 mg/kg/day or higher. An additional mechanistic study, consisting of male and female rats given 0, or 162.5 mg/kg/day OM/HCTZ, was conducted to clarify the toxicological significance of the increases in BUN and the increased incidence of CPN described above. This additional study clearly demonstrated that saline-supplementation through free access to saline in the drinking water ameliorated the elevation in BUN and also ameliorated the incidence of CPN. Consequently, the effects on BUN and CPN observed in the first study can be explained by the hemodynamic disturbances caused by the large doses and an exaggerated pharmacological action in volume-depleted normotensive animals. Importantly, the marked decreases in urinary protein were not affected by the saline-supplementation, and indicated that OM/HCTZ elicited a renoprotective effect, probably by an effect on the glomeruli. An additional toxicokinetic study revealed no drug interactions between OM and HCTZ. In conclusion, OM/HCTZ induced a renoprotective effect as well as changes probably attributed to the exaggerated pharmacological action of the ARB with diuretic in normotensive rats. These results suggest that OM/HCTZ may have renoprotective effects in clinical treatment of hypertensive patients.

Doxazosin GITS versus hydrochlorothiazide as add-on therapy in patients with uncontrolled hypertension.

The objective of this prospective, randomized, open-label, parallel-arm comparative study, with a 4-month follow-up, was to assess the antihypertensive efficacy, tolerability and metabolic safety of doxazosin GITS (gastrointestinal therapeutic system) 4-8 mg/day vs hydrochlorothiazide (HCTZ) 12.5-25 mg/day as add-on therapy in patients not controlled with monotherapy with other drugs. Ninety-eight patients completed the study (mean age 57.4 +/- 15 years, 53% female). Mean systolic/diastolic blood pressure reduction was 8.2/4.5 mmHg in the HCTZ group and 8.9/5.0 mmHg in the doxazosin GITS group, and a strict blood pressure control was achieved in 79% and 83% of the patients, respectively. The incidence rates of adverse events were low and similar in both groups. However, metabolic differences were seen between the groups, doxazosin GITS vs HCTZ, respectively: total cholesterol (mg/dl) 210 +/- 53 vs 231 +/- 62 (p < 0.05), low-density lipoprotein (LDL) cholesterol (mg/dl) 139 +/- 40 vs 161 +/- 57 (p < 0.01), high-density lipoprotein (HDL) cholesterol (mg/dl) 58 +/- 16 vs 48 +/- 13 (p < 0.01), HDL/total cholesterol ratio 27.6 +/- 8 vs 21.2 +/- 7 (p < 0.001), plasma uric acid (mg/dl) 5.3 +/- 2.6 vs 6.8 +/- 3.1 (p < 0.05) and serum potassium (mEq/l) 4.1 +/- 1.3 vs. 3.7 +/- 1.2 (p < 0.01). In conclusion, doxazosin GITS has a tolerability and efficacy profile similar to low doses of thiazide diuretics, with a better evolution of metabolic and electrolyte parameters. Therefore, in patients not controlled with monotherapy, doxazosin GITS can be considered an alternative to the addition of thiazide diuretics.

Efficacy and tolerability of the combination valsartan/hydrochlorothiazide compared with amlodipine in a mild-to-moderately hypertensive Brazilian population.

Most hypertensive patients need more than one drug to reach recommended blood-pressure targets. We investigated the effects on 24-h ambulatory blood pressure (ABP) of the angiotensin-receptor blocker, valsartan, in combination with hydrochlorothiazide (HCTZ), compared with the calcium-channel blocker amlodipine in a Brazilian population in a multicentre, double-blind, double-dummy, parallel group, controlled study in 373 patients with essential hypertension. After a 2-week washout period, patients with a mean sitting systolic blood pressure (SBP) of 160-190 mmHg were randomized to receive either valsartan 160 mg o.d., or amlodipine 5 mg o.d. for 2 weeks and subsequently force-titrated to valsartan 160 mg/HCTZ 25 mg o.d. or amlodipine 10 mg o.d. This regimen was continued until the end of the study at week 8. The primary efficacy parameter was the change from baseline to week 8 in mean 24-h SBP. Secondary endpoints were change in mean 24-h diastolic blood pressure (DBP), tolerability and safety of treatments. Valsartan/HCTZ achieved a mean reduction in systolic ABP of -19.1 +/- 11.3 mmHg compared with -20.7 +/- 12.0 mmHg with amlodipine (p = 0.324 for the comparison) and in diastolic ABP by -11.1 +/- 7.4 mmHg vs -11.6 +/- 7.2 mmHg by amlodipine (p = 0.853 for the comparison). The valsartan/HCTZ group exhibited markedly lower rates of adverse events and discontinuations than the amlodipine group. Peripheral oedemas were far more frequent with amlodipine than with valsartan/ HCTZ (1.6% with valsartan/HCTZ; 16.8% with amlodipine). Thus, the valsartan 160 mg/HCTZ 25 mg combination appears to be as efficacious as amlodipine 10 mg in this patient population but better tolerated.

Antihypertensive effects of valsartan/hydrochlorothiazide combination in essential hypertension.

