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The effect of heptaminol, an aliphatic amine with an alcoholic group on carbon 2, on sympathetic nerves and on isolated chromaffine granules was infestigated. In cats, heptaminol caused long-lasting, dose-dependent pressor effects accompanied by tachycardia and contractions of the nictitating membrane. In comparison with tyramine, heptaminol was 100 times less potent in increasing blood pressure and 10 times less effective in inducing contractions of the nictitating membrane. The rise in blood pressure as well as tachycardia and contraction of the nictitating membrane were diminished by cocaine. After pretreatment with cocaine, heptaminol in high doses caused short-lasting depressor effects. Also in rats the pressor effect of heptaminol was weaker but of longer duration than that of tyramine. The dose-response curve was depressed by pretreatment with reserpine. The tachycardia induced by heptaminol was markedly diminished after pretreatment with reserpine. After repeated injections heptaminol reduced the norepinephrine content of the rat heart by 20-40%, Tyramine and hexylamine were more effective than heptaminol in depleting the norepinephrine stores of the heart (50-60%). In fluorescence microscopic investigations on sympathetic nerves (rat iris) depleted of norepinephrine by reserpine, the uptake of alpha-methylnorepinephrine could be inhibited or prevented by heptaminol. The spontaneous release of catecholamines from isolated bovine chromaffine granules was enhanced (+30%) by heptaminol or methamphetamine in high concentrations. In lower concentrations, however, both drugs reduced the uptake of 14C-epinephrine in isolated medullary granules by 20-40%. In addition a non-specific papaverine-like spasmolytic effect of heptaminol could be demonstrated. The results suggest that heptaminol exerts its pharmacological action by interfering with release and uptake of norepinephrine.
1. The cardiotonic effect of heptaminol hydrochloride (Hept-a-myl, Delalande) was studied using 31P-nuclear magnetic resonance (n.m.r.) spectroscopy and left ventricular pressure (LVP) measurements in rat isolated hearts. The possibility of this effect being mediated by an intracellular realkalinisation was tested. 2. Isolated hearts were perfused at 10 ml min-1 by the Langendorff method with Krebs-Henseleit solution at 37 degrees C and stimulated at 5 Hz. Mechanical activity was measured as variations of left ventricular pressure (LVP). 31P-n.m.r. spectra were recorded every 2 min. Changes in cardiac adenosine triphosphate (ATP), phosphocreatine (PCr) and inorganic phosphate (Pi) were followed and intracellular pH (pHi) was estimated from the chemical shift of Pi. 3. The effects of heptaminol were tested in different conditions: normoxia, moderate ischaemia, severe ischaemia, and moderate ischaemia in the presence of amiloride or guanidinium chloride as inhibitors of the Na-H exchange. 4. In normoxia, heptaminol induced a cyclic increase of systolic LVP, associated with an increase in Pi. No significant effect on pHi was observed. In changing from normoxia to moderate ischaemia, PCr and systolic LVP decreased; a mild intracellular acidification (pHi 6.96) was obtained. Heptaminol induced a restoration of pHi and increased LVP. In severe ischaemia, the realkalinization effect and the restoration of LVP induced by heptaminol were no longer observed. During moderate ischaemia, Na-H exchange inhibitors decreased pHi and LVP. Heptaminol applied in the presence of these inhibitors was unable to restore pHi and LVP. In severe ischaemia, the realkalinization effect and the restoration of LVP induced by heptaminol were no longer observed. During moderate ischaemia, Na-H exchange inhibitors decreased pHi and LVP. Heptaminol applied in the presence of these inhibitors was unable to restore pHi and LVP. 5. These results suggest that the positive inotropic effect of heptaminol during moderate ischaemia could be related to a restoration of internal pH, possibly mediated by a stimulation of the Na-H exchange.
