A computer-aided drug design approach to discover tumour suppressor p53 protein activators for colorectal cancer therapy.

Colorectal cancer (CRC) is the third most detected cancer and the second foremost cause of cancer deaths in the world. Intervention targeting p53 provides potential therapeutic strategies, but thus far no p53-based therapy has been successfully translated into clinical cancer treatment. Here we developed a Quantitative Structure-Activity Relationships (QSAR) classification models using empirical molecular descriptors and fingerprints to predict the activity against the p53 protein, using the potency value with the active or inactive label, were developed. These models were built using in total 10,505 molecules that were extracted from the ChEMBL, ZINC and Reaxys® databases, and recent literature. Three machine learning (ML) techniques e.g., Random Forest, Support Vector Machine, Convolutional Neural Network were explored to build models for p53 inhibitor prediction. The performances of the models were successfully evaluated by internal and external validation. Moreover, based on the best in silico p53 model, a virtual screening campaign was carried out using 1443 FDA-approved drugs that were extracted from the ZINC database. A list of virtual screening hits was assented on base of some limits established in this approach, such as: (1) probability of being active against p53; (2) applicability domain; (3) prediction of the affinity between the p53, and ligands, through molecular docking. The most promising according to the limits established above was dihydroergocristine. This compound revealed cytotoxic activity against a p53-expressing CRC cell line with an IC50 of 56.8 µM. This study demonstrated that the computer-aided drug design approach can be used to identify previously unknown molecules for targeting p53 protein with anti-cancer activity and thus pave the way for the study of a therapeutic solution for CRC.

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.

Mechanism for the inhibition of contractile activity of the gastric antrum and pylorus in rabbits during psychogenic stress.

Psychogenic stress in rabbits (fixation to a frame) was accompanied by the inhibition of contractile activity of the gastric antrum and pylorus. These changes persisted during blockade of muscarinic receptors, nicotinic receptors, alpha(2)-adrenoceptors, and beta(1)/beta(2) adrenoceptors. A stress-induced decrease in gastric motor activity was mediated by the nonadrenergic noncholinergic mechanism. It resulted from the influence of a hormonal stress factor on the stomach, which was probably realized through nonadrenergic inhibitory neurons of the enteric nervous system.

Expression of gamma-aminobutyric acid receptor (subtype A) in prostate cancer.

BACKGROUND: In prostate cancer, gamma-aminobutyric acid (GABA) has been previously reported to increase cellular proliferation via the ionotropic GABAa receptor (GABAar) and to promote cellular invasiveness via the metabotropic GABAb receptor. METHODS: In this study, we have investigated, by immunohistochemistry, GABAar levels in 12 normal human prostate, 13 benign prostatic hyperplasia (BPH) and 148 human prostate cancer specimens. We have also examined the effect of several GABA agonists and antagonists on the in vitro proliferation of four human prostate cancer cell lines: LNCaP, MDA-PCA-2b, DU145 and PC3. RESULTS: GABAar immunoreactivity was present in the stroma of ~75% of the normal and BPH specimens, and in 95% of the prostate cancer specimens. Also, low to moderate GABAar staining was observed in the acinar epithelium of 50 (33%) prostate cancer specimens. No correlation was observed between GABAar staining and patient age, Gleason Sum or TNM stage. A GABAa agonist isoguvacine, at doses between 5-50 microg/ml (31-310 microM), stimulated the proliferation of all four human prostate cancer cell lines, tested. Baclofen, a GABAb agonist (up to 50 microg/ml, 234 microM) had no effect on growth. Also, at concentrations up to 100 microg/ml, GABA antagonists, bicuculline (223 microM), picrotoxin (166 microM) and saclofen (400 microM), did not have significant growth-inhibitory effects. However, dihydroergotoxine, which binds the GABAar chloride ion-channel, inhibited cellular proliferation (IC(50) 18-38 microM). CONCLUSIONS: These data indicate frequent expression of GABAar in prostate cancer and support a role for GABAar in the proliferation of prostate cancer cells.

[Mechanisms of inhibition of the contractile activity in the ileo-caecal zone in rabbits under psychogenic stress].

