[Experience and comparison of antihypertensive effect of ace inhibitor spirapril and calcium antagonist amlodipinein standard and chronotherapeutic prescription mode].

Arterial pressure is an effect of many physiologic processes of organism effected by daily rhytmus. The introduction of round the 24-hour monitoring of arterial pressure enabled to detect arterial pressure circular fluctuation. Chronotherapy with the application of amlodipin and spirapril due to the data of round the 24-hour arterial pressure monitoring increases the effectiveness of antihypertensive therapy.

Perfusion calorimetry in the characterization of solvates forming isomorphic desolvates.

In this study, the potential of perfusion calorimetry in the characterization of solvates forming isomorphic desolvates was investigated. Perfusion calorimetry was used to expose different hydrates forming isomorphic desolvates (emodepside hydrates II-IV, erythromycin A dihydrate and spirapril hydrochloride monohydrate) to stepwise increasing relative vapour pressures (RVP) of water and methanol, respectively, while measuring thermal activity. Furthermore, the suitability of perfusion calorimetry to distinguish the transformation of a desolvate into an isomorphic solvate from the adsorption of solvent molecules to crystal surfaces as well as from solvate formation that is accompanied by structural rearrangement was investigated. Changes in the samples were confirmed using FT-Raman and FT-IR spectroscopy. Perfusion calorimetry indicates the transformation of a desolvate into an isomorphic solvate by a substantial exothermic, peak-shaped heat flow curve at low RVP which reflects the rapid incorporation of solvent molecules by the desolvate to fill the structural voids in the lattice. In contrast, adsorption of solvent molecules to crystal surfaces is associated with distinctly smaller heat changes whereas solvate formation accompanied by structural changes is characterized by an elongated heat flow. Hence, perfusion calorimetry is a valuable tool in the characterization of solvates forming isomorphic desolvates which represents a new field of application for the method.

Effect of angiotensin-converting enzyme inhibitor quadropril on dynamic parameters of vascular tone under conditions of NO synthesis blockade in normotensive and spontaneously hypertensive rats.

The role of NO in the mechanism of quadropril modulation of the flow-dependent vasodilation was examined in normotensive (Wistar) and spontaneously hypertensive (SHR) rats. The abdominal aorta was cannulated and autoperfused at different volume rates to obtain the pressure-flow curves. In the first experimental series, the blood flow-pressure dependence was measured before and after intravenous injection of quadropril (1 mg/kg). In the next series, this dependence was obtained before and after injection of NO-synthase inhibitor L-NNA (10 mg/kg) and quadropril, respectively. Quadropril potentiated vasodilation caused by an increase in perfusion volume rate in both normo- and hypertensive rats and stabilized intravascular pressure. Inhibition of NO synthesis elevated hydraulic resistance and decreased stability of intravascular pressure in normo- and hypertensive rats. In normotensive rats, these changes were promoted by a decrease in vascular distensibility. Under these conditions, quadropril pronouncedly potentiated the flow-dependent vasodilation only in SHR rats, which was revealed methodically by an increase in perfusion rate in the posterior quarter of the body. Thus, in SHR rats the quadropril-potentiated vasodilation in response to increased perfusion rate does not depend on NO synthesis.

Administration-time-dependent effects of spirapril on ambulatory blood pressure in uncomplicated essential hypertension.

The administration of most angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) at bedtime results in a greater reduction of nighttime blood pressure (BP) than dosing upon awakening. It has been proposed that this effect may be a consequence of a short half-life and duration of action. However, those findings were also documented for long-acting medications, such as the ARB telmisartan. Accordingly, we investigated the administration-time-dependent effects on ambulatory BP of spirapril, an ACEI with an elimination half-life of about 40 h. We studied 165 previously untreated hypertensive subjects, 42.5 +/- 13.9 yrs of age, treated with spirapril (6 mg/day) as monotherapy for 12 weeks either upon awakening or at bedtime. BP was measured by ambulatory monitoring for 48 h before and after treatment. The BP reduction during diurnal activity was similar for both treatment times. Bedtime spirapril administration, however, was significantly more efficient than morning administration in reducing asleep BP. The awake/asleep BP ratio was decreased with the upon-awakening spirapril treatment schedule but significantly increased toward a more dipping pattern with the bedtime treatment schedule. The proportion of patients with controlled ambulatory BP increased from 23 to 59% (p < 0.001) with bedtime treatment. Sleep-time BP regulation is significantly better achieved with bedtime spirapril administration. This might be clinically important, as the sleep-time BP mean has been shown to be a more relevant marker of cardiovascular risk than the awake mean values. These administration-time-dependent effects of spirapril seem to be a class-related feature, and may be associated with the nocturnal activation of the renin-angiotensin-aldosterone system.

