Clinical evaluation of amiloride, a potassium‐sparing diuretic

Lant, A. F.; Smith, Anthony J.; Wilson, Graham M.

doi:10.1002/cpt196910150

Cited by 35 publications

(20 citation statements)

References 6 publications

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“…The amilorides are a wellcharacterized class of small molecules known to inhibit epithelial sodium channel (ENaC) activity (2,5,6,17,29). Due to this activity, amilorides are widely used as diuretics in humans (30,37). To determine the correlation between the osteogenic effects of phenamil and ENaC-blocking activity, we assayed three additional amiloride derivatives that are also known to inhibit ENaC.…”

Section: Resultsmentioning

confidence: 99%

The Small Molecule Phenamil Induces Osteoblast Differentiation and Mineralization

Park

Waki

Kim³

et al. 2009

Molecular and Cellular Biology

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Bone is continuously remodeled throughout life by a tightly coupled process involving absorption by osteoclasts and formation by osteoblasts. Dysregulation of this coupled remodeling can lead to diseases such as osteoporosis (18,19). The precursors of osteoblasts are pluripotent cells known as mesenchymal stem cells (MSCs) (3,7,36). MSCs are viewed as potential tools for therapeutic intervention in diseases related to impaired function of osteoblasts because they can be derived from bone marrow, manipulated in culture, and administered back to donor individuals (12,13,24,39,40). However, the mechanistic pathways that drive differentiation of MSCs along the osteoblast lineage are not completely understood. Therefore, elucidation of molecular mechanisms underlying osteogenesis not only is important for our understanding of bone development but also may advance strategies for bone repair. Targeting therapeutic molecules to bone in order to enhance the bone-forming activity of osteoblast precursors may aid in the treatment of bone disease.Osteoinductive factors are required to drive the lineagespecific differentiation of MSCs into osteoblastic cells in culture. Osteoblast differentiation is influenced by multiple signaling pathways, including transforming growth factor ␤1, Hedgehog, Wnt, fibroblast growth factors, insulin-like growth factor 1, and bone morphogenetic proteins (BMPs) (8,20,25,46,49). Strategies employing BMPs have been successfully used with animals and humans to regenerate bones (16,22,27). However, the high cost and supraphysiologic doses of BMPs necessary to achieve osteoinductive activity illustrate the need for additional strategies for the stimulation of osteoblast differentiation and bone formation in vivo (23,32,48). Recent studies of zebrafish have validated the concept of employing small molecules to modulate BMP activity in vivo (50). Similarly, certain oxysterols have been shown to activate sonic hedgehog (SHH) and to stimulate osteoblastic differentiation and bone formation (1, 15). However, smallmolecule BMP stimulators that are able to bypass the need for high doses of BMP and induce bone formation remain to be identified.Here we show that the small molecule phenamil, a derivative of the diuretic amiloride, induces osteoblastic differentiation and mineralization of mouse MSCs. Phenamil and BMPs show additive effects on the expression of BMP target genes, osteogenic markers, and matrix mineralization in M2-10B4 (M2) MSCs as well as in calvarial organ cultures. We show that phenamil acts, at least in part, by inducing the expression of tribbles homolog 3 (Trb3), a previously identified positive regulator of BMP signaling (9,33,51). We further show that phenamil reduces the protein level of SMAD ubiquitin regulatory factor 1 (Smurf1) and induces expression of SMAD, the critical transcription factor in BMP signaling. These results suggest that phenamil or related small molecules may represent a novel strategy for increasing BMP activity in the clinical setting.

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Section: Resultsmentioning

confidence: 99%

The Small Molecule Phenamil Induces Osteoblast Differentiation and Mineralization

Park

Waki

Kim³

et al. 2009

Molecular and Cellular Biology

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“…The patients who participated in this study varied in the extent of severity of their cardiac failure and as such were categorized into groups A and B. Using established comparative assay technique previously validated (Lant et al, 1969), we have compared the potency of piretanide with respect to frusemide at three different dose levels.…”

Section: Resultsmentioning

confidence: 99%

Acute and long‐term renal and metabolic effects of piretanide in congestive cardiac failure.

