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At least 19 recordsLinked to original sources

PubMed1975

Metabolism of minoxidil, a new hypotensive agent II: biotransformation following oral administration to rats, dogs, and monkeys.

The biotransformation of minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) was studied in the rat, dog, and monkey and compared to reported results in the human. Chromatographic profiles of urinary metabolites show that each species excreted substantially the same metabolites but in quite different relative amounts. The monkey and the human exhibited similar metabolite profiles, whereas the dog and rat were quantitatively different from each other and from the monkey and human. The major excretory product for the monkey and human was a glucuronide conjugate of minoxidil. Substantially smaller amounts of unchanged minoxidil, 2,4-diamino-6-(4'-hydroxypiperidino)pyrimidine 3-oxide, and more polar metabolites also were excreted by these two species. The major excretory product in the rat was unchanged minoxidil. Almost as much (combined) of the two acidic metabolites, 2,4-diamino-6-(4'-carboxy-n-butylamino)pyrimidine and its 3-oxide, also were produced. Smaller amounts of the glucuronide of minoxidil, 2,4-diamino-6-(4'-hydroxypiperidino)pyrimidine 3-oxide, its 3'-hydroxy isomer, and 2,4-diamino-6-piperidinopyrimidine also were excreted by the rat. The major metabolite of minoxidil excreted by the dog was the 4'-hydroxy metabolite. Smaller amounts of unchanged minoxidil and polar metabolites and much smaller amounts of the glucuronide of minoxidil, the 3'-hydroxy metabolite, and 2,4-diamino-6-piperidinopyrimidine also were excreted by the dog. Evidence was obtained for a glucuronide conjugate of the 4'-hydroxy metabolite in this species. The major circulatory material in dog plasma was the 4'-hydroxy metabolite, whereas it was the glucuronide of minoxidil in monkey plasma.

Animals↗

PubMed1975

Control plasma renin activity and changes in sympathetic tone as determinants of minoxidil-induced increase in plasma renin activity.

A study was made of the possible mechanism(s) underlying minoxidil-induced increase in plasma renin activity (PRA). 10 patients with essential hypertension were treated with minoxidil and subsequently with a combination of minoxidil plus propranolol. Minoxidil lowered mean arterial pressure 31.6 plus or minus 3.3 mm Hg, mean plus or minus SEM. There was an associated increase in both PRA, 6.26 plus or minus 2.43 NG/ML/H, and heart rate, 21.4 plus or minus 2.7 beats/min. The changes in PRA and heart rate were positively correlated, r, 0.79. Addition of propranolol reduced mean arterial pressure by a further 10.1 plus or minus 1.5 mm Hg and returned heart rate to control levels. Propranolol reduced PRA significantly but not to control levels. Control PRA positively correlated with PRA on minoxidil, r, 0.97, and with PRA on minoxidil plus propranolol, r, 0.98. We conclude that control PRA is a major determinant of change in PRA with minoxidil. Minoxidil increased PRA by at least two mechanisms: (a) an adrenergic mechanism closely related to change in heart rate and blocked by propranolol, and (b) a mechanism(s) not sensitive to propranolol and possibly related to decrease in renal perfusion pressure.

Adult↗

PubMed1992

Structure-activity relationship of minoxidil analogs as inhibitors of lysyl hydroxylase in cultured fibroblasts.

The structural features that confer upon minoxidil the ability to suppress lysyl hydroxylase activity in human skin fibroblasts were investigated. Substitution of the amino group in position 2 or 6 of the pyrimidine ring with a methyl group had no significant effect on the inhibitory activity of minoxidil, whereas substitution of both amino groups with methyl groups resulted in a complete loss of inhibitory activity. Together, these observations indicate that only one of the two amino groups ortho to the nitroxide oxygen is essential for the enzyme-suppressing effect of minoxidil. Derivatives of minoxidil formed by hydroxylation at position 3 or 4 of the piperidine ring were as active as the parent compound in suppressing lysyl hydroxylase activity. However, replacement of the piperidinyl group in position 4 of the pyrimidine ring with a pyrrolidinyl, morpholinyl, or N-methylpiperazinyl group resulted in loss of inhibitory activity, demonstrating that the piperidinyl group para to the nitroxide oxygen is essential for the enzyme-suppressing effect of minoxidil. Removing the nitroxide oxygen from position 1 of the pyrimidine ring resulted in a partial loss of the specificity of minoxidil for suppression of lysyl hydroxylase activity. The results indicate that distinct structural elements determine the enzyme-suppressing effect and the antihypertensive effect of minoxidil.

