Phase 1, single-dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia.

Essentials Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII. A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia. MarzAA was safe and tolerated at intravenous doses up to 30 µg kg-1 Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX. SUMMARY: Background Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia. Objectives To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non-bleeding patients with congenital hemophilia A or B with or without inhibitors. Methods This international, phase 1, open-label study (NCT01439971) enrolled males aged 18-64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single-dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 µg kg-1 ). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD. Results Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose-limiting toxicity. No treatment-emergent severe or serious adverse events occurred. MarzAA showed linear dose-response PK across the 4.5-30 µg kg-1 dose range, with a terminal half-life of ⁓ 3.5 h. Dose-dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses. Conclusions MarzAA was tolerated at doses up to 30 µg kg-1 . The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.

Effective control of hypertension: a project of the Hungarian Society of Hypertension, baseline data.

The aim of the project is to assess the quality and improve the preventive and curative practices at the primary care level in Hungary. A total of 50 general practitionaires were selected on a voluntary basis in Budapest, Hungary, and from them, 30 were randomized to the intervention (I) group and 20 to the reference (R) group. The members in the I group have been trained for the official hypertension guideline and their everyday work is monitored. Those in the R group have only been monitored to measure the efficacy of the training. In all, 10% from the known hypertensive persons (N=10,799) and 5% of the remaining (nonhypertensive) patients (N=60,341) were selected randomly from the GP's computer files and invited for screening investigation performed by trained medical students. They measured the blood pressure of patients, assessed the cardiovascular risk status and the quality of education of patients by standardized questionnaires. In total, 4083 patients were invited, but only 39.2% attended the screening visit. The prevalence of undetected hypertension was 34.6%. This prevalence was significantly higher in the older (>60 years: 46.8%) than in the younger (<50 years: 20.8%, P<0.0001) age group and it was higher in men (41.5%) than in women (30.1%, P<0.001). The proportion of H patients on drug treatment was 85.3% and the frequency of patients under effective blood pressure control (eg<140/90 mmHg) was 27.8%. Counselling to patients for a healthier lifestyle (exercise, smoking, alcohol consumption, diet) was very rare. In conclusion, our data represent the primary care of Budapest and may not be relevant to the whole country. As a consequence of this study, education of primary care physicians and patients is a must for further improvement of hypertension care.

Imidazoline receptors: from discovery to antihypertensive therapy (facts and doubts).

The hypothesis and indirect evidence of imidazoline receptors has been promoted since some 15 years ago and it gave a substantial impetus for research in this field, resulting in a better understanding of neuronal and cardiovascular regulatory processes. The nomenclature of the imidazoline receptors has been accepted by international forums but no direct proof for the existence of these receptors has been published. Authors summarise the most important available data, including facts and doubts as far as the discovery, characterisation, and function of imidazoline receptors and their subtypes, the differences between imidazoline receptors and alpha-2 adrenoceptors, and also on their participation in regulatory processes.

[Effect of fluvastatin on serum lipid levels in essential hypertension]. / A fluvastatin hatása a szérum lipid szintekre esszenciális hipertóniás betegekben.