Fixed-dose combination therapy has received increased interest since publication of JNC-VI report and WHO/ISH guidelines 1999. We compared in a randomized, double-blind study the efficacy and tolerability of valsartan 80 mg combined with hydrochlorothiazide (HCTZ) 12.5 mg to monotherapy with either HCTZ 12.5 mg or 25 mg in patients with essential hypertension inadequately controlled by previous HCTZ 12.5 mg monotherapy. Two hundred and seventeen patients whose blood pressure (BP) control remained poor (95 mmHg < or = sitting diastolic BP < 115 mmHg) after a 4-week single-blind period with HCTZ 12.5 mg were randomized to receive either combination therapy with valsartan 80 mg plus HCTZ 12.5 mg (V/HCTZ) or monotherapy with HCTZ 12.5 mg or HCTZ 25 mg for 8 weeks. Reduction of sitting trough diastolic BP between baseline and week 8 as well as tolerability was evaluated. Reduction in trough diastolic BP was most pronounced in the V/HCTZ group (-11.3 mmHg) and significantly greater than in the HCTZ 12.5 mg group (-2.9 mmHg, p < 0.001) and the HCTZ 25 mg group (-5.7 mmHg, p < 0.001). Tolerability of study medication was comparable between all three groups. In conclusion, switching to V/HCTZ combination therapy provides an additional lowering of BP compared to dosage increase of the thiazide in patients with BP insufficiently controlled by HCTZ 12.5 mg monotherapy.

Insuficiencia respiratoria aguda inducida por hidroclorotiazida / Acute respiratory failure induced by hydrochlorothiazide

Se describe una paciente con insuficiencia respiratoria aguda recurrente, inducida por la toma repetida de hidroclorotiazida. La patogenia de esta reacción adversa es aún desconocida. Lo más probable es que el mecanismo de producción sea idiosincrásico. El tratamiento es de soporte. Este efecto adverso es raro, pero de grave compromiso vital y producido por un fármaco de uso muy común, de ahí la importancia de que sea reconocido en los Servicios de Urgencias (AU)

To describe a patient with recurrent acute respiratory failure, induced after repeated intake of hydrochlorothiazide. The pathogenesis of this adverse reaction remains unknown. The mechanism of production is, probably idiosyncratic. The treatment of the syndrome involves supportive therapy. The adverse effect is rare, but the potential for life-threatening and because of the high use of this drug it is important to recognize it in the Emergency (AU)

Preclinical safety studies of the combination moexipril hydrochloride/hydrochlorothiazide.

The general pharmacological properties of a combination of the angiotensin converting enzyme (ACE) inhibitor moexipril hydrochloride (CAS 82586-52-5) and the thiazide diuretic hydrochlorothiazide (CAS 58-93-5, HCTZ), ratio 7.5 + 12.5, were studied in generally accepted models in vitro and in vivo. In vitro, the combination showed neither agonistic nor antagonistic activities on the isolated guinea pig trachea in concentrations up to 2 x 10(-4) g/ml. In mice, there was no effect on intestinal motility or the thiopental-induced sleeping time up to 1000 mg/kg. The only activity observed in mice was an inhibition of spontaneous motility after oral dosing with 300 and 1000 mg/kg, respectively. Both HCTZ (1-10 mg/kg) alone and the combination moexipril/HCTZ (1.6 or 4.8 mg/kg) produced dose-related increases in diuresis and electrolyte excretion in rats, however, without any potentiating effects for the drug combination. On the cardiovascular system of anaesthetised dogs, the effects observed were as expected, e.g. dose-related decrease in blood pressure. Repeated dose toxicity studies in rats and dogs revealed the kidney as target organ. This effect, based on highly exaggerated pharmacological activity, is well-known for other ACE inhibitors. No potential for teratogenic effects could be observed for the drug combination. In summary, the preclinical data indicate that the combination of moexipril and HCTZ (ratio 7.5 + 12.5) represents a safe drug without relevant side effects or gross toxicity.

The evaluation of the developmental toxicity of hydrochlorothiazide in mice and rats.

Timed-pregnant CD-1 outbred albino Swiss mice and CD Sprague-Dawley rats were administered hydrochlorothiazide (HCTZ, USP) in corn oil by gavage during major organogenesis, Gestational Days (GD) 6 through 15. The doses administered were 0, 300, 1000, or 3000 mg/kg/day for mice and 0, 100, 300, or 1,000 mg/kg/day for rats. Maternal clinical status was monitored daily during treatment. At termination (GD 17, mice; GD 20, rats), confirmed pregnant females (20-27 per group, mice; 36-39 per group, rats) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In mice, no maternal mortality was observed. However, clinical signs including dehydration, piloerection, lethargy, and single-day weight loss appeared to be dose-related. HCTZ had no effect on maternal weight gain or water consumption, gravid uterine weight, relative maternal liver weight, or relative maternal kidney weight. There was no definitive evidence of embryotoxicity or fetal toxicity for mice on GD 17. Thus, the no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was 3000 mg/kg/day. In rats, HCTZ had no effect on maternal survival, clinical signs, or water consumption. Clinical signs were not dose-related. Maternal weight gain during treatment was depressed at 1000 mg/kg/day. Gravid uterine weight and relative maternal liver weight were unaffected. Relative maternal kidney weight was slightly (7-8%) increased at all dose levels, but there was no evidence of a dose response. Thus, the maternal NOAEL for rats was 300 mg/kg/day, based on decreased maternal weight gain during treatment at 1000 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)