Effects of Triamterene in Hospitalized Patients with Heart Failure and Diuretic Resistance: A Randomized Clinical Trial.

Due to the potential benefits of triamterene in diuretic resistance, this study was performed to assess whether triamterene add-on to the standard treatment of heart failure (HF)-related diuretic resistance improves outcomes. A randomized clinical trial was performed on 45 hospitalized patients with HF with reduced ejection fraction who had diuretic resistance. Patients were randomized to receive either triamterene 50 mg plus hydrochlorothiazide 25 mg (n = 23) or hydrochlorothiazide 50 mg alone (n = 22) until hospital discharge. The primary outcomes were changes in weight and fluid input-to-output ratio. Secondary outcomes were respiratory rate, hospitalization duration, serum sodium and potassium, estimated glomerular filtration rate, creatinine, and blood urea nitrogen levels during the study period. The mean (standard deviation) of weight changes was not significantly different in the intervention and the control groups (-6.3 [4.8] vs -4.8 [2.4] kg, respectively; P = .1). No significant differences were shown in input-to-output changes between the 2 groups (208.0 [243.4] in the intervention and 600.2 [250.3] in the control group; P = .4). Although the respiratory rate of triamterene-treated patients decreased, the difference did not reach statistical significance (P = .2). Other secondary outcomes were also similar in both groups. This study did not support the use of triamterene as an add-on therapy for patients with HF-related diuretic resistance.

Repurposing of triamterene as a histone deacetylase inhibitor to overcome cisplatin resistance in lung cancer treatment.

PURPOSE: Cisplatin is the core chemotherapeutic drug used for first-line treatment of advanced non-small cell lung cancer (NSCLC). However, drug resistance is severely hindering its clinical efficacy. This study investigated the circumvention of cisplatin resistance by repurposing non-oncology drugs with putative histone deacetylase (HDAC) inhibitory effect. METHODS: A few clinically approved drugs were identified by a computational drug repurposing tool called "DRUGSURV" and evaluated for HDAC inhibition. Triamterene, originally indicated as a diuretic, was chosen for further investigation in pairs of parental and cisplatin-resistant NSCLC cell lines. Sulforhodamine B assay was used to evaluate cell proliferation. Western blot analysis was performed to examine histone acetylation. Flow cytometry was used to examine apoptosis and cell cycle effects. Chromatin immunoprecipitation was conducted to investigate the interaction of transcription factors to the promoter of genes regulating cisplatin uptake and cell cycle progression. The circumvention of cisplatin resistance by triamterene was further verified in a patient-derived tumor xenograft (PDX) from a cisplatin-refractory NSCLC patient. RESULTS: Triamterene was found to inhibit HDACs. It was shown to enhance cellular cisplatin accumulation and potentiate cisplatin-induced cell cycle arrest, DNA damage, and apoptosis. Mechanistically, triamterene was found to induce histone acetylation in chromatin, thereby reducing the association of HDAC1 but promoting the interaction of Sp1 with the gene promoter of hCTR1 and p21. Triamterene was further shown to potentiate the anti-cancer effect of cisplatin in cisplatin-resistant PDX in vivo. CONCLUSION: The findings advocate further clinical evaluation of the repurposing use of triamterene to overcome cisplatin resistance.

Triamterene in lithium-induced nephrogenic diabetes insipidus: a case report.

Lithium-induced nephrogenic diabetes insipidus (NDI) is a rare and difficult-to-treat condition. We describe the case of an 81-year-old woman with bipolar treated with lithium and no previous history of diabetes insipidus. She was hospitalized due to disturbance of consciousness and was diagnosed with, hypercalcemia, hyperparathyroidism, and NDI. Parathyroidectomy was contraindicated and parathyroid hormone level was improved insufficiently after cinacalcet initiation, percutaneous ethanol injection therapy was performed for the enlarged parathyroid gland. After improvement in hypercalcemia and unsuccessful indapamide treatment, triamterene was administrated to control polyuria. Lithium is one of the indispensable maintenance treatment options for bipolar disorder, but it has the side effect of NDI. Lithium enters the collecting duct's principal cells mainly via the epithelial sodium channel (ENaC) located on their apical membranes, ENaC shows high selectivity for both sodium and lithium, is upregulated by aldosterone, and inhibited by triamterene. To our knowledge, this is the first publication on triamterene use in lithium-induced NDI patients.