The efficacy and safety of the HMG-CoA reductase fluvastatin was investigated in a multicenter, open label clinical therapeutic trial in the treatment of hypercholesterinaemia in hypertensive patients (WHO I-II.). 49 patients were involved, 6 patients were dropped out because of th lack of compliance, 43 patients were investigated (mean age: 57.6 +/- 9.4 years, mean blood pressure: 146 +/- 16/88+/- g mmHg (systolic/diastolic). The antihypertensive treatment was unchanged during the study. An 8 weeks low-lipid diet was started if the fasting total cholesterol (TC) level was equal or higher than 6.5 mM/L and the triglyceride level was lower than 4.6 mM/L. After the dietary period fluvastatin treatment was started (20 mg o.d.), if the level of LDL-C was higher than 4,1 mM/L. Blood pressure, heart rate, TC, HDL-C (HDL2-C, HDL3-C), apoA1, apoB, TG were measured at the 4th, 8th, 12th weeks of treatment. LDL-C was calculated with Fridewald equation. The daily dose of fluvastatin was increased to 40 mg, if LDL-C level was higher than 3.5 mM/L after 4 weeks of treatment. 36 patients completed the study (Group B). 7 patients were dropped out at the end of the dietary period, because of the significant decrease of TC and LDL-C levels (Group A). In Group B fluvastatin significantly reduced the level of TC (from 7.22 +/- 0.88 to 5.99 +/- 0.98 mM/L), of LDL-C (from 5.13 +/- 0.71 to 3.95 +/- 0.88 mM/L), and the level of ApoB (from 0.97 +/- 0.26 to 0.85 +/- 0.15 mM/L), but did not influence significantly the level of HDL-C, ApoA1 and TG. The diastolic blood pressure decreased significantly during the dietary period, while after beginning the fluvastatin treatment the decrease of the systolic blood pressure became significant. There was no change in the heart rate. Only minor side effects were observed in 3 patients (dysuria, constipation, lack of appetite). Fluvastatin proved to be an effective and well-tolerated drug in the treatment of hypercholesterinaemia in hypertensive patients.

[Incidence of scurvy in Hungary today]. / Skorbut elöfordulása napjainkban Magyarországon.

The author reports the medical history of a 63-year-old woman. The patient collapsed on the street, and the National Ambulance Service transported her to the hospital. The clinical picture was characterized by serious anaemia and haemorrhagic diathesis. Scurvy has been identified by the measurement of low leucocyte-vitamin-C level. While in the last 20-30 years scurvy was not diagnosed in Hungary, one cannot easily recognize it. The author thinks necessary to report this case, because of its recent infrequency.

Hungarian Isradipine Study (HIS): long-term (3-year) effects on blood pressure and plasma lipids.

These are the preliminary data of an open multicenter trial of antihypertensive treatment with isradipine as monotherapy (dose, 4.55 +/- 0.56 mg twice daily; n = 11) or isradipine (7.5 +/- 0.63 mg twice daily) in combination with bopindolol (1.16 +/- 0.12 mg once daily; n = 30) administered for 3 years to patients with essential hypertension (WHO classification I or II). Blood pressure was significantly decreased in both treatment groups and there was no indication of resistance to therapy. Plasma levels of total cholesterol and triglycerides were decreased by the end of the second year of treatment, and there was a tendency toward increase in plasma levels of high-density lipoprotein cholesterol (HDL2 or HDL3). The atherogenic index (ratio between total cholesterol and HDL2 plus HDL3) was also decreased. Blood glucose levels remained unchanged in both normoglycemic patients and those with non-insulin-dependent diabetes mellitus (NIDDM) during 3 years of therapy. It is concluded that isradipine is safe and effective when administered long-term in the treatment of hypertensive patients with either hyperlipidemia or NIDDM.

Antihypertensive effect of the calcium antagonist isradipine and lipid profile.

The hypothesis that plasma lipids may modulate the antihypertensive effect of the calcium antagonist isradipine was tested in 85 patients who had essential hypertension. Significant linear correlations were found between the antihypertensive effect of isradipine and plasma levels of total cholesterol and high-density lipoprotein (HDL2 or HDL3) in normotriglyceridemic (n = 63), but not in hypertriglyceridemic (n = 22), patients. From this, we conclude that normal levels of plasma lipids may modulate the function of calcium channels and their interaction with calcium antagonists.

The effect of essential fatty acid deficiency on the adrenergic activation of glycogenolysis in rat hepatocytes.

