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British Journal of Clinical Pharmacology Jun 19821 The blood pressure lowering effect of xipamide, a non-thiazide diuretic given for 6 weeks was compared in a randomised cross-over trial with that of cyclopenthiazide... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
1 The blood pressure lowering effect of xipamide, a non-thiazide diuretic given for 6 weeks was compared in a randomised cross-over trial with that of cyclopenthiazide in 14 patients with essential hypertension. 2 Xipamide 10 or 20 mg given once daily was as effective in lowering supine blood pressure as daily cyclopenthiazide 0.5 mg. There was no difference in the blood pressure lowering effect of 10 mg xipamide daily for 2 weeks compared to 20 mg daily given for a further 4 weeks. 3 Plasma potassium was reduced by both drugs, but markedly more after both 10 mg and 20 mg xipamide than after cyclopenthiazide 0.5 mg. By the sixth week of treatment 13 of 14 patients on xipamide but only 6 of 14 on cyclopenthiazide has plasma potassium concentrations of, or less than, 3.5 mmol/l. The fall in plasma potassium was significantly greater and the final plasma potassium concentration was significantly lower after either dose of xipamide than after cyclopenthiazide. 4 These results suggest that 10 mg or 20 mg of xipamide daily is effective in lowering blood pressure in hypertensive patients but is associated with hypokalaemia. In view of recent evidence linking diuretic-induced hypokalaemia with cardiac dysrhythmias in patients with essential hypertension we would suggest that thiazide diuretics be used in preference to xipamide for the routine management of essential hypertension. Our results also suggest that the currently recommended dose of xipamide (20 mg) for the treatment of hypertension is excessive, and lower amounts than 10 mg per day might possibly be as effective in lowering blood pressure with less adverse metabolic consequences.
Topics: Adult; Blood Glucose; Blood Pressure; Cyclopenthiazide; Diuretics; Female; Humans; Hypertension; Male; Middle Aged; Potassium; Renin; Sodium Chloride Symporter Inhibitors; Time Factors; Xipamide
PubMed: 7046777
DOI: 10.1111/j.1365-2125.1982.tb01879.x -
British Journal of Clinical Pharmacology Apr 1989In a double-blind, placebo controlled, randomised parallel study we investigated the antihypertensive activity and metabolic adverse effects of three doses of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
In a double-blind, placebo controlled, randomised parallel study we investigated the antihypertensive activity and metabolic adverse effects of three doses of cyclopenthiazide in 53 patients with mild hypertension. After a 4 week placebo washout period, patients with diastolic blood pressures between 90-110 mm Hg were randomly assigned to receive 50 micrograms, 125 micrograms and 500 micrograms of cyclopenthiazide or matching placebo, over an 8 week active treatment period. Blood pressure was recorded at 2 weekly intervals during the trial. Venous samples were taken for evaluation of drug effect on indices of carbohydrate and lipid metabolism just prior to, and on completion of, the active treatment period. Systolic and diastolic blood pressure decreased significantly (P less than 0.05) with the 125 micrograms and 500 micrograms doses of cyclopenthiazide. No change was apparent in any index of glucose and lipid metabolism over time. Low and conventional doses of cyclopenthiazide lower blood pressure without alteration to the metabolic profile in the short term.
