Influence of dihydroergotoxine, bromocriptine, and ergotamine on penile erection in Wistar rats.

The pilot study presented was conducted to determine as to whether ergot alkaloids (alpha-adrenergic blockers) have a potential effect on penile erectile function. The influence of dihydroergotoxine, bromocriptine, and ergotamine was studied on the erection ability in intact, two-grade outbred male Wistar albino rats that were out of their estrous phase. The experimental animals were injected intrapenially with the substances under examination: dihydroergotoxine mesylate (0.1 mg/0.1 mL, 0.3 mg/0.1 mL, and 1 mg/0.1 mL), bromocriptine mesylate (0.3 mg/0.1 mL, 1 mg/0.1 mL, and 3 mg/0.1 mL), and ergotamine tartrate (0.1 mg/0.1 mL, 0.3 mg/0.1 mL, and 1mg/0.1 mL). Every dose was tested on a pattern of 30 rats. These mentioned substances were injected in the amount of 1 mm to the left of the proximal part of the superficial dorsal vein of the penis, in the region of the penis root. After injection, the animals were then observed within the next 90 minutes. In the trial, the following was observed: the number of rats with an erection achieved, the period of time from intrapenial application to the appearance of the first erection, and the duration of the erection. Ultimately, the research results confirm the efficiency of dihydroergotoxine and bromocriptine as erectogenic agents, as well as ergotamine as a detumescent compared with saline solutions.

[Experience in the administration of vasobral in sensorineural vascular hypoasusis]. / Obosnovanie primeneniia élasticheskoi tamponady posleoperatsionnykh polostei srednego ukha.

24 patients with neurosensory hypoacusis of vascular genesis related to chronic cerebral vascular deficiency in the vertebrobasillar bed combined with cervical osteochondrosis were given basobral. The drug produced positive changes in neurological symptoms, lowered hearing thresholds in the range of high frequencies, improved cerebral hemodynamics and hearing afferentation at the stem level of the acoustic analyzer.

Bioavailability and pharmacokinetic profile of dihydroergotoxine from a tablet and from an oral solution formulation.

Dihydroergotoxine mesylate (DHETM, CAS 8067-24-1), the combination of the mesylates of four dihydrogenated ergot alkaloid derivatives (dihydroergocornine, dihydroergocristine, alpha-dihydroergocryptine and beta-dihydroergocryptine), is used mainly for age-related cognitive impairment. The bioavailability of DHETM was investigated in a cross-over study on 20 male healthy volunteers to whom two single doses of 9 mg DHETM were administered either in tablets (Orphol spezial) or in oral solution (Orphol forte). DHETM was assayed in serum with a double radioimmunoassay method displaying a satisfactory cross-reactivity with the principal components of DHETM. After administration of tablets the peak of DHETM was (mean +/- SE) 124 +/- 16 pg/ml, the tmax 1.15 +/- 0.21 h, the AUC 790 +/- 93 pg/ml x h and the terminal elimination half-life 7.54 +/- 1.23 h. After oral solution the peak of DHETM was 176 +/- 16 pg/ml, the tmax 0.50 +/- 0.04 h, the AUC 779 +/- 94 pg/ml x h and the terminal elimination half-life 6.13 +/- 0.76 h. The bioavailability of DHETM from tablets vs. that from oral solution differed only by a retard related to the dissolution time of DHETM from the tablets, but not for other pharmacokinetic parameters. The relatively high two single doses of 9 mg DHETM administered to the 20 subjects were well tolerated, causing only known and expected adverse reactions to DHETM (tiredness, headache and vertigo) that did not require discontinuation of the study.

Alpha-dihydroergocryptine in the treatment of de novo parkinsonian patients: results of a multicentre, randomized, double-blind, placebo-controlled study.