Therapeutic potential of pteridine derivatives: A comprehensive review.

Pteridines are aromatic compounds formed by fused pyrazine and pyrimidine rings. Many living organisms synthesize pteridines, where they act as pigments, enzymatic cofactors, or immune system activation molecules. This variety of biological functions has motivated the synthesis of a huge number of pteridine derivatives with the aim of studying their therapeutic potential. This review gathers the state-of-the-art of pteridine derivatives, describing their biological activities and molecular targets. The antitumor activity of pteridine-based compounds is one of the most studied and advanced therapeutic potentials, for which several molecular targets have been identified. Nevertheless, pteridines are also considered as very promising therapeutics for the treatment of chronic inflammation-related diseases. On the other hand, many pteridine derivatives have been tested for antimicrobial activities but, although some of them resulted to be active in preliminary assays, a deeper research is needed in this area. Moreover, pteridines may be of use in the treatment of many other diseases, such as diabetes, osteoporosis, ischemia, or neurodegeneration, among others. Thus, the diversity of the biological activities shown by these compounds highlights the promising therapeutic use of pteridine derivatives. Indeed, methotrexate, pralatrexate, and triamterene are Food and Drug Administration approved pteridines, while many others are currently under study in clinical trials.

Newly Diagnosed Meniere's Disease: Clinical Course With Initiation of Noninvasive Treatment Including an Accounting of Vestibular Migraine.

OBJECTIVE: To describe the course of Meniere's disease with noninvasive treatment during the first few years after initial diagnosis. METHODS: A retrospective review of consecutive patients with newly diagnosed definite Meniere's disease between 2013 and 2016 and a minimum follow-up of 1 year. Patients received a written plan for low sodium, water therapy, and treatment with a diuretic and/or betahistine. Subjects were screened and treated for vestibular migraine as needed. Vertigo control and hearing status at most recent follow-up were assessed. RESULTS: Forty-four subjects had an average follow up of 24.3 months. Thirty-four percent had Meniere's disease and vestibular migraine, and 84% had unilateral Meniere's disease. Seventy-five percent had vertigo well controlled at most recent follow-up, with only noninvasive treatments. Age, gender, body mass index, presence of vestibular migraine, bilateral disease, and duration of follow-up did not predict noninvasive treatment failure. Worse hearing threshold at 250 Hz and lower pure tone average (PTA) at the time of diagnosis did predict failure. Fifty-two percent of ears had improved PTA at most recent visit, 20% had no change, and 28% were worse Conclusions: Encountering excellent vertigo control and stable hearing after a new diagnosis of Meniere's disease is possible with noninvasive treatments. Worse hearing status at diagnosis predicted treatment failure.

Liddle syndrome: clinical and genetic profiles.

Liddle syndrome is a rare autosomal dominant monogenic form of hypertension. The authors analyzed clinical and genetic features of 12 cases of Liddle syndrome, the largest sample size ever reported. Clinical data were studied retrospectively. The exon 13 of the ß and γ subunits of the epithelial sodium channel were amplified and sequenced in the peripheral blood leukocytes of the patients. The onset age of the 12 patients was 15.5±3.3 years. Their blood pressures were poorly controlled, and serum potassium levels in most patients were <3.0 mmol/L. Upright plasma renin activity and plasma aldosterone concentration were suppressed in all patients. All patients were treated with triamterene, and blood pressures were well controlled and serum potassium levels returned to normal. The serum creatinine level rose to 124 and 161 µmol/L, respectively, in two patients upon triamterene treatment, and returned to normal soon after treatment was discontinued. Eight mutation alleles were identified, and three mutations were newly identified.

A practical approach for measurement of antihypertensive medication adherence in patients with resistant hypertension.