In experiments on unanaesthetized rabbits, myoelectric activity (contractile activity index) of distal ileum, caecum, and proximal colon in two sites was studied under stress induced by fastening a rabbit to the table in supine position. The stress caused sharp decrease (up to complete disappearance) of the contractile activity in all studied compartments of the ileocaecal intestine with partial or complete restoration after release of the animal. Nonselective blockade of pre- and postsynaptic alpha-adrenoceptor with dihydroergotoxin abolished the initial component of the specified inhibitory response. The latter was caused by "adrenergic inhibition" as a result of action of catecholamines circulating in blood on inhibitory smooth muscle alpha-adrenoceptor. Against the background of muscarinic cholinoceptor blockade, the stressor inhibition of ileocaecal contractile activity observed in control experiments was completely preserved. The periods of supression of ileoceacal contractile activity under stress resistant to blockade of alpha-, beta-adrenoceptor and muscarinic cholinoceptor, are caused by the mechanism of "nonadrenergic noncholinergic inhibition", which is realized at the expence of activation of the enteric inhibitory neurones.

The distribution of major lymphocyte subsets in cord blood is associated with its pH.

OBJECTIVES: To assess in venous cord blood the distribution of major lymphocyte subsets according to pH and medications used during labor. DESIGN AND METHODS: Venous cord blood was sampled immediately after labor from 70 newborns (35 males and 35 females) delivered vaginally. Lymphocytes were immunophenotyped by flow cytometry and pH was measured using the AVL 900 automated blood gas analysis system. Data on birth weight, gestational age at delivery, length of labor, presence of stained amniotic fluid, medications used during labor, maternal risk factors, age and parity were collected. RESULTS: The percentage of T lymphocytes decreased while the percentage of NK lymphocytes increased with decreasing pH over the whole range of pH values. The proportions of T and NK lymphocytes were associated with the administration of neuroplegics, spasmolytics or dihydroergotoxin in the first stage of labor. CONCLUSIONS: Cord blood pH and labor-associated variables should be taken into account to adequately interpret the profile of major lymphocyte subsets as a marker of the effect of different prenatal factors on the immune system of neonates.

The dopamine D2 receptor agonist alpha-dihydroergocryptine modulates voltage-gated sodium channels in the rat caudate-putamen.

Alpha-Dihydroergocryptine (alpha-DHEC), a Dopamine (DA) D2 receptor agonist, is widely used as dopaminergic drug in the treatment of Parkinson's disease. To study the mechanisms involved in the signal transduction process induced by alpha-DHEC on the presynaptic site of the dopaminergic neuron, we incubated slices of the rat caudate-putamen with alpha-DHEC and the indicated substances in static chambers. Following incubation the resulting DA outflow was measured by high-performance-liquid chromatography with electrochemical detection. The addition of alpha-DHEC (10 microM-0.1mM) did not modulate basal DA outflow. Activation of voltage-gated sodium channels by veratridine (VER) from low to relatively high concentrations (1-10 microM) led to a concentration-dependent increase of DA outflow. Using concentrations as high as 10 microM a dramatic increase of DA levels (600% of baseline levels) was observed. The ability of VER to provoke DA release was sensitive to the addition of tetrodotoxin (TTX) and was completely blocked by 1 mM TTX. Coincubation of alpha-DHEC (10microM-0.1mM) and VER (10microM) reduced VER-stimulated DA outflow in a concentration-dependent manner. The time-concentration course of VER-induced DA outflow was not modulated by alpha-DHEC. As described in our earlier studies, the specific D2 receptor antagonist (-)sulpiride (SLP) concentration-dependently enhances extracellular DA levels. Addition of alpha-DHEC almost completely blocked SLP-induced DA-outflow. When slices were incubated with the non-selective DA receptor agonist haloperidol (HLP, 0.1 mM) the effect of alpha-DHEC on VER-induced DA outflow was partially but not completely abolished. These data strongly suggest that the effect of alpha-DHEC on the presynaptic site implies an activation of D2 receptors as well as an inhibitory action on voltage-gated sodium channels. Alpha-DHEC seems to modulate voltage-gated sodium channels in part independently from DA receptors since blockade of D2 receptors with saturating concentrations of haloperidol did not completely abolish its effect. Based on our data we have no evidence that voltage-gated potassium channels, N-type calcium channels or D1, D3-receptors are involved in the action of alpha-DHEC at the presynaptic site of the dopaminergic neuron. The results give one rationale for the proposed neuroprotective effect of alpha-DHEC.