[A comparative analysis of normodipin and spirapril effects on intravascular activity of platelets in patients with metabolic syndrome].

AIM: To study effects of two hypotensive drugs--normodipin and spirapril--on intravascular activity of platelets in patients with metabolic syndrome (MS). MATERIAL AND METHODS: Normodipin was given to 25 patients with MS for 3 months, spirapril--to 20 patients for 3 months. The effect was evaluated by changes in lipid peroxidation in plasm and platelets, antioxidant defense of liquid blood and platelets, intravascular activity of platelets. RESULTS: Administration of normodipin in MS patients had a positive effect on lipid peroxidation and normalized intravascular activity of platelets. Such pronounced positive effects on lipid peroxidation of plasm and platelets as well as on intravascular activity of the latter were not registered after use of spirapril. CONCLUSION: Optimization of platelet function in MS patients can be achieved with long-term normodipin treatment.

Plasticity and impact of the central renin-angiotensin system during development of ethanol dependence.

Pharmacological and genetic interference with the renin-angiotensin system (RAS) seems to alter voluntary ethanol consumption. However, understanding the influence of the RAS on ethanol dependence and its treatment requires modeling the neuroadaptations that occur with prolonged exposure to ethanol. Increased ethanol consumption was induced in rats through repeated cycles of intoxication and withdrawal. Expression of angiotensinogen, angiotensin-converting enzyme, and the angiotensin II receptor, AT1a, was examined by quantitative reverse transcription polymerase chain reaction. Increased ethanol consumption after a history of dependence was associated with increased angiotensinogen expression in medial prefrontal cortex but not in nucleus accumbens or amygdala. Increased angiotensinogen expression also demonstrates that the astroglia is an integral part of the plasticity underlying the development of dependence. The effects of low central RAS activity on increased ethanol consumption were investigated using either spirapril, a blood-brain barrier-penetrating inhibitor of angiotensin-converting enzyme, or transgenic rats (TGR(ASrAOGEN)680) with reduced central angiotensinogen expression. Spirapril reduced ethanol intake in dependent rats compared to controls. After induction of dependence, TGR(ASrAOGEN)680 rats had increased ethanol consumption but to a lesser degree than Wistar rats with the same history of dependence. These data suggest that the central RAS is sensitized in its modulatory control of ethanol consumption in the dependent state, but pharmacological or genetic blockade of the system appears to be insufficient to halt the progression of dependence.

Pharmacokinetics and pharmacodynamics of a nitric oxide-releasing derivative of enalapril in male beagles.

1. Pharmacological compounds that release nitric oxide (NO) have been useful tools in the evaluation of the broad role of NO in physiopathology and therapeutics. The present study compared the pharmacokinetics and pharmacodynamics of enalapril and an NO-releasing enalapril molecule (NCX899) in conscious male beagles. The effects of both enalapril and NCX899 in the arterial hypertension and bradycardia induced by acute NO inhibition in anaesthetized dogs were also investigated. 2. Dogs received either NCX899 (4 micromol/kg, i.v.) or enalapril (4 micromol/kg, i.v.), after which plasma concentrations of the analytes and metabolites were quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). 3. In the NCX899 group, the area under the time-course curve (AUC(0-24h)) was 29.18 +/- 4.72, 229.37 +/- 51.32 and 5159.23 +/- 514.88 microg.h/L for the analytes nitro-enalapril, enalapril and enalaprilat, respectively. In the enalapril group, the AUC(0-24h) was 704.53 +/- 158.86 and 4149.27 +/- 847.30 microg.h/L for the analytes enalapril and enalaprilat, respectively. Statistical analysis of data from both groups showed a significant difference for the analyte enalapril, but not for enalaprilat. Moreover, NCX899 and enalapril were equally effective in inhibiting the activity of serum angiotensin-converting enzyme. 4. In anaesthetized dogs, i.v. administration of the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 0.1-10 mg/kg) significantly elevated arterial blood pressure, with concomitant bradycardia. The compound NCX899 significantly attenuated both arterial hypertension and bradycardia, whereas enalapril had no significant effect. 5. In conclusion, the present results showed that the NO-releasing derivative of enalapril NCX899 presents a pharmacokinetic/pharmacodynamic relationship similar to its parent compound enalapril. Moreover, NCX899 (but not enalapril) was effective in protecting against the cardiovascular changes induced by acute NOS inhibition.