Confirmation of medication adherence is a challenge in clinical practice and essential for the accurate diagnosis of resistant hypertension. Although it is well established that drug adherence is critical for controlling blood pressure, there are still difficulties applying a simple, inexpensive, and reliable assessment of adherence in the clinical setting. We aimed to test a simple method to assess adherence in resistant hypertensive (RH) patients. A pilot study with normotensives or mild/moderate hypertensive subjects was performed to provide a fluorescence cutoff point for adherence. After that, 21 patients referred to the Resistant Hypertension Clinic had triamterene prescribed and were monitored for a 30-day period. We conducted two unannounced randomly selected home visits for urine collection to test drug intake that day. Office, home and 24-hour ambulatory blood pressure, biochemical data, and the 8-item Morisky Medication Adherence Scale (MMAS-8) were systematically acquired. According to adherence indicated by urine fluorescence, subjects were divided into adherent and nonadherent groups. We found 57% of nonadherence. No differences were found between groups regarding baseline characteristics or prescribed medications; Kappa's test showed concordance between adherence through MMAS-8 items and fluorescence (kappa = 0.61; 95% confidence interval: 0.28-0.94; P = .005). Nonadherent patients had higher office (81 ± 11 vs. 73 ± 6 mm Hg, P = .03), 24-hour ambulatory blood pressure monitoring (75 ± 9 vs. 66 ± 7 mm Hg, P = .01), and home blood pressure measurement (77 ± 9 vs. 67 ± 8 mm Hg, P = .01) diastolic blood pressure than their counterparts. Nonadherence to antihypertensive therapy is high in patients with RH, even when assessed in clinics specialized in this condition. Fluorometry to detect a drug in the urine of RH patients is safe, easy, and reliable method to assess adherence.

A role for ATP-sensitive potassium channels in the anticonvulsant effects of triamterene in mice.

There are reports indicating that diuretics including chlorothiazide, furosemide, ethacrynic acid, amiloride and bumetanide can have anticonvulsant properties. Intracellular acidification appears to be a mechanism for the anticonvulsant action of some diuretics. This study was conducted to investigate whether or not triamterene, a K(+)-sparing diuretic, can generate protection against seizures induced by intravenous or intraperitoneal pentylenetetrazole (PTZ) models. And to see if, triamterene can withstand maximal electroshock seizure (MES) in mice. We also investigated to see if there is any connection between triamterene's anti-seizure effect and ATP-sensitive K(+) (KATP) channels. Five days triamterene oral administration (10, 20 and 40 mg/kg), significantly increased clonic seizure threshold which was induced by intravenous pentylenetetrazole. Triamterene (10, 20 and 40 mg/kg) treatment also increased the latency of clonic seizure and decreased its frequency in intraperitoneal PTZ model. Administration of triamterene (20 mg/kg) also decreased the incidence of tonic seizure in MES-induced seizure. Co-administration of a KATP sensitive channel blocker, glibenclamide, in the 6th day, 60 min before intravenous PTZ blocked triamterene's anticonvulsant effect. A KATP sensitive channel opener, diazoxide, enhanced triamterene's anti-seizure effect in both intravenous PTZ or MES seizure models. At the end, triamterene exerts anticonvulsant effect in 3 seizure models of mice including intravenous PTZ, intraperitoneal PTZ and MES. The anti-seizure effect of triamterene probably is induced through KATP channels.

The R900S mutation in CACNA1S associated with hypokalemic periodic paralysis.

Primary hypokalemic periodic paralysis is an autosomal dominant skeletal muscle channelopathy. In the present study, we investigated the genotype and phenotype of a Chinese hypokalemic periodic paralysis family. We used whole-exome next-generation sequencing to identify a mutation in the calcium channel, voltage-dependent, L type, alpha subunit gene (CACNA1S), R900S, which is a rare mutation associated with hypokalemic periodic paralysis. We first present a clinical description of hypokalemic periodic paralysis patients harboring CACNA1SR900S mutations: they were non-responsive to acetazolamide, but combined treatment with triamterene and potassium supplements decreased the frequency of muscle weakness attacks. All male carriers of the R900S mutation experienced such attacks, but all three female carriers were asymptomatic. This study provides further evidence for the phenotypic variation and pharmacogenomics of hypokalemic periodic paralysis.