Study on the interaction of the dopamine agonist alpha-dihydroergocryptine with the pharmacokinetics of digoxin.

AIM: The study was carried out to explore the potential for pharmacokinetic interaction of a single oral dose of alpha-dihydroergocryptine (CAS 14271-05-7, DHEC, Almirid) with digoxin. METHODS: The serum pharmacokinetics of digoxin were analysed after the administration of single oral doses of 0.5 mg digoxin administered either alone or concomitantly with 20 mg DHEC according to a randomised, non-blinded, two-period cross-over design, with study periods 2 weeks apart. Twelve healthy male subjects, 23 to 39 years of age were enrolled and were investigated in accordance with the protocol. Venous blood was sampled up to 48 h after dosing. Concentrations of digoxin in serum were determined by a competitive radioimmunoassay. RESULTS: The mean Cmax were 1.97 +/- 0.87 (after a median tmax of 1 h) and 2.05 +/- 0.95 ng/ml (after a median tmax of 0.83 h) after the administration of digoxin with (test) and without (reference) concomitant DHEC, respectively; the corresponding estimated treatment ratio for test: reference was 0.939, 95% CI: 0.781 to 1.129. The mean AUC(0-48) were 13.6 +/- 5.0 ng.h/ml and 13.3 +/- 4.7 ng.h/ml for the test and reference treatment, respectively; the corresponding estimated treatment ratio for test: reference was 1.011, 95% CI: 0.866 to 1.142. In addition, no clinically significant changes were observed by ECG monitoring. The tolerability of digoxin alone was good, significantly more adverse events occurred when co-administered with DHEC; these corresponded with the known adverse reaction profile and were of moderate intensity. No premature study termination was thus necessary. CONCLUSION: The present study did not demonstrate clinically relevant interaction of a single dose of DHEC on the pharmacokinetics of digoxin. On the basis of these observations there is no indication for an a priori adjustment of the dose of digoxin when concomitant treatment with DHEC is initiated.

[The influence of alpha-dihydroergocryptine derivatives on psychomotor manifestations in Parkinson disease]. / Vliianie proizvodnogo al'fa-digidroérgokriptina na psikhicheskie i dvigatel'nye proiavleniia parkinsonizma.

The paper presents the results of administration of alpha-dihydroergocryptine preparation (vasobral) to parkinsonic patients. It was prescribed to 20 patients with parkinsonism together with the specific therapy. Clinical state as well as the level of anxiety and depression was estimated using standard scales both before and after treatment. A high efficiency of vasobral was found as regards such symptoms as disorders of memory, headache, vertigo, a noise in ears and head, asthenic state. In some patients functional activity increased, in 4 patients a dose of dopaminergic preparations was successfully decreased by 25%. An important aspect of vasobral activity was also a decrease of anxious-depressive symptoms. A conclusion was made about efficiency of vasobral in combined treatment of parkinsonic patients.

Nicergoline facilitates vestibular compensation in aged male rats with unilateral labyrinthectomy.

The ergoline derivatives, nicergoline (NIC) or dihydroergocristine (DHE) were administered at various doses (0.1, 0.5 and 1 mg/kg) to aged male rats subjected to labyrinth unilateral lesion (LBX). The nystagmus rate appeared to be lower in animals treated with DHE or NIC 1mg/kg than in saline-injected rats, when observed on day 1 and 2 after operation. The number of falls in the rotorod test of LBX animals was decreased by NIC 0.5 or 1 mg/kg at all observation times. This parameter was affected by DHE only at the higher dose. These results suggest that NIC facilitates vestibular compensation of LBX rats. DHE appeared to be less potent in this respect. Since both drugs act on central dopaminergic neurotransmission, it is possible that this neurotransmission may be involved in their mechanism of action.