INTRODUCTION: A multicentre, randomized, double-blind, placebo-controlled, parallel group study was carried out in 123 patients suffering from never treated (de novo) idiopathic Parkinson's disease (PD). The aim of the study was to confirm the efficiency and safety of alpha-dihydroergocryptine (alpha-DHEC) given as monotherapy in the symptomatic treatment of PD. The total score of the Unified Parkinson's Disease Rating Scale (UPDRS) was identified as the efficacy target variable. PATIENTS AND METHODS: Sixty-two patients (32 males, 30 females, mean age +/- SD 64 +/- 10) were randomized to alpha-dihydroergocryptine and 61 (30 males, 31 females, mean age 63.8 +/- 9.1) to placebo. According to the experimental design, a 18-month double-blind phase vs placebo was followed. Two interim analyses were planned both at the 3rd and 12th month of treatment, in order to avoid continuation on placebo, if clear differences between groups were found (stopping criterium: nominal significance level equal to 0.022 in the analysis of the target variable). Analysis of variance was performed both on the per protocol (PP) and intent-to-treat (ITT) sample. RESULTS: The results on the first interim analysis showed significant differences between treatment groups of the UPDRS total score both in the ITT (115 patients, alpha-DHEC: No. 56; placebo: No. 59; P=0.019) and PP (96 patients, alpha-DHEC: No. 46; placebo: No. 50; P=0.001) sample, why the trial was stopped. At the time of stopping the trial, 73 patients (alpha-DHEC: No. 37; placebo: No. 36) had reached the 6-month observation visit; the analysis carried out on this subset of patients confirmed the efficacy of alpha-dihydroergocryptine in early PD and the correctness of the decision to stop. The incidence of adverse drug reactions (ADR) did not differ between alpha-dihydroergocryptine and placebo recipients, gastrointestinal complaints being the most frequent. CONCLUSION: The results indicate that alpha-dihydroergocryptine is safe and effective in improving symptoms of de novo parkinsonian patients.

The effect of topical dihydroergocristine on the intraocular pressure in alpha-chymotrypsin-induced ocular hypertensive rabbits.

Having previously reported that topical dihydroergocristine dose-dependently reduces intraocular pressure in ocular normotensive rabbits with a maximum response and potency higher than those of timolol and pilocarpine, the aim of the present work was to assess the effect of this drug in alpha-chymotrypsin-induced ocular hypertensive rabbits. Intraocular pressure was measured with a pneumatonometer. The experiments examining the effects of dihydroergocristine on intraocular pressure were conducted in 10 albino rabbits in which ocular hypertension was induced by intracameral injection of alpha-chymotrypsin. Intraocular pressure responses to drug vehicle and 5 different doses of topical dihydroergocristine were studied in order to obtain a dose-response curve. Tonographies were also performed in ocular hypertensive rabbits 2 h after vehicle and dihydroergocristine instillation to ascertain the actions of this drug on aqueous humor dynamics. Topical dihydroergocristine was found to lower intraocular pressure in alpha-chymotrypsin-induced ocular hypertensive rabbits in a dose-related manner, with the ED50 of the concentration-response curve very similar to that previously obtained in ocular normotensive rabbits. Data from tonographic studies indicate that dihydroergocristine reduces intraocular pressure in this animal model for glaucoma by decreasing the aqueous humor inflow. Our findings suggest that topical dihydroergocristine may be useful in the treatment of ocular hypertension.

Comparison of the efficacy and safety of daily dosages of 6 mg and 20 mg dihydroergocristine in the treatment of chronic cerebro-vascular disease.

The efficacy and safety of two different regimens of dihydroergocristine, in the treatment of patients with chronic cerebro-vascular disease, were compared in this double-blind study. Forty out-patients, 11 males and 29 females, aged 55-80 years were randomly assigned to treatment with 6 or 20 mg dihydroergocristine, daily, for 3 months. The Sandoz Clinical Assessment for Geriatrics (SCAG) scale was used to assess the efficacy of treatment. Both doses induced a statistically significant improvement (P < 0.01) in total SCAG scores after both 45 and 90 days of treatment. The higher dose produced a significantly greater improvement in total SCAG scores than did the lower dose after both 45 and 90 days. There were no statistically or clinically significant changes in any of the laboratory parameters after either treatment; neither were there any statistically significant changes in blood-pressure or pulse-rate except in the case of standing systolic pressure which decreased significantly (P < 0.01) in the 20 mg group. The only adverse event reported was a case of mild gastric pain at the end of treatment with 20 mg dihydroergocristine.

Changes in urinary enzyme levels following the use of antihypertensive agents in patients with essential hypertension.