Topics: Apoproteins; Blood Glucose; Blood Pressure; Clinical Trials as Topic; Cyclopenthiazide; Diuretics; Double-Blind Method; Glycated Hemoglobin; Humans; Hypertension; Insulin; Lipids; Lipoproteins; Random Allocation; Sodium Chloride Symporter Inhibitors
PubMed: 2655692
DOI: 10.1111/j.1365-2125.1989.tb05403.x -
BMJ (Clinical Research Ed.) Jul 1988In a double blind placebo controlled randomised parallel study the antihypertensive activity and adverse biochemical effects of three doses of cyclopenthiazide were... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
In a double blind placebo controlled randomised parallel study the antihypertensive activity and adverse biochemical effects of three doses of cyclopenthiazide were evaluated in patients with mild essential hypertension that had been recently diagnosed or was being treated with a single drug. After a four week placebo washout period 53 patients with diastolic blood pressures between 90-110 mm Hg were randomly assigned to 50, 125, or 500 micrograms cyclopenthiazide or matching placebo for an eight week period of treatment. Blood pressure was measured in the patients' homes by the same observer every two weeks. Serum urea, electrolytes, urate, and creatinine concentrations and 24 hour urinary sodium excretion were monitored every four weeks and serum magnesium concentration and plasma renin activity at the end of the washout and treatment periods. After eight weeks of treatment systolic and diastolic blood pressures were significantly reduced in patients taking 125 and 500 micrograms cyclopenthiazide when compared with those taking placebo. The decrement in serum potassium concentration (0.6 mmol/l) and increase in serum urate concentration 0.06 mmol/l) were greatest with the 500 micrograms dose, the increase in serum urate concentration alone being significant. No change in serum magnesium concentration or 24 hour urinary sodium excretion was noted with any dose of cyclopenthiazide. Only the 500 micrograms dose of cyclopenthiazide significantly increased the mean plasma renin activity (1.8 (95% confidence interval 0.2 to 3.4)-5.4 (3.9 to 6.8) nmol angiotensin I/l/h); the other doses like the placebo had no effect. Cyclopenthiazide 125 micrograms, a dose lower than is currently marketed, produced a similar hypotensive response to 500 micrograms of the drug without upsetting the biochemical profile.
Topics: Aged; Clinical Trials as Topic; Cyclopenthiazide; Diuretics; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypertension; Male; Middle Aged; Random Allocation; Sodium; Sodium Chloride Symporter Inhibitors
PubMed: 3044503
DOI: 10.1136/bmj.297.6641.95 -
Biomolecules Feb 2024The pathophysiologic heterogeneity of heart failure (HF) necessitates a more detailed identification of diagnostic biomarkers that can reflect its diverse pathogenic...
BACKGROUND
The pathophysiologic heterogeneity of heart failure (HF) necessitates a more detailed identification of diagnostic biomarkers that can reflect its diverse pathogenic pathways.
METHODS
We conducted weighted gene and multiscale embedded gene co-expression network analysis on differentially expressed genes obtained from HF and non-HF specimens. We employed a machine learning integration framework and protein-protein interaction network to identify diagnostic biomarkers. Additionally, we integrated gene set variation analysis, gene set enrichment analysis (GSEA), and transcription factor (TF)-target analysis to unravel the biomarker-dominant pathways. Leveraging single-sample GSEA and molecular docking, we predicted immune cells and therapeutic drugs related to biomarkers. Quantitative polymerase chain reaction validated the expressions of biomarkers in the plasma of HF patients. A two-sample Mendelian randomization analysis was implemented to investigate the causal impact of biomarkers on HF.
RESULTS
We first identified , , , and as candidate biomarkers with robust diagnostic performance. We revealed that regulating biomarkers in HF pathogenesis involves TFs (, ) and pathways (cell adhesion molecules, chemokine signaling pathway, cytokine-cytokine receptor interaction, oxidative phosphorylation). Moreover, we observed the elevated infiltration of effector memory CD4+ T cells in HF, which was highly related to biomarkers and could impact immune pathways. Captopril, aldosterone antagonist, cyclopenthiazide, estradiol, tolazoline, and genistein were predicted as therapeutic drugs alleviating HF via interactions with biomarkers. In vitro study confirmed the up-regulation of as a plasma biomarker of HF. Mendelian randomization analysis suggested that genetic predisposition toward higher plasma promoted the risk of HF.
CONCLUSIONS
We propose as a diagnostic biomarker for HF, which may advance our understanding of the diagnosis and pathogenesis of HF.
Topics: Humans; Biomarkers; Captopril; Carrier Proteins; Extracellular Matrix Proteins; Glycoproteins; Heart Failure; Intercellular Signaling Peptides and Proteins; Molecular Docking Simulation; Oxidative Phosphorylation; Machine Learning
PubMed: 38397416
DOI: 10.3390/biom14020179 -
The British Journal of Ophthalmology Nov 1988A case-control study of cataract in Oxfordshire explored the risks and benefits associated with a variety of drugs. Steroids including the diuretic spironolactone,...