Antihypertensive Agents↗

PubMed1979

Pulmonary hemodynamics in systemic hypertension. Long-term effect of minoxidil.

To assess the effect of minoxidil on pulmonary hemodynamics, we performed cardiac catheterization on ten patients, prior to the administration of minoxidil, at six months after its addition to their existing drug regimens, and on seven patients following 12 or more months of minoxidil therapy. Systemic blood pressure and systemic vascular resistance were significantly reduced at six months and following 12 or more months of minoxidil therapy. Before receiving minoxidil, nine of ten patients had elevated pulmonary vascular resistance. There were no significant changes in pulmonary vascular resistance following the initiation of minoxidil. The data suggest that pulmonary hypertension is common in patients with long-standing poorly controlled systemic hypertension, and that minoxidil, in doses sufficient to significantly reduce systemic blood pressure, does not cause or aggravate pulmonary hypertension.

Adult↗

PubMed1978

Long-term clinical effects, bioavailability, and kinetics of minoxidil in relation to renal function.

Minoxidil was used to treat 26 patients (17 to 67 years old) with severe hypertension and varying degrees of renal function. Our object was to assess long-term clinical efficacy, kinetics (acute and chronic), and bioavailability of minoxidil in chronic renal insufficiency. Minoxidil, 27 to 30 mg per day, decreased systolic and diastolic blood pressure during the first three months of therapy. Between the third and 24th months (30 months in one patient) there was no further change. Propranolol or clonidine was needed to control heart rate, and furosemide or dialysis was needed to control edema induced by minoxidil. Renal function improved in some of the mildy azotemic patients. Minoxidil kinetics after the customary dose did not differ whether the drug was taken as tablet or solution. Kinetic parameters during chronic administration of minoxidil did not differ from those after acute administration. The kinetics in chronic renal insufficiency do not differ from these in subjects with normal renal function.

Adolescent↗

PubMed1978

Minoxidil in severe hypertension.

Minoxidil has been administered to 16 patients with severe hypertension and renal failure. In every patient the indication for minoxidil treatment was resistance to conventional drugs. The final dose of minoxidil was 2.5--30 mg (average 20) and it was combined with a beta-blocking agent and a diuretic (or dialysis). The therapy was given for 1--27 months (average 12). The average supine BP fell from 200/130 to 164/96 mmHg and the upright BP from 200/120 to 152/90 mmHg. No hypotensive reactions occurred. In most patients the progression of hypertensive organ changes was arrested. No major vascular complications have occurred during the 16 years of treatment. Prickling of the skin and hirsutism were common side-effects. The other side-effects observed were oedema in five patients and development of latent diabetes in three. In four patients minoxidil treatment was discontinued for following reasons: successful reconstruction of the renal artery after stenosis, renal transplantation, severe oedema and hirsutism. The risk of hirsutism is a contraindication to prolonged minoxidil administration in most femal patients. Minoxidil is especially indicated in uncontrolled renal hypertension.

Adolescent↗

PubMed1992

Minoxidil sulfotransferase, a marker of human keratinocyte differentiation.

The sulfation of minoxidil is catalyzed by a sulfotransferase activity in a number of tissues including skin. To investigate further the nature of the minoxidil sulfotransferase activity in epithelial tissue and to compare this activity to that of cholesterol sulfotransferase, which has already been shown to be induced during the differentiation of epithelial cells, we cultured normal human epidermal keratinocytes in a keratinocyte growth medium for 4 d, after which the media were replaced with either the same growth media or media with increasing Ca++ concentrations. Cholesterol sulfotransferase, minoxidil sulfotransferase, and transglutaminase were determined during the differentiation of the cells in the three media. Time-activity curves that suggested two different sulfotransferase activities were induced during the differentiation process. U-77581, a competitive inhibitor of minoxidil sulfotransferase activity, inhibited the sulfation of minoxidil sulfotransferase activity in the keratinocyte homogenates, but it did not inhibit the sulfation of cholesterol. These data indicate that at least two sulfotransferase activities are induced during the differentiation of epithelial keratinocytes and minoxidil sulfotransferase is an early marker of that differentiation.