McNabb

Noormohamed

Lant

1988

Brit J Clinical Pharma

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1 The renal and metabolic effects of the sulphamoylbenzoic acid diuretic, piretanide, have been studied, under controlled dietary conditions, in 39 patients with congestive cardiac failure.2 In acute studies, peak saluresis occurred within 4 h of oral piretanide administration; saluresis was complete within 6 h, after which a significant antidiuretic effect was observed. Addition of triamterene, 50 mg, blunted the 0-6 h kaliuretic effect of piretanide. Over 24 h, piretanide, alone, caused insignificant urinary losses of potassium when compared with control. 3 In comparative studies, the piretanide dose-response curve was found to be parallel to that of frusemide over the dose range studied. The 0-6 h saluretic responses of piretanide, 6, 12 and 18 mg, were found to be equivalent to frusemide, 40,80 and 120 mg respectively. The collective mean ratios of all the saluretic responses to each dose of piretanide with the corresponding dose of frusemide was observed to be 0.99 ± 0.12, over 0-6 h period, and 0.86 ± 0.09 over the 24 h period. The relative potency of piretanide, when compared with frusemide was found to be 6.18 (95% confidence limits 4.87 -8.33), over the 0-6 h period, and 4.73 (95% confidence limits 3.65 -6.14), over 24 h period. 4 In 15 patients in severe cardiac failure, urinary recovery of piretanide, over first 6 h, at the start of treatment was 21.2 ± 2.1% while efficiency of the diuretic (mmol Na/mg drug) was 47.3 ± 4.1. Long-term piretanide therapy was continued in the same group for up to and in some cases over 3 years. No other diuretics or potassium supplements were given.Piretanide dosage ranged from 6 to 24 mg day-' according to clinical need. Plasma potassium fell significantly at 12 and 24 months, though remaining within the normal range. At these same times, significant elevations in both plasma urate and total fasting cholesterol were observed. Two patients developed overt gout on high dose piretanide therapy (24 mg day-1). Piretanide was well tolerated, and effective in the management of congestive cardiac failure without any other recognized metabolic or electrolyte changes.

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“…Previous dose-response studies using single doses of amiloride suggested that maximum effects on urine volume and sodium, chloride, and potassium excretion occurs with a dose of 40 mg (Lant et al, 1969). In the light of these data and our previous longterm use of amiloride at a dose of 40 mg (Kremer et al, 1977), we suggest that the maximum recommended daily dose of amiloride should be doubled.…”

Section: Discussionmentioning

confidence: 86%

Metabolic effects of high dose amiloride and spironolactone: a comparative study in normal subjects.

Ja¹,

Fraser²,

Mason³

et al. 1984

Brit J Clinical Pharma

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1 Amiloride (75 mg daily) and spironolactone (300 mg daily) were given to five normal subjects for 7 days in order to compare metabolic effects at maximal doses. 2 Blood pressure, body weight, Na+ and K' balance, and plasma concentrations of Na+, K+, active and total renin, angiotensin II, aldosterone, 11-deoxycorticosterone (DOC), 18-hydroxydeoxycorticosterone (18-OH DOC), corticosterone (B), 18-hydroxycorticosterone (18-OH B) and cortisol were measured before and on each day of treatment. 3 Natriuresis and K+ retention were significantly greater with amiloride. Plasma K+ increased from 4.1 ± 0.2 to 4.9 ± 0.2 mmol/l (mean + s.d.) on amiloride and from 4.0 + 0.2 to 4.4 + 0.2 mmol/l with spironolactone. Stimulation of renin, angiotensin II, aldosterone and 18-OH B occurred with both drugs but was greater with amiloride in each case. A transient decrease in systolic and diastolic blood pressure was observed after 2 days of spironolactone treatment but not with amiloride. The slope of the regression of aldosterone on angiotensin II during spironolactone treatment was less than that with amiloride, consistent with partial blockade of aldosterone synthesis by spironolactone. 4 These data suggest that the maximum metabolic effects of amiloride exceed those of spironolactone.

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Clinical evaluation of amiloride, a potassium‐sparing diuretic

Cited by 35 publications

References 6 publications

The Small Molecule Phenamil Induces Osteoblast Differentiation and Mineralization

The Small Molecule Phenamil Induces Osteoblast Differentiation and Mineralization

Acute and long‐term renal and metabolic effects of piretanide in congestive cardiac failure.

Metabolic effects of high dose amiloride and spironolactone: a comparative study in normal subjects.

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