Partial agonism at serotonin 5-HT1B and dopamine D2L receptors using a luciferase reporter gene assay.

We have used a luciferase reporter gene assay to study the functional responses of two G-protein-coupled receptors in Chinese hamster ovary (CHO) cells. The rank order of potency of drugs for the endogenous 5-HT1B receptor was 5-Hydroxytryptamine (5-HT) > zolmitriptan > dihydroergocristine > (-)lisuride (with no response to bromocriptine). However, only 5-HT and (-)lisuride produced a full functional response, with zolmitriptan and dihydroergocristine achieving 69+/-2% and 50+/-1% of the maximal response. In the same cells stably transfected with the rat dopamine D2L receptor, dopamine and bromocriptine produced a full agonist functional response, whilst (-)lisuride produced a biphasic response curve, indicating activity at both the endogenous 5-HT1B and exogenous dopamine D2L receptors. Using the receptor specific antagonists, pindolol and (+)butaclamol, (-)lisuride was shown to produce 52% of the maximal response at the dopamine D2 receptor relative to dopamine. In comparison to a cAMP accumulation assay, the rank orders of potency and intrinsic activity were the same for all compounds used. These results demonstrate that this reporter gene assay is capable of discriminating both potency and efficacy of drugs and can be used to characterise partial agonists at endogenously and heterologously expressed receptors in CHO cells.

On the mechanisms of adenosine induced pulmonary vasoconstriction in rats.

The effect of adenosine on pulmonary vessels was studied in isolated perfused rat lungs. Drugs were administered intra-arterially in a fixed volume of 0.1 ml Krebs solution as bolus injections. Adenosine responses were obtained before and 10 min after drug injections. When applied in logarithmically increasing doses (1-100 micrograms/ml), adenosine caused dose-dependent increases in pulmonary perfusion pressure (e.g. pulmonary vasoconstriction) which were readily reversible. Challenging adenosine with quinidine, dihydroergocristine and cyproheptadine (2 micrograms/ml each) did not significantly alter adenosine responses. Pretreatment of lungs with 0.5 mM theophylline, 10 micrograms/ml indomethacin, 30 micrograms/ml tebokan (a PAF antagonist) or 1 microgram/ml methylene blue for 10 min, however, antagonized the vasoconstrictor effect of the drug significantly. From these experiments, it was concluded that the mechanisms underlying the pulmonary vasoconstrictor action of adenosine are complex, and that both types of purinoceptors, prostaglandins, PAF and other vascular endothelial hormones might be involved.

Coenzyme Q, peroxidation and cytochrome oxidase features after parkinson's-like disease by MPTP toxicity in intra-synaptic and non-synaptic mitochondria from Macaca fascicularis cerebral cortex and hippocampus: action of dihydroergocriptine.

The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration on respiratory chain features were studied in synaptic and non-synaptic mitochondrial populations from cerebral cortex and hippocampus of Macaca Fascicularis (Cynomolgus monkey). Enzymatic activity, cytochrome a + a3 content and turnover numbers of Complex IV, contents of Coenzyme Q10, of hydroperoxides and membrane fluidity were assessed in non-synaptic "perikaryal" and intra-synaptic "light" and "heavy" mitochondria isolated: (a) from the dopaminergic ascending terminal areas of cerebral cortex of monkeys treated p.o. with dihydroergocriptine at the dose of 2, 6 or 20 mg/kg/day for 52 weeks; (b) from the dopaminergic terminal areas of hippocampus of monkeys treated p.o. with dihydroergocriptine at the dose of 12 mg/kg/day before and during the induction of a Parkinson's-like syndrome by MPTP administration (i.v., 0.3 mg/kg/day for 5 days). Dihydroergocriptine administration moderately increased both cytochrome oxidase activity and cytochrome a + a3 content in "light" intra-synaptic mitochondria and hydroperoxides/CoQ10 ratio in all the types of mitochondria, as a consequence of the enhanced energy metabolism. The Parkinson's-like syndrome by MPTP changed the biochemical investigated parameters, affecting both directly the respiratory chain structures, i.e. by respiratory chain complexes inhibition and indirectly, i.e. by free radical mediated damages. MPTP administration negatively influenced Complex IV activity and Turnover Number of intra-synaptic mitochondria, without affecting the total cytochrome a + a3 amount. In all types of mitochondria and particularly on the "light" intra-synaptic ones, MPTP-induced lesion enhanced hydroperoxides/Coenzyme Q10 molar ratio due to the fall in Coenzyme Q10 levels and the concomitant increase in hydroperoxides. Dihydroergocriptine treatment appeared to be effective in MPTP-treated animals in improving those mitochondrial features that probably suffered free radical insults.