Biomarkers↗

PubMed1979

Rapid blood pressure control with minoxidil: acute and chronic effects on blood pressure, sodium excretion, and the renin-aldosterone system.

Changes in blood pressure, heart rate, electrolyte excretion, and the renin-angiotensin-aldosterone system were monitored before and after minoxidil was added to a regimen of a diuretic and propranolol hydrochloride in 12 severely hypertensive patients. None required more than 40 mg of minoxidil daily for control. On a constant intake, urinary sodium excretion decreased, while urinary potassium excretion remained stable. Heart rate, body weight, and plasma volume increased, while creatinine clearance did not change. Although plasma renin activity increased fourfold, the plasma aldosterone concentration did not increase. Six subjects were restudied after two months of minoxidil treatment. Although blood pressure control continued to be excellent in these subjects, plasma renin values and plasma volume had returned to pretreatment levels. These studies suggest that minoxidil rapidly and effectively lowers blood pressure. Although sodium retention accompanies minoxidil administration acutely, the effect is independent of aldosterone and may be transient.

Adult↗

PubMed1975

Metabolism of minoxidil, a new hypotensive agent I: absorption, distribution, and excretion following administration to rats, dogs, and monkeys.

Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide), a potent new hypotensive agent, was 14C-labeled in the 2-position of the pyrimidine ring in 17 percent yield from Ba14CO3. This material was used to study the absorption, distribution, and excretion of the drug in rats, dogs, and monkeys. Following oral administration of a single dose, the drug was rapidly and well absorbed and rapidly eliminated by each species as judged by plasma levels and urinary excretion of unchanged drug and total drug-related materials. Chronic oral administration of the drug at a high level (10 mg/kg) for 30 days slightly increased the rate of clearance of minoxidil and minoxidil-related material from circulation. Water diuresis, resulting from water loading of dogs, caused an even greater increase in the rates of disappearance of the drug and drug-related material. Whole-body autoradiography studies in rats showed that minoxidil was rapidly distributed following its oral and intravenous administration. It was subsequently concentrated, primarily in the excretory system. Minoxidil-related material was detected in aorta walls, but not in the CNS, following both routes of drug administration.

Animals↗

PubMed1977

Radioimmunoassay of minoxidil in human serum.

A simple, sensitive, and specific radioimmunoassay for determining minoxidil was developed. Antiserums to two minoxidil haptens were compared for cross-reactivity and assay levels on human serums. One antiserum had little cross-reactivity with minoxidil metabolites. The radioimmunoassay is specific for determining minoxidil directly in serum without extraction. Human serum minoxidil levels were determined from a single oral dose.

Animals↗

PubMed1977

Minoxidil therapy in children with severe hypertension.

Six children, from 1.3 to 18 years of age, with severe hypertension associated with the hemolytic uremic syndrome, periarteritis, and renal transplant rejection received minoxidil, an antihypertensive agent, for three to 36 weeks. All had severe hypertension resistant to oral antihypertensive medications; five required frequent intravenous diazoxide therapy prior to minoxidil therapy. The mean pretreatment systolic and diastolic blood pressures were 176 and 117 mm Hg, respectively. Following treatment, the mean systolic and diastolic blood pressures were 133 and 82 mm Hg, respectively. Concomitant antihypertensive medications were decreased in all six patients once optimal blood pressure control was obtained. The initial dosage of minoxidil was 0.1 to 0.2 mg/kg/day; maximal dosage for blood pressure was 0.3 to 1.4 mg/kh/day. Major complications of therapy were fluid retention and hirsutism. Transient asymptomatic pericardial effusions occurred in two patients. Three patients on prolonged minoxidil therapy had persistent increases in right ventricular end diastolic diameters. Minoxidil is an effective oral antihypertensive agent for treatment of severe hypertension in pediatric patients. Avoidance of fluid retention is mandatory to prevent congestive heart failure.

Adolescent↗

PubMed1992

Hair growth effects of oral administration of finasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque.