Heptaminol is an antihypotensive drug and is one of the stimulants banned in sport competitions. When heptaminol was fortified to a drug-free urine sample and subjected to solid-phase extraction, trifluroacetic anhydride derivatization, and gas chromatography-mass spectrometry analysis, the results indicated three chromatographic peaks, with one major peak [peak 1 (P1) as heptaminol-2TFA], appearing at retention time 7.17 min, and two minor peaks [peak 2 (P2) and peak 3 (P3) as heptaminol-TFA], appearing at RT 5.87 and 5.81 min, respectively. The characteristic ions of peak mass spectra were m/z 322, 224, and 140 for P1, m/z 223 (molecular ion), 208, 140, and 110 for P2, and m/z 208, 140, and 110 for P3. The urine samples collected from healthy male volunteers who orally ingested a single dose (100 mg) of heptaminol were similar to the analytical results shown in the heptaminol-spiked control urine samples. This result suggested that the unchanged heptaminol was the sole form found in urine. The unchanged parent compound was completely eliminated in urine within 24 h and an average of approximately 97% of the dose was excreted through the renal pathway.
1. The effects of heptaminol on calcium current amplitude and characteristics were studied in single ventricular myocytes of guinea-pig by use of the whole cell configuration of the patch clamp technique. 2. A concentration-dependent decrease in ICa amplitude was observed. At heptaminol concentration as low as 10(-6) M, this effect was observed in only two cells (n = 6). At 10(-5) M the reduction of ICa was of 30 +/- 15% (n = 11). 3. The current recovery from inactivation at -40 mV holding potential (HP) seemed less sensitive to perfusion with heptaminol (greater than 10(-6) M). However, at -80 mV HP the overshoot of the recovery curve was decreased by heptaminol. 4. Both at -40 mV and -80 mV HP, heptaminol (10(-5) M) significantly increased the steady state inactivation of ICa. 5. As previously proposed by others to explain the effects of membrane active substances, the effects of heptaminol may result from alterations in cell membrane properties and possibly from an increase in intracellular free calcium ion concentration.
In ten healthy volunteers the plasma and urine concentrations of heptaminol (Heptylon) were determined by high-performance liquid chromatography after intravenous administration of 250 mg heptaminol and oral intake of 2 x 150 mg heptaminol in tablet form, and the pharmacokinetic parameters were calculated. Heptaminol was rapidly and entirely absorbed following oral administration of heptaminol. Mean plasma peak concentrations of 1.6 mg/l were reached after 1.8 h, the area under the plasma concentration-time curve was equal to that after intravenous administration. The dominant terminal plasma half-life was 2.5-2.7 h. The total clearance amounted to 700 ml/min, and nearly all the dose given was recovered unchanged in urine within 24 h, indicating renal elimination by glomerular filtration and tubular secretion without metabolization.
Heptaminol was measured in plasma and urine following pre-column derivatisation with o-phthalaldehyde and reversed-phase high-performance liquid chromatography employing fluorescence detection. The limits of detection were sufficient for pharmacokinetic studies of the drug after clinically-used doses. Plasma concentrations of heptaminol reached peak levels (2.19 micrograms/ml) at 0.75 h after single oral doses (0.47 g of heptaminol) and declined with a half-life of 2.1 h (+/- 0.5 S.D.). Heptaminol was well absorbed and excreted rapidly, mainly unchanged in urine, 82% dose (+/- 10 S.D.).
Heptaminol is a molecule with experimental cardiovascular analeptic properties. In this double-blind vs placebo trial, the potency, so far unproven, of the injectable form of a 626 mg dose of heptaminol chlorhydrate on spontaneous or induced orthostatic hypotension (OH), was assessed. Nineteen patients were included in the study: 7 displayed spontaneous OH, and in the other 12 OH was induced by bromocriptine, as monitored 103 min/after an oral intake of 6.6 mg on average. Neither spontaneous nor induced OH were recorded in 32% of the Parkinsonian population registered, with no obvious distinctive characteristics. Potency tilt-trials, performed 15, 30 and 45 min after parenteral administration of heptaminol, revealed a significant and expressive potency of the molecule on the systolic blood pressure after 15 min (P less than 0.05). Clinical and biological tolerance was excellent. Low plasma renin activity and the absence of response to orthostatism indicated, in this population of Parkinsonian extrapyramidal syndromes, a loss in positive tonus likely to be of sympathetic origin. The anti-hypotensive action of heptaminol does not seem to be related to any renal or even sympathetic interaction.