A case-control study of cataract in Oxfordshire explored the risks and benefits associated with a variety of drugs. Steroids including the diuretic spironolactone, nifedipine, heavy smoking, and beer drinking were associated with a raised risk. On the other hand aspirin-like analgesics (paracetamol, ibuprofen, aspirin, etc. appeared to protect against cataract. Cyclopenthiazide appeared to provide a similar protection.
Topics: Aged; Alcohol Drinking; Anti-Inflammatory Agents, Non-Steroidal; Cataract; Cyclopenthiazide; Diuretics; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Nifedipine; Risk Factors; Smoking; Sodium Chloride Symporter Inhibitors; Steroids
PubMed: 3207655
DOI: 10.1136/bjo.72.11.809 -
The Journal of the College of General... Jan 1967
Clinical Trial Comparative Study
Topics: Aged; Benzothiadiazines; Clinical Trials as Topic; Female; Humans; Kidney Function Tests; Male; Middle Aged; Phytotherapy; Plants, Medicinal; Rauwolfia
PubMed: 4382539
DOI: No ID Found -
The Cochrane Database of Systematic... May 2014Hypertension is a modifiable cardiovascular risk factor. Although it is established that low-dose thiazides reduce mortality as well as cardiovascular morbidity, the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hypertension is a modifiable cardiovascular risk factor. Although it is established that low-dose thiazides reduce mortality as well as cardiovascular morbidity, the dose-related effect of thiazides in decreasing blood pressure has not been subject to a rigorous systematic review. It is not known whether individual drugs within the thiazide diuretic class differ in their blood pressure-lowering effects and adverse effects.
OBJECTIVES
To determine the dose-related decrease in systolic and/or diastolic blood pressure due to thiazide diuretics compared with placebo control in the treatment of patients with primary hypertension. Secondary outcomes included the dose-related adverse events leading to patient withdrawal and adverse biochemical effects on serum potassium, uric acid, creatinine, glucose and lipids.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 1), Ovid MEDLINE (1946 to February 2014), Ovid EMBASE (1974 to February 2014) and ClinicalTrials.gov.
SELECTION CRITERIA
We included double-blind, randomized controlled trials (RCTs) comparing fixed-dose thiazide diuretic monotherapy with placebo for a duration of 3 to 12 weeks in the treatment of adult patients with primary hypertension.
DATA COLLECTION AND ANALYSIS
Two authors independently screened articles, assessed trial eligibility, extracted data and determined risk of bias. We combined data for continuous variables using a mean difference (MD) and for dichotomous outcomes we calculated the relative risk ratio (RR) with 95% confidence interval (CI).