A 5 alpha-reductase inhibitor, finasteride, was administered orally at 0.5 mg/day, alone or in combination with topical 2% minoxidil, for 20 weeks to determine the effects on scalp hair growth in balding adult male stumptail macaque monkeys. A 7-day dose-finding study showed that both 0.5- and 2.0-mg doses of the drug produced a similar diminution in serum dihydrotestosterone (DHT) in male stumptails. Hair growth was evaluated by shaving and weighing scalp hair at baseline and at 4-week intervals during treatment to obtain cumulative delta hair weight (sum of the 4-week changes in hair weight from baseline) for the 20-week study. The activity of the 5 alpha-reductase enzyme was assessed by RIA of serum testosterone (T) and DHT at 4-week intervals. The combination of finasteride and minoxidil generated significant augmentation of hair weight (additive effect) compared to either drug alone. Finasteride increased hair weight in four of five monkeys. When the data of the one nonresponsive monkey were excluded, finasteride elicited a significant elevation in hair weight compared to topical vehicle alone. Minoxidil also evoked a significant increase in hair weight compared to vehicle alone. Serum T was unchanged, whereas serum DHT was significantly depressed in monkeys that received either finasteride or the combination of finasteride and minoxidil. These data suggest that inhibition of the conversion of T to DHT by this 5 alpha-reductase inhibitor reverses the balding process and enhances hair regrowth by topical minoxidil in the male balding stumptail macaque.

5-alpha Reductase Inhibitors↗

PubMed1979

[Minoxidil in treatment resistant hypertension].

22 patients (4 female, 18 male, mean age 47 +/- 10.7 years) with severe essential hypertension (n = 21) and renovascular hypertension (n = 1) were treated with a mean daily dosage of 16.3 +/- 5.1 mg minoxidil for up to 42 weeks. In addition, all patients received a diuretic (hydrochlorothiazide or furosemide) and a beta-blocker (pindolol or propranolol). 8 patients were treated simultaneously with alpha-methyl-dopa. Within one week minoxidil led to a significant reduction in both systolic and diastolic supine blood pressure (p less than or equal to 0.005) from 201.3 +/- 29.0/125.4 +/- 19.2 mm Hg to 172.8 +/- 28.3/106.0 +/- 19.9 mm Hg. The maximum initial blood pressure response was observed after 3 weeks with a mean daily dosage of 12.2 +/- 9.4 mg of minoxidil (160.5 +/- 20.7/99.4 +/- 13.8 MM Hg, p less than or equal to 0.001). Throughout the remaining period a constant and significant reduction in supine systolic and diastolic and upright diastolic blood pressure was achieved (p less than 0.005-less than 0.001) whereas at times systolic blood pressure values could not be lowered significantly. Body weight and pulse rate showed no significant changes throughout the study. In some cases furosemide had to be added by up to 500 mg/day to counteract minoxidil induced water and salt retention. Only moderate doses of beta-blockers were required to prevent a drug induced rise in pulse rate. In these patients a significant change in renal function was not observed. The results show that minoxidil is a potent drug in the treatment of severe essential hypertension.

Adult↗

PubMed1976

Long-term effects of minoxidil in the treatment of malignant hypertension in chronic renal failure.

Thirteen acutely symptomatic malignant hypertensive patients were treated with minoxidil in combination with a beta-adrenergic blocking agent and diuretics or dialysis. The degree of endorgan involvement varied, with the kidney being the most compromised in 11 of 13 patients. In 12 of 13 patients, MABP (mean arterial blood pressure) fell significantly within 72 hours, P less than 0.005. After 20 months of therapy, all have now had a favorable response, with a mean reduction in MABP of 48 mm Hg, and with no adverse cardiac disturbances. In addition, the patients with mild azotemia had an improvement in renal function as determined by a reduction in serum creatinine. PRA (peripheral renin activity) rose with the addition of minoxidil despite therapeutic concentration of serum propranolol and a reduction in MABP and heart rate. It was also noted that those patients who had been on guanethidine prior to minoxidil had a more pronounced lowering of MABP within 72 hours of minoxidil therapy. It is concluded that minoxidil is a safe, fast, and effective agent to achieve rapid and sustained control of MABP in malignant hypertensive states associated with chronic renal insufficiency.

Adolescent↗

PubMed1977

Increased pulmonary vascular resistance with systemic hypertension. Effect of minoxidil and other antihypertensive agents.