When choosing antihypertensive agents for the treatment of hypertension, it is necessary to consider the predisposition of individuals to renal damage, which may be associated with the long-term effect of such agents. In this respect, this study examined the effect of two commonly used antihypertensive drugs (Brinerdin and Minizide) on renal function over 24 months in patients diagnosed as having essential hypertension. We utilized urinary enzyme studies, which are indicators of subtle renal dysfunction. Other parameters of glomerular and tubular function were also determined in the pretreatment period, as well as during and at the end of treatment of 28 patients (16 males and 12 females) with therapeutic doses of Brinerdin and 22 patients (12 males and 10 females) with conventional doses of Minizide. During the follow-up period, blood pressure (BP) fell from a mean of 160/108 +/- 9/4 (SD) mmHg to 130/90 +/- 7/4 on Brinerdin and from a mean of 160/106 +/- 5/2 (SD) mmHg to 130/90 +/- 8/5 on Minizide. There was no significant difference in the levels of BP between the patients taking Minizide and those taking Brinerdin before, during, and at the end of treatment. Significant elevation (p < 0.05) of the levels of urinary protein, lactate dehydrogenase (LDH), and N-acetyl-B-D-glycosaminidase (NAG) was observed in patients on Minizide during treatment, and these levels remained elevated during the latter part of the study. Normotensive, untreated, age- and sex-matched control subjects showed no such urinary parameter changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopaminergic drugs in congestive heart failure: hemodynamic and neuroendocrine responses to ibopamine, dopamine, and dihydroergotoxine.

Ibopamine has hemodynamic and neurohumoral effects potentially useful for the treatment of congestive heart failure (CHF), but its mechanism of action is not completely clear. To evaluate the role of dopaminergic receptor stimulation in the hemodynamic and neurohumoral activity of ibopamine, we compared the effects of ibopamine, 100 mg orally (p.o.) with those of the dopamine 2, 4, and 6 micrograms/kg/min intravenously (i.v.) and of the DA2 agonist dihydroergotoxine 6 micrograms/kg i.v. in 13 patients with chronic CHF [left ventricular ejection fraction (LVEF) < or = 35%]. All patients underwent right heart Swan-Ganz catheterization with determination of hemodynamic parameters at baseline, after 30 min of infusion of each dose of dopamine (DA) and < or = 6 h after ibopamine and dihydroergotoxine administration. Blood samples for the assessment of plasma renin activity (PRA), aldosterone, norepinephrine (NE), and epinephrine (Epi) were also obtained. Ibopamine induced a peak 21% increase of cardiac index (CI) with a 23 and 25% increase in stroke volume (SV) and stroke work indexes (SWI), respectively, and an 18% reduction in systemic vascular resistance (SVR). Similar changes were observed after DA infused at the doses of 2 and 4 micrograms/kg/min, whereas with the dose of 6 micrograms/kg/min heart rate (HR) increased by 23% and SV index (SVI) did not change further. Dihydroergotoxine administration induced only a significant 9% decrease in mean arterial pressure (MAP), with a 13% reduction in SVR.(ABSTRACT TRUNCATED AT 250 WORDS)

[Chronosensitivity to adelphane-esidrex and sinepres and effectiveness of treatment of patients with hypertension]. / Khronochuvstvitel'nost' k adel'fanu-ézidreksu i sinepresu i éffektivnost' lecheniia bol'nykh gipertonicheskoi bolezn'iu.

24-h trends in central and peripheral circulation in response to pharmacological tests were registered in 40 patients with stage II essential hypertension (EH). Rhythmic patterns of hemodynamic parameters (heart rate, systolic pressure, stroke volume, etc.) sensitivity to adelphane-esidrex were found. Hypotensive effect of this drug was maximal in morning hours because of the fall in arterial pressure due to reduced peripheral resistance. Sinepres chronotherapy given to 18 EH patients turned out superior to conventional treatment (1 pill 3 times a day) given to 20 EH patients. When taken into consideration, chronosensitivity to the above drugs may bring about a reduction in daily and course doses and earlier occurrence of a hypotensive effect.

Effect of dihydroergocryptine on serum prolactin levels and milk secretion in puerperal women.