The fatty acid composition of total lipids and the adrenoceptor-mediated activation of glycogenolysis were studied in isolated hepatocytes from rats maintained on a control diet or on an essential fatty acid (EFA)-free diet. In cells from rats on the EFA-free diet there was a marked reduction in linoleic and arachidonic acid (AA) contents and an increase in eicosatrienoic, oleic, and palmitoleic acid contents compared to controls. In freshly isolated cells from both groups, phosphorylase a activity was increased by phenylephrine or epinephrine but not by isoproterenol, and the effect of epinephrine was inhibited by phenoxybenzamine but not by propranolol. When control cells were preincubated in a serum-free buffer for 4 h before testing, the effect of phenylephrine on phosphorylase a activity was reduced, isoproterenol became a potent agonist and the effect of epinephrine was partially inhibited either by phenoxybenzamine or by propranolol. The emerging beta-adrenergic response in 4-h cells was associated with a marked potentiation of isoproterenol-induced cAMP accumulation. A similar 4-h preincubation of EFA-deficient cells resulted in a reduced response to phenylephrine while isoproterenol remained ineffective for increasing either phosphorylase a activity or cAMP production. The response of these 4-h cells to isoproterenol could be restored by in vivo replacement of the EFA-deficient diet with control diet for the last 4 weeks prior to the experiment, but not by the in vitro exposure of the EFA-deficient cells to 10 microM AA throughout the 4-h incubation period. Extending previous observations (Refs. (6-8)), the present results suggest that the time-dependent emergence of beta-adrenergic glycogenolysis, but not the parallel reduction of the alpha-adrenergic response, is mediated by AA or its metabolite(s), which probably act by facilitating the G-protein-dependent coupling of beta-receptors.

Possible role of alpha-2 and alpha-1 adrenoceptors in the experimentally-induced depression of the central nervous system.

The alpha-2 adrenoceptor agonists clonidine and xylazine were employed in chicks and rats to induce a loss of the righting reflex, a sign for depression of the central nervous system. These effects of clonidine and xylazine were antagonized by yohimbine, idazoxan and CH-38083 (7,8-(methylenedioxi)-14-alpha-hydroxyalloberbane HCl), compounds having alpha-2 adrenoceptor antagonist properties. Prazosin, an antagonist for alpha-1 adrenoceptors, enforced the alpha-2 adrenoceptor agonist-induced depression in both species. 6-Hydroxydopamine treatment, which reduced the norepinephrine concentrations in the rat cerebral cortex by 76%, increased the duration of the loss of righting reflex induced by xylazine indicating that central postsynaptic alpha-2 adrenoceptors might also be involved in this behavioral alteration. The electrically-stimulated tritium release was also determined from the isolated rat cerebral cortex slices which had been preloaded with 3H-norepinephrine. Clonidine and xylazine inhibited the stimulation-induced tritium release and this inhibition was counteracted by yohimbine, idazoxan or CH-38083, but not by prazosin. We have concluded from the present data that stimulation of alpha-2 adrenoceptors with pre- and postsynaptic locations or inhibition of alpha-1 adrenoceptors in the central nervous system may shift the depression/vigilance balance to the direction of depression which might be accompanied by a decreased activity of cortical noradrenergic neural transmission.

Presynaptic alpha 2-adrenoceptors exclusively sensitive to agonists of phenylethylamine structure on the sympathetic nerves of the human gall bladder artery.

The influence of alpha 2-adrenoceptor agonists and antagonists on the release of noradrenaline was studied in human gall bladder (cystic) artery preparations, in which transmitter stores were labelled with [3H]noradrenaline. The preparations were stimulated at 2 Hz for 3 min (360 shocks each of 1 ms duration two times (S1 and S2)). Both the L-noradrenaline and alpha-methylnoradrenaline (10(-6) M) significantly reduced (S2/S1 = 0.27 +/- 0.05; 0.43 +/- 0.04, respectively), whilst clonidine, xylazine and guanfacine at 10(-6) M failed to affect the stimulation evoked release of [3H]noradrenaline. Yohimbine (10(-6) M), CH-38083, which is a new, selective alpha 2-adrenoceptor antagonist (10(-7) M) and prazosin (10(-6) M) enhanced the evoked release of radioactivity, where S2/S1 were 2.50 +/- 0.19; 2.99 +/- 0.32; 1.48 +/- 0.05, respectively. Administering the alpha 2-antagonists and prazosin together, we were unable to demonstrate an additive effect. Yohimbine and CH-38083 prevented, while prazosin reduced, the inhibitory effects of L-noradrenaline or alpha-methylnoradrenaline on the release of radioactivity. Our results suggest that one type of presynaptic alpha 2-adrenoceptor modulates the release of noradrenaline evoked by electrical stimulation of the human cystic artery. This receptor is sensitive to alpha 2-adrenoceptor agonists which have a phenylethylamine structure, but is insensitive to imidazolines and guanfacine.