Identification of hepatic, non-monoamine, dihydroergocryptine binding sites with significant gender differences.

High affinity [3H] dihydroergocryptine binding sites different from alpha1/alpha2-adreno, dopamine or serotonin receptors were detected in a crude membrane fraction from hamster liver by radioligand binding filtration assay. The binding was saturable and reversible, as well as time and protein dependent. Scatchard analysis revealed a single population of binding sites with Kd 3.8 +/- 0.9 nM and Bmax = 675 +/- 130 pmol/g tissue (mean +/- S.E.M., n=6) in the male hamster crude liver membrane fraction. In the female liver membranes the Kd value was 4.4 + 1.2 nM and Bmax = 1025 +/- 190 pmol/g tissue (mean + S.E.M., n = 6). Differences between males and females in Bmax values were significant (P < 0.01). The most potent inhibitors of [3H] dihydroergocryptine binding were bromocriptine > ergotamine > dihydroergocryptine > dihydroergocristine > alpha ergocristine > dihidroergotamine > ergocornine > ergocristine > nicardipine > (+) butaclamol > PK 11195 > nitrendipine > domperidone > (-)butaclamol (in order of decreasing affinity). The described type of dihydroergocryptine binding sites was not detected in hamster brain, kidney, spleen or lungs. Obtained data support the concept that some ergot-derivatives may induce metabolic effects in the liver through peripheral mechanisms other than those, mediated by alpha-adrenoreceptors.

Immunoreactive endogenous ouabain in primary aldosteronism and essential hypertension: relationship with plasma renin, aldosterone and blood pressure levels.

OBJECTIVE: To investigate the role of ouabain in human hypertension and to establish whether immunoreactive endogenous ouabain is secreted by the adrenal gland under the influence of dopaminergic regulation. METHODS: We measured plasma levels of endogenous ouabain by immunoassay, together with other variables, including plasma renin activity and aldosterone levels, in 91 clinically selected hypertensives and 19 healthy volunteers. We also measured endogenous ouabain in adrenal venous blood and the effect of DA2 dopaminergic receptor blockade and stimulation. After a thorough clinical evaluation, 64 patients were diagnosed with essential hypertension and 24 with primary aldosteronism. RESULTS: Plasma levels of endogenous ouabain were higher in essential hypertensives than in controls. Multiple regression analysis showed a significant relationship of mean blood pressure with plasma endogenous ouabain, age and body mass index, but not with other measured parameters. The plasma levels of endogenous ouabain were more than two standard deviations above the mean value for normotensives in 45% of patients with essential hypertension in whom plasma renin activity was normal. Higher plasma levels of endogenous ouabain were found in patients with aldosterone excess, specifically affecting 56% of 17 patients with surgically confirmed adrenal cortical adenoma and one (14%) of seven patients with idiopathic causes. Removal of adenomas lowered blood pressure in half of the patients in whom plasma levels of endogenous ouabain normalized after surgery. Plasma endogenous ouabain levels were similar in venous blood from the adrenal and inferior vena cava, and plasma levels were not influenced by DA2 dopaminergic blockade and stimulation. CONCLUSION: Approximately half of Caucasian patients with essential hypertension and with hyperaldosteronism exhibit elevated circulating levels of endogenous ouabain. The latter do not appear to be secondary to hypertension, are unrelated to plasma renin activity, and may not involve adrenal type-2 dopaminergic receptors.

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.