[Effect of spirapril on remodeling of the heart in patients with mild and moderate arterial hypertension].

Patients (n=62) with mild and moderate arterial hypertension were examined with the help of echocardiography and Doppler echocardiography. For 12 weeks these patients received 6 mg/day of spirapril. Under influence of this therapy severity of left ventricular hypertrophy diminished, and quantity of pathological types of cardiac remodeling decreased.

[Clinical application of spirapril in patients with arterial hypertension combined with chronic obstructive pulmonary disease].

In this study quadropril (Spirapril, Pliva) was given for 2 months to patients with arterial hypertension combined with chronic obstructive pulmonary disease. The results show that quadropril (6 mg/day) is highly effective as monotherapy in patients with mild and moderate hypertensive disease. Its effects appear as significant lowering of mean 24 hour systolic and diastolic blood pressure (BP), lowering of diurnal and nocturnal BP. Therapy with quadropril for 8 weeks did not impair parameters of external respiration, produced no negative action on lipid and carbohydrate metabolism, was well tolerated, and caused no considerable side effects.

[Rational approach to selection of antihypertensive therapy in persons with metabolic syndrome: efficacy of monotherapy with spirapril and its combination with retard form of nifedipine].

AIM: Achievement of target blood pressure (BP) levels in subjects with metabolic syndrome (MS) by the method of stepwise antihypertensive therapy and assessment of metabolic effects of combination of spirapril and nifedipine retard. MATERIAL AND METHODS: Patients (n=20, 12 women, 8 men, mean age 54+/-3 years) with MS were first given spirapril (6 mg/day). Nifedipine retard (40 mg/day) was added if target BP was not achieved after 4 weeks. Study duration was 12 weeks. The following parameters were measured at baseline and at study end: heart rate, blood pressure, body mass, waist circumference, parameters of lipid spectrum, content of insulin including index HOMA IR, blood glucose (fasting and during oral glucose tolerance test). RESULTS: Target BP levels were achieved in 18 patients (90%)--in 11 with moexipril monotherapy, in 9--after addition of nifedipine. Lowering of systolic and diastolic BP from baseline was 11 and 14%, respectively. After 3 months of combination antihypertensive therapy triglyceride levels decreased by 28% while high density lipoprotein cholesterol (CH) increased 6%. Total, low density lipoprotein CH and coefficient of atherogenecity did not change as well as fasting blood glucose after fast and oral glucose tolerance test. Concentration of fasting immunoreactive insulin significantly decreased by 34% entailing 35% decrease of insulin resistance. Therapy was well tolerated, side effects were transitory and did not cause withdrawal of treatment. CONCLUSION: In patients with MS and mild hypertension monotherapy with spirapril and combination of spirapril with nifedipine retard caused lowering of BP to target level in 55 and 90%, respectively. Combination of spirapril and nifedipine retard exerts positive metabolic action.

[Advantages of long-term controlled stepwise therapy of arterial hypertension with the use of angiotensin converting enzyme inhibitor spirapril].

AIM: Achievement of long-term effective control of blood pressure (BP) in patients suffering from arterial hypertension by means of elaboration of stage by stage program of antihypertensive therapy and proof of its advantage over prescription of hypotensive drugs in real clinical practice. MATERIAL AND METHODS: Effect of spirapril on parameters of vasomotor function of the endothelium were assessed. In randomized comparative prospective study with 1 year duration we included patients with mild and moderate arterial hypertension. The study group received stepwise antihypertensive therapy based on angiotensin converting enzyme inhibitor spirapril. Comparison group continued to take hypotensive drugs prescribed in conditions of outpatients clinic. RESULTS: Sixty patients (79.6% women) were included in the study (30--in the study group, 30--in comparison group). Lowering of BP was observed in the process of therapy in both groups. Among patients of spirapril group lowering of BP was more pronounced and occurred more quickly with achievement of target level of systolic BP <140 mm Hg and diastolic BP <80 1 month after beginning of treatment. Under the influence of therapy with spirapril for 6 months improvement of function of the endothelium was noted. CONCLUSION: In the process of stepwise therapy with the use of spirapril effective long-term control of BP is more quickly achieved compared with standard treatment of arterial hypertension, and improvement of vasomotor function of endothelium also occurs.