Neurochemical evidence for two types of presynaptic alpha 2-adrenoceptors.

Neurochemical and pharmacological evidence has been obtained that noradrenergic varicosities (in mouse and rat vas deferens) and cholinergic varicosities (in the Auerbach's plexus) contain heterogenous alpha 2-adrenoceptors through which the release of [3H]noradrenaline and [3H]acetylcholine can be modulated. The quantitative data also support the hypothesis that different noradrenaline and xylazine sensitive alpha 2-adrenoceptors are present prejunctionally in the vas deferens and Auerbach's plexus preparations. Prazosin, although it has a presynaptic inhibitory effect on alpha 2-adrenoceptors of noradrenergic axon terminals, has no effect on cholinergic axon terminals. These data suggest that there are two different types of alpha 2-adrenoceptors at the presynaptic axon terminals.

Prazosin partly blocks clonidine-induced hypotension in patients with essential hypertension.

Prazosin has been reported to reduce the hypotensive and/or bradycardic effect of clonidine in various animal models. Investigations in humans have given conflicting conclusions about the effectiveness of the combination of clonidine and prazosin. In patients with essential hypertension prazosin significantly reduced the hypotensive effect of intravenous clonidine, but it failed to affect the clonidine-induced bradycardia. This finding means that the combination of prazosin and clonidine is inappropriate in antihypertensive therapy.

CH-38083, a selective, potent antagonist of alpha-2 adrenoceptors.

The selectivity and specificity of CH-38083 [7,8-(methylenedioxi)-14-alpha-hydroxyalloberbane HCl], a berbane derivative for alpha adrenoceptors has been studied and compared with yohimbine and idazoxan in peripheral tissues and in the central nervous system. In isolated tissue experiments CH-38083 was a competitive antagonist at presynaptic alpha-2 adrenoceptors on the axon terminals of the rat vas deferens (pA2 against xylazine = 8.17 +/- 0.06) and of the longitudinal muscle strip of guinea pig ileum (pA2 against xylazine = 8.07 +/- 0.20). As far as its postsynaptic alpha-2 adrenoceptor antagonistic activity is concerned its affinity in rat vas deferens (pA2 = 4.95 +/- 0.11) against l-phenylephrine and in rabbit pulmonary artery (pA2 = 5.38 +/- 0.33 against l-norepinephrine) was markedly less than that displayed for presynaptic sites. From pA2 values obtained in rat vas deferens the calculated alpha-1/alpha-2 adrenoceptor selectivity ratios for yohimbine, idazoxan and CH-38083 were 4.7, 117.5 and 1659, respectively. CH-38083 failed to show any affinity for histamine and muscarinic receptors and it even potentiated the effect of serotonin on atropinized longitudinal muscle strip of guinea pig ileum. It enhanced the release of [3H]norepinephrine from electrically stimulated mouse vas deferens loaded previously with labeled [3H]norepinephrine. In binding studies carried out in rat brain membrane preparations using [3H]prazosin and [3H]idazoxan, the selectivity ratios (Ki alpha-1/Ki alpha-2) proved to be 32.5, 289.5 and 1368 for yohimbine, idazoxan and CH-38083, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Transmitter release from the cytoplasm is of physiological importance but not subject to presynaptic modulation.

Ca2+-dependent release of [3H] noradrenaline ([3H] NA) evoked by electrical stimulation of the isolated mouse vas deferens was subject to negative feedback modulation by idazoxan an alpha 2-adrenoceptor blocking agent. Both the resting release and that evoked by 1-phenylephrine proved to be Ca0-independent and unaffected by idazoxan. Ouabain-evoked release of [3H] acetylcholine from the myenteric plexus of ileal longitudinal muscle strips in the presence of eserine was not affected by atropine, but that evoked by electrical stimulation was enhanced. Since the release of NA or ACh by 1-phenylephrine and ouabain respectively is mainly of cytoplasmic origin, it is concluded that the release of transmitter from the cytoplasm is not subject to negative feedback modulation.

beta-Endorphin and essential hypertension: importance of the clonidine-naloxone interaction.