1. Heptaminol stopped or delayed the progressive decline in tension which characterizes the phenomenon of fatigue in frog isolated twitch muscle fibre. 2. Heptaminol had no action on the sodium, potassium and calcium voltage-dependent ionic conductances. 3. The hypothesis of an action via an internal alkalinization was tested by comparison with the action of NH4Cl. Both substances increased the tension. 4. The action of heptaminol was suppressed in sodium-free (TRIS) solution or in the presence of amiloride while the action of NH4Cl was always observed. 5. These results could be explained by a stimulation of the Na/H antiport by heptaminol.
Heptaminol hydrochloride is widely used for the treatment for orthostatic hypotension. It continues to elicit controversy as to its mode of action since Loubatières (1951) described its powerful inotropic action on an ischaemic preparation. Twenty five years later it has been suggested that this drug exerts its action by interfering with the release and uptake of catecholamines (Grobecker and Grobecker, 1976). The aim of this review was to report new experimental approaches and new data relative to the mode of action of heptaminol hydrochloride. In the rat, heptaminol hydrochloride prevented orthostatic hypotension, and increased the noradrenaline plasma concentration. In bovine chromaffin cells maintained in primary cultures, it was found to be a competitive inhibitor of noradrenaline uptake. This inhibition may partially account for its antihypotensive effect. The cardiotonic effect was studied using 31 P nuclear magnetic resonance spectroscopy and left ventricular pressure measurement in rat isolated hearts. The results suggest that the inotropic effect during moderate ischemia could be related to a restoration of internal pH possibly mediated by a stimulation of the Na+/H+ exchange. The satellite cells of adult skeletal muscles are myogenic cells involved in muscle regeneration. In culture, they differentiate into myotubes and thus mimic some aspects of the in vivo myogenic process. Heptaminol hydrochloride, which did not significantly alter the cloning efficiency or proliferation, increased the capacity of satellite cells to differentiate into myotubes.
6-Amino-2-methyl-2-heptanol chlorhydrate, heptaminol chlorhydrate, blocks the response to indirect stimulation of the mouse diaphragm in vitro. This effect is due to a dose-dependent pre- and post-synaptic block of neuromuscular transmission starting at 1 mM heptaminol (HEPT). The complete block of neuromuscular transmission occurs at 10 mM. At 2 mM, the decrease in quantal size is more significant in the presence of d-tubocurarine than when the extracellular calcium is lowered. At this concentration, heptaminol also prolongs the depolarization time of the motor end plate potential. Slightly higher concentrations of heptaminol produce a decrease in quantal content. This latter effect is associated with an increase in synaptic delay.
Absorption, distribution, excretion and metabolism studies with 14C-labelled 6-amino-2-methyl-2-heptanol hydrochloride (14C-heptaminol hydrochloride, Hept-amyl) were carried out in rat. After a 10 mg/kg p.o. dose heptaminol was rapidly and entirely absorbed. Following the administration of 8 mg/kg i.v. or 12 mg/kg p.o., all tissues studied, except brain, contained higher levels of radioactivity than did plasma. No evidence of accumulation of the drug was seen in any tissue. Whole-body autoradiography revealed a preferential localisation in salivary glands, hypophysis and adrenal medulla 1 h after a 10 mg/kg i.v. or p.o. dose. Brain autoradiography showed radioactivity localised only in highly vascularised areas (choroid plexus and pia mater). Excretion occurred mainly by kidney, 68% of the radioactivity being excreted in urine 4 h after a dose of 10 mg/kg i.v. Biliary and faecal elimination accounted for less than 1% of the radioactivity administered. Heptaminol was metabolized to a hydroxylated metabolite, 6-amino-2-methyl-1,2-heptanediol, which was excreted unconjugated in urine. As doses increased from 10 to 200 mg/kg p.o., the amount of metabolite excreted in the 24-h urines decreased from 7.05% to 4.24% of the urinary radioactivity, indicating a saturation of the metabolism at high doses. Pretreatment of rats with phenobarbital increased the percentage of metabolite excreted in urine, but was unable to prevent the saturation of the metabolism at high doses of heptaminol.