MAIN RESULTS
We included 60 randomized, double-blind trials that evaluated the dose-related trough blood pressure-lowering efficacy of six different thiazide diuretics in 11,282 participants treated for a mean duration of eight weeks. The mean age of the participants was 55 years and baseline blood pressure was 158/99 mmHg. Adequate blood pressure-lowering efficacy data were available for hydrochlorothiazide, chlorthalidone and indapamide. We judged 54 (90%) included trials to have unclear or high risk of bias, which impacted on our confidence in the results for some of our outcomes.In 33 trials with a baseline blood pressure of 155/100 mmHg, hydrochlorothiazide lowered blood pressure based on dose, with doses of 6.25 mg, 12.5 mg, 25 mg and 50 mg/day lowering blood pressure compared to placebo by 4 mmHg (95% CI 2 to 6, moderate-quality evidence)/2 mmHg (95% CI 1 to 4, moderate-quality evidence), 6 mmHg (95% CI 5 to 7, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence), 8 mmHg (95% CI 7 to 9, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence) and 11 mmHg (95% CI 6 to 15, low-quality evidence)/5 mmHg (95% CI 3 to 7, low-quality evidence), respectively.Direct comparison of doses did not show evidence of dose dependence for blood pressure-lowering for any of the other thiazides for which RCT data were available: bendrofluazide, chlorthalidone, cyclopenthiazide, metolazone or indapamide.In seven trials with a baseline blood pressure of 163/88 mmHg, chlorthalidone at doses of 12.5 mg to 75 mg/day reduced average blood pressure compared to placebo by 12.0 mmHg (95% CI 10 to 14, low-quality evidence)/4 mmHg (95% CI 3 to 5, low-quality evidence).In 10 trials with a baseline blood pressure of 161/98 mmHg, indapamide at doses of 1.0 mg to 5.0 mg/day reduced blood pressure compared to placebo by 9 mmHg (95% CI 7 to 10, low-quality evidence)/4 (95% CI 3 to 5, low-quality evidence).We judged the maximal blood pressure-lowering effect of the different thiazides to be similar. Overall, thiazides reduced average blood pressure compared to placebo by 9 mmHg (95% CI 9 to 10, high-quality evidence)/4 mmHg (95% CI 3 to 4, high-quality evidence).Thiazides as a class have a greater effect on systolic than on diastolic blood pressure, therefore thiazides lower pulse pressure by 4 mmHg to 6 mmHg, an amount that is greater than the 3 mmHg seen with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and renin inhibitors, and the 2 mmHg seen with non-selective beta-blockers. This is based on an informal indirect comparison of results observed in other Cochrane reviews on ACE inhibitors, ARBs and renin inhibitors compared with placebo, which used similar inclusion/exclusion criteria to the present review.Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides. These effects were dose-related and were least for hydrochlorothiazide. Chlorthalidone increased serum glucose but the evidence was unclear for other thiazides. There is a high risk of bias in the metabolic data. This review does not provide a good assessment of the adverse effects of these drugs because there was a high risk of bias in the reporting of withdrawals due to adverse effects.
AUTHORS' CONCLUSIONS
This systematic review shows that hydrochlorothiazide has a dose-related blood pressure-lowering effect. The mean blood pressure-lowering effect over the dose range 6.25 mg, 12.5 mg, 25 mg and 50 mg/day is 4/2 mmHg, 6/3 mmHg, 8/3 mmHg and 11/5 mmHg, respectively. For other thiazide drugs, the lowest doses studied lowered blood pressure maximally and higher doses did not lower it more. Due to the greater effect on systolic than on diastolic blood pressure, thiazides lower pulse pressure by 4 mmHg to 6 mmHg. This exceeds the mean 3 mmHg pulse pressure reduction achieved by ACE inhibitors, ARBs and renin inhibitors, and the 2 mmHg pulse pressure reduction with non-selective beta-blockers as shown in other Cochrane reviews, which compared these antihypertensive drug classes with placebo and used similar inclusion/exclusion criteria.Thiazides did not increase withdrawals due to adverse effects in these short-term trials but there is a high risk of bias for that outcome. Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides.
Topics: Adult; Antihypertensive Agents; Blood Pressure; Chlorthalidone; Essential Hypertension; Humans; Hydrochlorothiazide; Hypertension; Indapamide; Middle Aged; Randomized Controlled Trials as Topic; Sodium Chloride Symporter Inhibitors
PubMed: 24869750
DOI: 10.1002/14651858.CD003824.pub2 -
British Medical Journal Oct 1980In patients with hypertension resistant to three or four drugs including a thiazide diuretic substitution of frusemide for the thiazide, or the addition of...
In patients with hypertension resistant to three or four drugs including a thiazide diuretic substitution of frusemide for the thiazide, or the addition of spironolactone, produced significant reductions in blood pressure and body weight. The response did not depend on the presence of overt fluid retention, renal impairment, or the use of antihypertensive drugs of high potency. Women had larger responses than men. Expansion of the plasma or extracellular fluid volume is an important cause of resistance to treatment even when a thiazide diuretic is used. An increase in diuretic treatment should be tried before using the postganglionic adrenergic blockers or minoxidil in resistant hypertension.