Analysis of the effect of naloxone (0.4 mg iv.) on clonidine hypotension in 80 patients with essential hypertension revealed that two groups could be separated. In the responding group (43 pts) naloxone increased blood pressure and heart rate in clonidine-treated patients while in the non-responding group (37 pts) it has no such effect. Patients in the responding group had higher cardiac output, stroke volume, plasma renin activity, plasma adrenaline and beta-endorphin levels and lower total peripheral resistance, shorter history of hypertension and lesser body weight than those in the non-responding group. The pressor effect of naloxone in four responding patients treated with clonidine for 29 months tended to be smaller compared to the response obtained after a 3-day clonidine therapy. Results favour the hypothesis of the existence of two (responding, non-responding) groups of patients with essential hypertension. Further work will clarify whether these groups represent different pathogenesis or they indicate only a different stage of hypertension.

Effects of clonidine and guanfacine in essential hypertension.

Daily doses of 0.3 mg clonidine and 3 mg guanfacine were equiactive in decreasing blood pressure and heart rate in 17 subjects with essential hypertension. Clonidine decreased cardiac output and guanfacine decreased total peripheral resistance, while clonidine had no effect on stroke volume but guanfacine increased it. Both clonidine and guanfacine decreased plasma renin activity. Naloxone, 0.4 mg iv, reversed the antihypertensive effect of clonidine but was ineffective even at higher doses (1.6 mg iv) when subjects were treated with placebo or guanfacine. It is suggested that the hemodynamic differences between the two centrally acting alpha 2-adrenoceptor agonist antihypertensive drugs may at least in part result from the involvement of opioid mechanisms only in the action of clonidine.

Beta-endorphin contributes to the antihypertensive effect of clonidine in a subset of patients with essential hypertension.

Naloxone [0.4 mg iv.] increased blood pressure and heart rate of 13 clonidine-treated [0.3 mg per os for 3 days] patients with essential hypertension [reacting group] while it has no such effect in 11 clonidine-treated patients [non-reacting gr.] Clonidine increased plasma beta-endorphin concentration of the reacting patients by 17.53 +/- 1.68 pM/1 and in the non-reacting ones by 5.91 +/- 0.88 pM/1. Significant linear correlation was found between the clonidine-induced increase in plasma beta-endorphin level and the naloxone-induced change in mean blood pressure [r = 0.9572, n:24, p less than 0.001]. In another group of 8 patients clonidine [0.15 mg iv.] decreased mean blood pressure but naloxone, 30 min after the clonidine injection, did not reverse the clonidine hypotension. We suggest that beta-endorphin, released by chr. clonidine therapy, contributes to the anti-hypertensive effect only in the reacting group.

Reversal by naloxone of the antihypertensive action of clonidine: involvement of the sympathetic nervous system.

The effects of clonidine, naloxone, and their combination on arterial blood pressure (BP), heart rate (HR), and hemodynamic and biochemical parameters were examined in 29 patients with essential hypertension. Treatment for 3 days with 0.3 mg/day clonidine reduced BP and HR, and these effects were quickly reversed by a single injection of 0.4 mg iv naloxone in 17 of the patients (responders), but not in the remaining 12 (nonresponders). Responders had higher control values for cardiac output, stroke index, plasma renin activity (PRA), and plasma epinephrine levels than did nonresponders. Basal BP was similar in the two groups, but clonidine decreased BP, PRA, and plasma epinephrine more in responders than in nonresponders. Naloxone given during placebo treatment had no significant effects. During clonidine treatment naloxone increased BP, HR, total peripheral resistance, PRA, and plasma epinephrine and norepinephrine, and decreased stroke volume in responders, whereas in nonresponders its only effect was a small increase in HR. It is concluded that in a subset of hyperadrenergic, hypertensive patients the antihypertensive effect of clonidine involves a naloxone-reversible inhibition of central sympathetic outflow, probably mediated by the release of an endogenous opioid.