The aim of the present study was to evaluate the efficacy and tolerability of the dopamine agonist drug dihydroergocryptine in the suppression of puerperal lactation. A single blind and placebo-controlled study was performed. A total of 90 postpartum women was acutely or repeatedly treated with dihydroergocryptine at different doses in order to investigate the efficacy of this drug in the suppression of puerperal lactation and to find the optimum dose for therapy. Prolactin levels, mammary symptomatology and rebound effects were monitored during the repeated treatment and also 1 and 8 days after drug discontinuation. With acute administration, dihydroergocryptine significantly reduced prolactin levels only at the dose of 10 mg and not at 5 mg. With repeated administration, a daily dose of 15 mg was more effective than 10 mg in reducing prolactin levels and in suppressing puerperal lactation. No side-effects occurred during the treatment. These results suggest that dihydroergocryptine might be considered an effective drug in the suppression of puerperal lactation.

[The pharmacokinetics of dihydroergocristine after intravenous and oral administration in rats]. / Pharmakokinetik von Dihydroergocristin nach intravenöser und oraler Applikation bei Ratten.

The pharmacokinetic properties of dihydroergocristine (DHEC, CAS 17479-19-5) were investigated in rats using a specific radioimmunoassay technique specific for non-metabolized drugs. DHEC, administered intravenously at the dose of 6 mg/kg, showed a plasma profile conforming to an open two-compartment pharmacokinetic model with a long terminal half-life (t1/2 = 13.6 h). DHEC kinetics after oral administration (6 mg/kg) showed two peaks. The first peak (C = 37 micrograms/l) occurred at the first collection point (0.5 h) indicating a quick absorption of the drug. The second peak (C = 34 micrograms/l) occurred at 2 h and may be considered an indication of an enterohepatic cycle. A long terminal half-life (t1/2 = 18.1 h) was observed. An extensive biotransformation of DHEC was indicated by an almost complete absence of unchanged drug in the urine and a high systemic clearance (2.65 l.h-1 x kg-1). A large volume of distribution (52 l.kg-1) was calculated.

[Dihydroergocristine in the treatment of organic brain psychosyndrome. Dose-finding study against placebo]. / Dihydroergocristin bei der Behandlung des hirnorganischen Psychosyndroms. Dosis-Findungs-Studie gegen Plazebo.

Purpose of this study was to evaluate the activity of dihydroergocristine (DHEC, CAS 17479-19-5) at three different dosages, when administered to aged patients with senile dementia of Alzheimer type. Eighty patients, 48 males and 32 females, aged 55-80 years, affected with senile organic brain syndrome, were admitted to the trial. Clinical evaluation was made by SCAG (Sandoz Clinical Assessment Geriatric Scale). Inclusion criteria considered patients presenting at the basal evaluation a total SCAG score between 60 and 90, with stressed impairment of cognitive function. All the patients were divided in four groups and treated with DHEC 1.5, 3, 6 mg/d or placebo for three months. The evaluation of the total SCAG score demonstrated a significant activity of the drug compared vs placebo, and a dose-related effect. Also for the single clusters it was demonstrated a significant (p < 0.05) dose/effect relation, except for the "affective" one; on the contrary "cognitive functioning" cluster displayed the best benefit. The drug was very well tolerated, as only some cases of dyspepsia, mild gastralgia and nausea were reported in some patients.

Dihydroergocryptine in the management of senile psycho-organic syndrome.

A double-blind, placebo-controlled, randomized study is described of an assessment of the efficacy and relative safety of the ergot alkaloid, dihydroergocryptine, on 52 patients with mild organic brain syndrome over a period of three months using a series of neurophysiological tests. The results indicated that short-term treatment with the alkaloid improved memory impairment. The side-effects were mild and transient in both the dihydroergocryptine and placebo groups and there were no alterations in blood chemistry.

[Combined uni- and multicenter double-blind studies in hypertensive patients. Comparison of blood pressure measurements]. / Kombinierte uni- und multizentrische Doppelblindstudie bei Hypertonikern. Vergleich der Blutdruckmessungen.

In a double-blind study to investigate the antihypertensive effect of a fixed triple combination with 0.05 mg reserpine, 2.5 mg clopamide and 0.4 mg dihydroergocristine in comparison to a fixed double combination with 0.05 mg reserpine and 2.5 mg clopamide, a patient subgroup of 34 patients followed a unicenter (central unit, 'institute') as well as a multicenter (established physicians) study design. The patients visited both investigation units on the day of admission to the study (week 0), after four weeks and after eight weeks of therapy (after the morning intake of the drugs). The paper in hand looks at the results of this subgroup with respect to the conformity of blood pressure values in the two investigative units. The analyses confirm the already published results of the entire study: Both combinations proved to be highly effective antihypertensive drugs. The triple combination showed therapeutical advantages for systolic blood pressure after four weeks, for diastolic pressure after eight weeks of therapy at the 'institute' as well as, although less distinct, in the medical offices. A comparison of the individual values did not show a convincing coherence of the measurements between institute and offices. All investigated possible systematic sources of error (different methods of measurement, days or times of measurement) could be excluded by correlation statistics as a reason for the divergences. The results show the necessity--particularly in multicenter studies--of a careful documentation of all accompanying data (e.g. method or time of measurement) as well as a greatest possible standardization of investigation (e.g. identical measuring apparatus and investigator.)