Chemometrics-assisted determination of amiloride and triamterene in biological fluids with overlapped peaks and unknown interferences.

BACKGROUND: Amiloride (AMI) and triamterene (TRI) are both potassium-saving diuretics, which are ordinarily used as doping to enhance the performance of athletes in sports. For the similar structures and complex matrices existence, chromatography and extraction are commonly employed to realize the determination of AMI and TRI in biological fluids, which are very time-consuming and laborious. RESULTS: A novel method is presented to simultaneous interference-free determination of AMI and TRI in complex biological fluids samples using excitation-emission matrix fluorescence coupled with second-order calibration method based on alternating normalization-weight error algorithm. CONCLUSION: The proposed method can obtain accurate qualitative and quantitative information of the analytes, even in the presence of the interference from complex biological fluids, which requires few prior purification and separation procedures.

Garlic for the prevention of cardiovascular morbidity and mortality in hypertensive patients.

BACKGROUND: Garlic is widely used by patients for its blood pressure lowering effects. A meta-analysis published in 2008 concluded that garlic consumption lowers blood pressure in hypertensive and normotensive patients. Therefore, it is important to review the currently available evidence to determine whether garlic may also have a beneficial role in the reduction of cardiovascular events and mortality rates in patients with hypertension. OBJECTIVES: To determine whether the use of garlic as monotherapy, in hypertensive patients, lowers the risk of cardiovascular morbidity and mortality compared to placebo. SEARCH METHODS: A systematic search for trials was conducted in the Cochrane Hypertension Group Specialised Register, CENTRAL, MEDLINE, EMBASE, AGRICOLA, AMED, and CINAHL up to November 2011. A hand search of reference lists of identified reviews was conducted. Experts in the area were also contacted to identify trials not found in the electronic search. Clinicaltrials.gov was searched for ongoing trials. SELECTION CRITERIA: Randomized, placebo-controlled trials of any garlic preparation versus placebo for the treatment of hypertension were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality using the risk of bias tool. Data synthesis and analysis was performed using RevMan 5. MAIN RESULTS: The search identified two randomized controlled trials for inclusion. One trial included 47 hypertensive patients and showed that garlic significantly reduces mean supine systolic blood pressure by 12 mmHg (95% CI 0.56 to 23.44 mmHg, p=0.04) and mean supine diastolic blood pressure by 9 mmHg (95% CI 2.49 to 15.51 mmHg, p=0.007) versus placebo. The authors state that garlic was "free from side effects" and that no serious side effects were reported. There were 3 cases "where a slight smell of garlic was noted."The second trial could not be meta-analysed as they did not report the number of people randomized to each treatment group. They did report that 200 mg of garlic powder given three times daily, in addition to hydrochlorothiazide-triamterene baseline therapy, produced a mean reduction of systolic blood pressure by 10-11 mmHg and of diastolic blood pressure by 6-8 mmHg versus placebo.Neither trial reported clinical outcomes and insufficient data was provided on adverse events. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine if garlic provides a therapeutic advantage versus placebo in terms of reducing the risk of mortality and cardiovascular morbidity in patients diagnosed with hypertension. There is also insufficient evidence to determine the difference in withdrawals due to adverse events between patients treated with garlic or placebo.Based on 2 trials in 87 hypertensive patients, it appears that garlic reduces mean supine systolic and diastolic blood pressure by approximately 10-12 mmHg and 6-9 mmHg, respectively, over and above the effect of placebo but the confidence intervals for these effect estimates are not precise and this difference in blood pressure reduction falls within the known variability in blood pressure measurements. This makes it difficult to determine the true impact of garlic on lowering blood pressure.

Use of a rhesus Plasmodium cynomolgi model to screen for anti-hypnozoite activity of pharmaceutical substances.