Topics: Adult; Aged; Bendroflumethiazide; Body Weight; Cyclopenthiazide; Drug Resistance; Female; Furosemide; Humans; Hypertension; Male; Middle Aged; Spironolactone
PubMed: 7427599
DOI: 10.1136/bmj.281.6248.1101 -
The Journal of International Medical... 1981In a within-patient comparison of conventional oxprenolol administered twice daily with slow-release oxprenolol administered once daily in the treatment of hypertension,... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
In a within-patient comparison of conventional oxprenolol administered twice daily with slow-release oxprenolol administered once daily in the treatment of hypertension, twenty patients previously responsive to beta-blockers took each formulation for 4 weeks, after wash-out periods off beta-blocker of 2 weeks' duration. The order of administration of the two forms was randomized, and sixteen patients continued medication with cyclopenthiazide 0.5 mg daily. Blood pressure levels at the end of the 4-week treatment periods were compared with levels at the end of the preceding 2-week wash-out periods. Both formulations lowered blood pressure and pulse rate significantly. There was no difference in their effects on pulse rate or on blood pressure, whether measured by the doctors using standard sphygmomanometers or by the hypertension sister using a random-zero sphygmomanometer. In four patients who measured their own blood pressures at home each morning (before medications), afternoon and night, mean levels were similar with the two formulations. Both formulations were very well tolerated.
Topics: Adult; Aged; Blood Pressure; Clinical Trials as Topic; Delayed-Action Preparations; Drug Administration Schedule; Female; Humans; Hypertension; Male; Middle Aged; Oxprenolol; Pulse
PubMed: 7009256
DOI: 10.1177/030006058100900102 -
BMC Cancer Jul 2011Breast cancer is the second leading cause of cancer-related death in women in the United States. During the advanced stages of disease, many breast cancer patients...
BACKGROUND
Breast cancer is the second leading cause of cancer-related death in women in the United States. During the advanced stages of disease, many breast cancer patients suffer from bone metastasis. These metastases are predominantly osteolytic and develop when tumor cells interact with bone. In vivo models that mimic the breast cancer-specific osteolytic bone microenvironment are limited. Previously, we developed a mouse model of tumor-bone interaction in which three mouse breast cancer cell lines were implanted onto the calvaria. Analysis of tumors from this model revealed that they exhibited strong bone resorption, induction of osteoclasts and intracranial penetration at the tumor bone (TB)-interface.
METHODS
In this study, we identified and used a TB microenvironment-specific gene expression signature from this model to extend our understanding of the metastatic bone microenvironment in human disease and to predict potential therapeutic targets.
RESULTS
We identified a TB signature consisting of 934 genes that were commonly (among our 3 cell lines) and specifically (as compared to tumor-alone area within the bone microenvironment) up- and down-regulated >2-fold at the TB interface in our mouse osteolytic model. By comparing the TB signature with gene expression profiles from human breast metastases and an in vitro osteoclast model, we demonstrate that our model mimics both the human breast cancer bone microenvironment and osteoclastogenesis. Furthermore, we observed enrichment in various signaling pathways specific to the TB interface; that is, TGF-β and myeloid self-renewal pathways were activated and the Wnt pathway was inactivated. Lastly, we used the TB-signature to predict cyclopenthiazide as a potential inhibitor of the TB interface.
CONCLUSION
Our mouse breast cancer model morphologically and genetically resembles the osteoclastic bone microenvironment observed in human disease. Characterization of the gene expression signature specific to the TB interface in our model revealed signaling mechanisms operative in human breast cancer metastases and predicted a therapeutic inhibitor of cancer-mediated osteolysis.
Topics: Animals; Bone Neoplasms; Cell Line, Tumor; Cluster Analysis; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Histocytochemistry; Humans; Mammary Neoplasms, Experimental; Mice; Osteoclasts; Osteolysis; Reproducibility of Results; Signal Transduction; Transforming Growth Factor beta; Tumor Microenvironment; Wnt Proteins
PubMed: 21774828
DOI: 10.1186/1471-2407-11-304