Recent case reports suggest that pulmonary hypertension could be caused by minoxidil, a new potent vasodilating antihypertensive drug. Therefore, we evaluated the incidence and severity of pulmonary hypertension in 110 patients with systemic hypertension. Fourteen patients were treated with minoxidil for 2 to 35 months (mean 19.9 months), 15 were treated with no drugs, and the remaining 81 patients received conventional antihypertensive agents of several types. Pulmonary vascular resistance correlated positively (P is less than 0.05) with systemic vascular resistance. Minoxidil-treated patients with hypertension previously refractory to conventional therapy had slightly lower pulmonary vascular resistance than other hypertensive subjects. There was no correlation between pulmonary vascular resistance and duration of minoxidil therapy or other types of antihypertensive regimens. The positive correlation between pulmonary and systemic vascular resistance suggests the possibility of a causal hypertension relation in the two vascular beds.

Adolescent↗

PubMed1977

Management of severe childhood hypertension with minoxidil: a controlled clinical study.

The therapeutic efficacy of four antihypertensive regimens (minoxidil, propranolol, and hydrochlorothiazide; propranolol and hydrochlorothiazide; methyldopa and hydroch-orothiazide; and hydrochlorothiazide alone) was evaluated in one child with systolic hypertension and in eight children with systolic and diastolic hypertension. The mean blood pressure of 148/98+/-8/4 mm Hg observed during the hydrochlorothiazide control period fell to 142/88+/-8/4 mm Hg following methyldopa and hydrochlorothiazide, 141/85+/-6/2 mm Hg following propranolol and hydrochlorothiazide, and 128/74+/-4/2 mm Hg following minoxidil, propranolol, and hydrochlorothiazide. The only side effect directly associated with administration of minoxidil was hypertrichosis. The effectiveness of minoxidil in the present study suggests that this drug offers an important adjunct to current antihypertensive therapy in children.

Adolescent↗

PubMed1977

The outpatient treatment of refractory hypertension with minoxidil.

Minoxidil is a potent orally administered vasodilator under investigation for use in severe hypertension. Fifteen patients with moderate to severe hypertension refractory to conventional antihypertensive drugs were treated with minoxidil on an outpatient basis. Propranolol and furosemide were administered concomitantly to control reflex tachycardia and fluid retention. Good blood pressure control was achieved in all but one patient with the average supine mean arterial blood pressure falling from 140 mm Hg with conventional drugs to 106 mm Hg with minoxidil (P less than 0.0005). The major side effects of fluid retention (9/15), hirsutism (15/15), and tachycardia were adequately controlled in all but one patient. We conclude that minoxidil will be a valuable drug in the outpatient management of refractory hypertension.

Adult↗

PubMed1992

Characterization of a partial cDNA for lysyl hydroxylase from human skin fibroblasts; lysyl hydroxylase mRNAs are regulated differently by minoxidil derivatives and hydralazine.

Lysyl hydroxylase (LH) is an essential enzyme in collagen biosynthesis that catalyzes the formation of hydroxylysine required for intermolecular crosslinking of collagen. We have isolated a partial (2.2-kb) cDNA for LH from human skin fibroblasts using PCR. DNA sequencing revealed 72% homology of the human coding sequence with the chick LH sequence at the nucleotide level and 76% homology predicted at the amino acid level. The LH cDNA hybridized strongly with two mRNA species of 2.4 and 3.4 kb on Northern blots of normal fibroblast RNA. Administration of minoxidil decreased both mRNA species without affecting levels of the mRNAs for the beta subunit of prolyl 4-hydroxylase (PH) or alpha 1(I) collagen. Two derivatives of minoxidil (3' hydroxyminoxidil and 4' hydroxyminoxidil) produced similar decreases in LH mRNAs. In contrast hydralazine increased the mRNAs for LH in parallel with its previously reported effect on the mRNA for the beta subunit of PH. This effect is accompanied by virtual elimination of the alpha 1(I) collagen mRNAs. These results on the action of minoxidil and hydralazine at the pretranslational level correlate well with their previously reported effect on enzyme activity and collagen biosynthesis and indicate that changes in steady-state mRNA levels can account directly for changes at the protein level. Moreover, the unique action of minoxidil in specifically decreasing LH mRNAs contrasts with the less specific stimulatory effects of hydralazine and suggests that these pharmaceuticals are regulating expression of LH at a pretranslational level by different mechanisms.

Base Sequence↗