There remains a need for new drugs to prevent relapse of Plasmodium vivax or P. ovale infection. The relapsing primate malaria P. cynomolgi has been used for decades to assess drugs for anti-hypnozoite activity. After sporozoite inoculation and blood-stage cure of initial parasitemia with chloroquine, rhesus macaques were treated on subsequent relapses with chloroquine in conjunction with test regimens of approved drugs. Tested drugs were selected for known liver or blood-stage activity and were tested alone or in conjunction with low-dose primaquine. Tinidazole and pyrazinamide prevented relapse when used in conjunction with chloroquine and low-dose primaquine. Triamterene and tinidazole administered without primaquine achieved radical cure in some animals. All other tested drugs or combinations failed to prevent relapse. The rhesus macaque-P. cynomolgi model remains a useful tool for screening drugs with anti-hypnozoite activity. Tinidazole and pyrazinamide require further investigation as agents to enable dose reduction of primaquine.

Amiloride off-target effect inhibits podocyte urokinase receptor expression and reduces proteinuria.

The urokinase receptor (uPAR) and its soluble form play a key role in the pathogenesis of focal segmental glomerulosclerosis (FSGS). The modification of uPAR pathological actions on podocytes will become an important task for the development of improved nephroprotective therapeutics. Here we show that podocyte uPAR expression can be reduced using amiloride. Amiloride has a significant role in the reduction of podocyte cell motility in vitro and proteinuria in mice. Amiloride inhibited the induction of uPAR protein and PLAUR messenger RNA (encoding uPAR) and with that it reduced uPAR-mediated ß3 integrin activation in lipopolysaccharide (LPS)-treated podocytes. Transwell migration assay and wound healing assay showed that directed and random podocyte motility of LPS-treated podocytes were increased and substantially reduced by amiloride. The off-target effect of amiloride was independent of its function as epithelial sodium channel blocker and different from triamterene. Amiloride was also effective in the LPS mouse model of transient proteinuria (LPS mice) and in the 5/6 nephrectomy rat FSGS model (NTX) by significantly inhibiting podocyte uPAR induction, reducing proteinuria. In addition, amiloride attenuated glomerulosclerosis, as determined by glomerulosclerotic index. Thus, our observations show that amiloride inhibits podocyte uPAR induction and reduces proteinuria in NTX rats and LPS mice. Given the pathological relevance of the uPAR-ß3 integrin signaling axis in FSGS, amiloride may be utilized in patients with FSGS.

Long-term efficacy and tolerability of a fixed-dose combination of antihypertensive agents: an open-label surveillance study in China.

BACKGROUND: A fixed-dose combination (FDC) of four compounds, hydrochlorothiazide 12.5 mg, triamterene 12.5 mg, dihydralazine 12.5 mg and reserpine 0.1 mg (HTDR), is widely used as an antihypertensive treatment in China. Although HTDR has been used in China for more than 30 years, there have been few comprehensive evaluations of this treatment. OBJECTIVE: The aim of this study was to investigate the long-term efficacy and tolerability of HTDR in Chinese patients with essential hypertension. METHODS: This was a 36-month, community-based, open-label surveillance study, conducted in the Huangpu District (Shanghai, China). The study was based in local primary healthcare settings. Subjects were recruited if they had essential hypertension, were aged ≥35 years at the time of enrolment, were expected to remain in the area for 3 years, and were able to provide informed consent. Patients who had secondary hypertension, myocardial infarction or stroke within 6 months of screening, impaired renal or hepatic function, history of cardiomyopathy or chronic heart failure, or were pregnant or lactating were excluded. HTDR was administered as one or two tablets per day in the morning. If necessary, additional hydrochlorothiazide was added. Blood pressure (BP) was measured at baseline and throughout the 36-month surveillance period every 3 months. Biochemical indicators (e.g. fasting blood glucose, plasma lipid parameters, plasma sodium and potassium, plasma uric acid and serum creatinine) were also measured, and adverse events were noted. BP reductions and the rate at which patients achieved BP targets (systolic BP [SBP] <140 mmHg and diastolic BP [DBP] <90 mmHg) throughout the period were determined. Subgroup analyses by sex and age were also conducted. RESULTS: A total of 1529 patients (550 male, 979 female; mean age 65.7 years) entered the study. After the 36-month treatment period, 93.1% of patients had achieved the SBP target, 97.9% had achieved the DBP target, and 92.1% had achieved both. The mean decreases in SBP and DBP were 15.3 mmHg and 9.9 mmHg, respectively. Overall, 127 adverse events in 119 patients (7.8%) occurred during the follow-up period, most of which were mild to moderate. Plasma lipid profiles were improved after 24 months of treatment. In addition, a significant increase in plasma potassium and a significant reduction in plasma uric acid were seen. CONCLUSION: HTDR was found to have good long-term efficacy and tolerability in Chinese patients with essential hypertension.