The efficacy of the adenosine phosphate of heptaminol on the functional symptomatology of the premenstrual syndrome has been assessed in the framework of an "open" controlled trial against a reference product. 45 women received adenosine phosphate of heptaminol (6 gelatine capsules/day) or the reference product during 2 cycles. The statistical analysis of the results by symptom demonstrates the markedly superior activity of the adenosine phosphate of heptaminol on pelvic pains (p less than 0.02), and on the pains and heaviness of the lower limbs (p less than 0.05). The superiority of adenosine phosphate of heptaminol was similarly demonstrated in the global evaluation of results. The tolerance must be regarded as excellent.
The effects of tuamine (1-methylhexylamine), a sympathomimetic compound with hypertensive properties, heptaminol (6-amino-2-methyl-2-heptanol), an aliphatic amine with pressor properties, and two structural analogues of tuamine on high-affinity Na(+)-dependent noradrenaline uptake and on nicotine-evoked release were examined in bovine chromaffin cells maintained in primary culture for 3 to 6 days. Tuamine was found to be a potent competitive inhibitor of noradrenaline uptake with an effect similar to that of cocaine. Its inhibition constant (Ki) was 1.1 +/- 0.1 microM while Ki values of heptaminol, of 1-methylamino-5-pentanol oxalate and of 5-amino-2-methylhexanol oxalate, which were also found to be competitive inhibitors of noradrenaline uptake, were 60 +/- 2 microM, 260 +/- 28 microM and 48 +/- 76 microM, respectively. Tuamine, hepataminol and 5-amino-2-methyl-2-hexanol were also shown to be inhibitors of nicotine-induced release of catecholamines, with IC50 values of 26 +/- 2 microM, 650 +/- 11 microM and 500 +/- 10 microM, respectively. Tuamine and hepataminol did not inhibit noradrenaline release evoked by 59 mM K+, suggesting that it acts at a step prior to calcium entry. The pharmacological properties of heptaminol as an anti-hypotension agent may partially account for its inhibitory effect on catecholamine uptake and release.
In order to investigate the pharmacokinetics of heptaminol in dogs, a high-performance liquid chromatographic assay of the drug was devised and it was evaluated in a general purpose validation design through analysis of variance. Heptaminol and its internal standard n-propylamine were salted out from plasma together with acetonitrile, the previously proposed "solvent demixing " extraction procedure. Both amines were derivatised in acetonitrile with the o-phthaldialdehyde, 2-mercaptoethanol procedure of Roth. The adducts were quantitated by reversed-phase high-performance liquid chromatography on Radial-Pak cartridges with ultraviolet detection. Peak height ratios were linearly related to concentrations up to 250 mumol l-1 with a 2% coefficient of variation. Sensitivity was 3.5 mumol l-1 (signal-to-noise ratio of 5). Means of the usual pharmacokinetic parameters in four dogs were: elimination half-life 3.75 h, apparent distribution volume 2.18 l kg-1 and total clearance 0.402 l kg-1 h-1, similar to the results obtained in humans by other authors using radiolabelled heptaminol .
OBJECTIVE: The aim of this study was to assess the clinical efficacy, compliance and safety of Ginko biloba--Troxerutin-Heptaminol Hce in the treatment of patients with acute hemorrhoidal attacks in Thailand. MATERIAL AND METHOD: In a prospective clinical study on hospital outpatients, the authors studied the effect of Ginko biloba--Troxerutin-Heptaminol Hce for a week in adults (18-70 years old) with acute hemorrhoidal attacks. RESULT: Twenty-two patients, with a mean age of 41.7 years were included in the study. The male to female ratio was 1 : 1.2. Most patients (77%) had grade 1 and 2 hemorrhoids with an average duration of attacks of 3 days. On intention to treat analysis, bleeding, pain, tenesmus and discharge were significantly improved. Treatment was well accepted and safe. CONCLUSION: In the short-term, Ginko biloba--Troxerutin-Heptaminol Hce is effective, acceptable and safe in the treatment of patients with acute hemorrhoidal attacks.