[Comparative efficacy and safety of contemporary Angiotensin converting enzyme inhibitors moexipril and spirapril in women with postmenopausal metabolic syndrome].

Moexipril (7.4-15 mg/day) was given to 34, spirapril (3-6 mg/day) -- to 18 postmenopausal women with hypertension and metabolic syndrome for 16 weeks. Hydrochlorthiazide was added when therapy was not sufficiently effective. Both angiotensin converting enzyme inhibitors had similar hypotensive activity: blood pressure normalized in 71 and 61% of moexipril and spirapril treated women, respectively. Both drugs promoted normalization of metabolism of lipid (lowering of levels of cholesterol, atherogenic lipoproteins and triglycerides) and carbohydrates (lowering of hyperinsulinemia). Patients with postmenopausal metabolic syndrome had elevation of leptin level up to 27.5+/-5.5 pg/ml. Moexipril and spirapril caused lowering of elevated levels of leptin. These drugs did not affect levels of sex hormones. They exerted vasoprotective (normalization of endothelium dependent and independent vasodilatation) and nephroprotective (attenuation and normalization of microalbuminuria) effects. Thus spirapril and moexipril are effective in treatment of hypertension in patients with postmenopausal metabolic syndrome.

Thermodynamics of non-stoichiometric pharmaceutical hydrates.

Different physical and mathematical models of non-stoichiometric hydrates derived form previous work in inorganic hydrates are reviewed. A theoretical link between the order of water molecules in the hydrate and the shape of the isotherm is outlined. The comparison of the models with sorption isotherms and structural data of well-known cases from the literature and one in-house case shows that the model can fit many experimental situations and is in good agreement with qualitative assessments of the order in the hydrates.

Central angiotensin II controls alcohol consumption via its AT1 receptor.

Pharmacological and genetic manipulations of the renin-angiotensin system (RAS) have been found to alter the voluntary consumption of alcohol. Here we characterize the role of central angiotensin II (Ang II) in alcohol intake first by using transgenic rats that express an antisense RNA against angiotensinogen and consequently have reduced Ang II levels exclusively in the central nervous system [TGR(ASrAOGEN)680]. These rats consumed markedly less alcohol in comparison to their wild-type controls. Second, Spirapril, an inhibitor of the angiotensin-converting enzyme (ACE), which passes the blood-brain barrier, did not influence the alcohol consumption in the TGR(ASrAOGEN)680, but it significantly reduced alcohol intake in wild-type rats. Studies in knockout mice indicated that the central effect of Ang II on alcohol consumption is mediated by the angiotensin receptor AT1 whereas the AT2 receptor and the bradykinin B2 receptor are not involved. Furthermore, the dopamine concentration in the ventral tegmental area (VTA) is markedly reduced in rats with low central Ang II, strengthening our hypothesis of a role of dopaminergic transmission in Ang II-controlled alcohol preference. Our results indicate that a distinct drug-mediated control of the central RAS could be a promising therapy for alcohol disease.

A nitric oxide-releasing derivative of enalapril, NCX 899, prevents progressive cardiac dysfunction and remodeling in hamsters with heart failure.

Nitric oxide (NO) production is known to be impaired in heart failure. A new compound (NCX 899), a NO-releasing derivative of enalapril was characterized, and its actions were evaluated in Bio 14.6 cardiomyopathic (CM) hamsters with heart failure. The hamsters were randomized to oral treatment for 4 weeks with vehicle (n=11), NCX 899 (NCX, 25 mg/kg, n=10), or enalapril (25 mg/kg, n=10). In the vehicle group, fractional shortening by echocardiography decreased (-23.6+/-2.0%) and LV end-diastolic dimension) increased (+10.9+/-1.0%), whereas fractional shortening increased (+17.5+/-4.4%) in NCX and was unchanged in the enalapril group (both P<0.01 vs. vehicle). End-diastolic dimension decreased only in NCX. LV contractility (LVdP/dt max and Emax) was significantly greater in NCX than in enalapril or vehicle, while relaxation (Tau) was shortened in both NCX and enalapril vs. vehicle. ACE activity was inhibited equally by NCX and enalapril in the CM hamster, and plasma nitrate levels were increased only in NCX (P<0.05 vs. enalapril and vehicle). In aortic strips endothelium-independent relaxation occurred only with NCX. The superior effects of NO-releasing enalapril (NCX) vs. enalapril alone to enhance vascular effects, increase LV contractility and prevent unfavorable remodeling and are consistent with vascular delivery of exogenous NO. NCX 899 may hold promise for the future treatment of heart failure.