Pharmacokinetics of alpha-dihydroergocryptine in rats after intravenous and oral administration.

The pharmacokinetic properties of alpha-dihydroergocryptine methanesulphonate (alpha-DHEK, CAS 19467-62-0) were investigated in rat using a radioimmunoassay technique for nonmetabolized drug. alpha-DHEK, intravenously administered at the dose of 6 mg/kg, showed a plasma profile according to an open 3-compartment pharmacokinetic model with a long half-life (about 7.56 h). The kinetics of alpha-DHEK after oral administration (6 mg/kg) showed two peaks; the second peak at 8 h was probably due to an enterohepatic cycle. The disposition of alpha-DHEK consisted in a fast absorption and a slow elimination (t1/2el about 6.78 h). The alpha-DHEK was largely metabolized as results from the complex metabolite profile in body fluids and from very low urinary elimination of unchanged drug.

Effect of co-dergocrine in the autoperfused superior mesenteric vascular bed of the rat.

1. The influence of local administration of co-dergocrine in the in situ, constant flow autoperfused, superior mesenteric vascular bed of the rat was investigated. 2. Local infusion of co-dergocrine (0.1 micrograms kg-1 min-1) reduced the pressor response to electrical stimulation of the periarterial sympathetic nerves for the whole frequency range studied during cumulative frequency-response curves (1-8 Hz). 3. Co-dergocrine (0.01, 0.03, 0.1 micrograms kg-1 min-1) dose-dependently inhibited the pressor response to electrical stimulation at 4 Hz; increases in perfusion pressure produced by locally administered noradrenaline were inhibited to the same degree. 4. Pressor responses induced by locally administered phenylephrine were also inhibited by co-dergocrine (0.1 micrograms kg-1 min-1) while those produced by local injection of angiotensin II were not. 5. Local administration of the DA1-/DA2-receptor antagonist haloperidol (1 microgram kg-1), the DA2-receptor antagonist domperidone (10 micrograms kg-1) and the alpha 2-adrenoceptor antagonist rauwolscine (100 micrograms kg-1) partially prevented the influence of co-dergocrine on the electrically induced response. 6. The results show that the effect of co-dergocrine in the rat superior mesenteric vascular bed cannot simply be ascribed to interaction with the presynaptic inhibitory DA2-receptors on the noradrenergic nerve endings; it also has an antagonistic action at the postsynaptic alpha 1-adrenoceptors and an agonist action at the presynaptic alpha 2-adrenoceptors.

Effects of topical dihydroergocristine on intraocular pressure, aqueous humor dynamics and pupil diameter in conscious rabbits. A comparative study with timolol and pilocarpine.

This work comparatively studies the effects of dihydroergocristine, timolol and pilocarpine on intraocular pressure and pupil diameter in conscious rabbits. Intraocular pressure was measured by applanation tonometry and the pupil diameter by a photographic technique. In anesthetized rabbits, changes in tonographic facility of aqueous humor outflow and rate of aqueous humor formation were evaluated. Dihydroergocristine reduced the intraocular pressure more than timolol and much more than pilocarpine. The ocular hypotensive effect of dihydroergocristine was accomplished by a great reduction in aqueous humor formation, which surpasses the decrease in aqueous humor outflow, while timolol mainly reduced aqueous humor formation and pilocarpine increased aqueous humor outflow. Pupil diameter remained unchanged on dihydroergocristine, whereas timolol induced a slight mydriasis and pilocarpine provoked a clear myosis. Effects of dihydroergocristine might result in blockade of alpha-adrenoceptors in ciliary body, although available data about pretreatment with either metoclopramide or domperidone suggest that dopamine DA2-receptors might participate in ocular hypotensive effect of ergot derivatives.