Hydrochlorothiazide-induced noncardiogenic pulmonary edema: an underrecognized yet serious adverse drug reaction.

Noncardiogenic pulmonary edema is a rare but potentially life-threatening complication of hydrochlorothiazide therapy. We describe three patients who developed this serious adverse reaction. A 64-year-old woman developed dypsnea and hypotension within 60 minutes of taking a single dose of hydrochlorothiazide 25 mg. She was admitted to the critical care unit with acute respiratory failure and subsequent multiple-organ dysfunction. The second patient was a 56-year-old woman who experienced sudden onset of shortness of breath that developed 10 minutes after taking a single dose of hydrochlorothiazide 25 mg. The third was a 59-year-old woman who developed sudden onset of shortness of breath, nausea, vomiting, and diarrhea after her first dose of hydrochlorothiazide-triamterene. All three women had a history of a similar, albeit minor, reaction to a thiazide diuretic. Review of the literature identified 36 additional cases of noncardiogenic pulmonary edema after thiazide use. The patients developed symptoms 10-150 minutes after ingestion of hydrochlorothiazide or another thiazide. Symptoms can occur on first exposure to the drug or in patients taking the drug intermittently. Of interest, 90% of documented cases occurred in women. With the increasing use of thiazide diuretics in the treatment of hypertension, clinicians need to be aware of the possible association of these drugs with the development of noncardiogenic pulmonary edema.

[Differential diagnosis of a macrocytic, hyperchromic anemia following alcohol abuse and simultaneous therapy with triamterene and cotrimoxazole]. / Differentialdiagnose einer makrozytären, hyperchromen Anämie bei Alkoholabusus und gleichzeitiger Triamteren- und Cotrimoxazoltherapie.

HISTORY AND ADMISSION FINDINGS: A 50-year-old woman was admitted to our emergency room because of progressive weakness. She collapsed the night before admission. Skin and mucosa were pale, she denied major infections or bleedings. An alcohol abuse was known for many years. Because of edema she received a therapy with triamteren, an infection of the urinary tract was treated with cotrimoxacol. INVESTIGATIONS: In addition to thrombocytopenia (50 Gpt/l) and leukocytopenia (1,51 10 (9)/l) we diagnosed a hyperchromic and macrocytic anemia (Hb 3,6 mmol/l [5,8 g/dl], Hk 0,17, MCH 2.52 fmol, 116,8 fl). Folic acid was decreased to 0.677 ng/ml, whereas levels of cobalamin, ferritin and iron were normal. Examination of bone marrow showed a hypercellular marrow with typical megaloblastic features of erythropoiesis and granulopoiesis. A systemic hematological disorder could be ruled out. The folic acid deficiency in our patient was the result of a long time alcohol abuse and a simultaneous therapy with mild folate antagonists (triamteren and cotrimoxacol). CLINICAL COURSE: The patient received folic acid (5 mg/d orally). Within one week the peripheral blood counts increased to normal, the follow up bone marrow examination showed a hyperplastic marrow with normal hematopoietic maturation. CONCLUSIONS: Folic acid deficiency can be aggravated because of simultaneous therapy with mild folate antagonists. In addition to megaloblastic anemia this can lead to thrombocytopenia and/or leukocytopenia. Therefore in patients with pancytopenia a deficiency of folic acid should be ruled out.