Drug interaction of spirapril hydrochloride monohydrate and hydrochlorothiazide. A clinical study to compare the pharmacokinetics after administration of spirapril hydrochloride monohydrate tablets, hydrochlorothiazide tablets and fixed combination bi-layer tablets.

The potential influence of concomitantly administered hydrochlorothiazide (CAS 58-93-5) on the pharmacokinetics of spirapril (CAS 94841-17-5)/spiraprilat (CAS 83602-05-5) and of concomitantly administered spirapril on the pharmacokinetics of hydrochlorothiazide was investigated in an open, randomised, 3-way crossover study in 12 healthy male subjects. The test drug was a newly developed bi-layer tablet containing a fixed combination of spirapril hydrochloride monohydrate and hydrochlorothiazide (Quadroplus). The reference formulations were tablets containing solely spirapril hydrochloride monohydrate (Quadropril) or hydrochlorothiazide (produced exclusively for study medication). For spirapril, spiraprilat and hydrochlorothiazide the 90% confidence intervals of the AUC(0-infinity) as a measure for the extent of absorption were entirely included within the equivalence range of 0.8 to 1.25 and the 90% confidence intervals of the Cmax as a measure for the rate of absorption were entirely included within the extended equivalence range of 0.7 to 1.43. Therefore, bioequivalence was concluded for the test and reference formulations. The results suggest that hydrochlorothiazide does not interact in the fixed combination with the pharmacokinetics of spirapril and vice versa.

Simultaneous determination of spirapril and spiraprilat in plasma by capillary gas chromatography-mass spectrometry.

A specific, sensitive and precise method for the simultaneous determination of spirapril (CAS 94841-17-5) and spiraprilat (CAS 83602-05-5) in human plasma is described. The method involves the use of enalapril as internal standard, solid-phase extraction, derivatization and capillary gas chromatography with mass sensitive detection. The working range is from 2.5 to 500 micrograms/l for spirapril and spiraprilat, respectively. Data demonstrating the precision and accuracy of the analytical method are given. Moreover, data concerning freeze-thaw stability, long-term stability of frozen samples, short-term stability of thawed samples, and stability of the extracts in the autosampler are given.

[Blood pressure lowering by the ACE-inhibitor spirapril. "24-hour efficacy of real once daily application of spirapril (HERAS study)"]. / Blutdrucksenkung unter dem ACE-Hemmer Spirapril.

AIM, PATIENTS AND METHODS: In this open multicentre study, the effect of the ACE-inhibitor spirapril on office blood pressure and 24-hour blood pressure regulation was investigated. A total of 845 general practices recruited 2,491 patients to the 12-week study. Included were patients with newly diagnosed hypertension receiving spirapril alone, and patients who had already been taking antihypertensive agents and who were changed over to monotherapy with spirapril. Also included was a group of patients receiving spirapril in addition to other antihypertensives. Data were collected separately both from the group as a whole and also from a subgroup of patients receiving spirapril (6 mg/day) for whom 24-hour blood pressure records were available at the start and termination of the study (n=606). RESULTS: The 24-hour blood pressure measurements showed a decrease of the mean diurnal systolic blood pressure from 150.9 mmHg to 134.7 mmHg, and of the mean nocturnal blood pressure from 138.1 mmHg to 123.2 mmHg. The corresponding mean diurnal diastolic blood pressure decreased from 88.8 mmHgto 81.4 mmHg, and the mean nocturnal pressure from 79.6 mmHg to 72.2 mmHg. The toterability of spirapril proved to be very good with a side effect rate of 1.3 %. No serious adverse reactions were observed. CONCLUSION: The results show that in general practice use spirapril effectively lowers blood pressure, and is very well tolerated. The blood pressure decrease is maintained over the entire 24 hours and is still clearly evident towards the end of the period, that is, in the critical early morning hours.