Development of Novel Delivery System for Cardiovascular Drug Molsidomine: Influence of Synthesis Method and Conditions on Molsidomine Release From Its Composites With Hydrophilic Silica In Vitro.

Composites of cardiovascular drug molsidomine with silica materials (unmodified and mercaptopropyl modified) were prepared by 2 methods, adsorption and sol-gel technology. The effects of sol pH and release medium pH (1.6 and 7.4) as well as molsidomine loading on the drug release kinetics were also investigated. Mechanisms of molsidomine release from all the synthesized composites were elucidated. The obtained results showed that different principles of the composites formation (adsorption or sol-gel) lead to their different release behavior because the composites obtained by the indicated methods differ by distribution of the drug over the silica matrixes and their capability to degradation. The drug release from the composites prepared by adsorption is characterized by a high burst effect, sustained release up to 36 h irrespective of release medium pH. The release behavior of sol-gel composites depends on the amount of the loaded drug and release medium pH. These effects were explained by different stability of the sol-gel composites with high and low loading in acidic and neutral media. In general case, the ascertained effects are independent on chemistry of the silica surface organic groups.

Magnetic silica hybrids modified with guanidine containing co-polymers for drug delivery applications.

Guanidine containing co-polymers grafted onto silica nanoparticles to form core-shell structure were prepared by sol-gel method in the presence of γ-Fe2O3 nanoparticles. The morphological features for uncoated and coated silica particles have been characterized with scanning electron microscopy. The results show that the polymer coated silicas exhibit spherical morphology with rough polymeric surface covered by γ-Fe2O3 nanoparticles. The grafting amount of guanidine containing co-polymers evaluated by thermogravimetric analysis was in the range from 17 to 30%. Then, the drug loading properties and cumulative release of silica hybrids modified with guanidine containing co-polymers were evaluated using molsidomine as a model drug. It was shown that after polymer grafting the loading content of molsidomine could reach up to 3.42±0.21 and 2.34±0.14mg/g respectively. The maximum drug release of molsidomine is achieved at pH1.6 (approximately 71-75% release at 37°C), whereas at pH7.4 drug release is lower (50.4-59.6% release at 37°C). These results have an important implication that our magneto-controlled silica hybrids modified with guanidine containing co-polymers are promising as drug carriers with controlled behaviour under influence of magnetic field.

Design of silica carrier for controlled release of molsidomine: effect of preparation methods of silica matrixes and their composites with molsidomine on the drug release kinetics in vitro.

Biodegradable, controlled-release carrier materials with non-toxic degradation products are very valuable for delivery of cardiovascular drugs. This study is a part of development of novel form of vasodilator molsidomine to improve pharmacokinetic and consumer properties of the drug. It focuses on the effect of preparation methods of the drug-silica composites on their release kinetics. Phenyl modified silica materials prepared by different ways were studied as potential carriers for molsidomine. The composites of molsidomine with the modified silica were synthesized via one-step sol-gel route and adsorption. The drug was adsorbed onto the phenyl modified silica prepared by co-condensation and grafting. Furthermore, the one-step sol-gel derived composites were prepared at pH 4.4 (the isoelectric point of the drug) and pH 6.3 (the zero point of charge of the silica). In vitro release kinetics of molsidomine from the synthesized composites in simulated gastric (pH 1.6) and simulated blood (pH 7.4) media was studied. Our findings demonstrate that the release of the drug can be controlled by manipulating the synthesis ways and changing the sol-gel pH. The comparative analysis of molsidomine release profiles from the composites prepared by one-step sol-gel synthesis at different pH and adsorption allows to reveal perspective composites which exhibit sustained release of molsidomine for about 36h in acidic medium close to the zero order release kinetics.

How to photostabilize molsidomine tablets.

Different methods of photostabilization are presented for the very light sensitive molsidomine tablets. The incorporation of photostabilizers such as light absorber or pigments into the tablets considerably improved the photostability. Nevertheless, photodegradation was still detected after 12 h of intense light stress. Pigments are superior to colorants or ultraviolet absorbers. The use of titanium dioxide needs to be considered carefully. Preblending the pigment with the drug substance is very helpful for taking full advantage of its photostabilizing properties. Surface-treated titanium dioxide with reduced photocatalytic activity was less suitable than untreated. That was due to a change of particle agglomeration and adhesion behavior, which was demonstrated by scanning electron microscopy pictures. However, only the protection of the tablets by a cover, either by blistering or film coating, gave a photostable drug product.

Inactivation of wild-type p53 protein function by reactive oxygen and nitrogen species in malignant glioma cells.

Malignant gliomas are the most common primary brain tumors in adults, and the most malignant form, glioblastoma multiforme (GBM), is usually rapidly fatal. Most GBMs do not have p53 mutations, although the p53 tumor suppressor pathway appears to be inactivated. GBMs grow in a hypoxic and inflammatory microenvironment, and increased levels of the free radicals nitric oxide (NO) and superoxide () occur in these malignancies in vivo. Peroxynitrite (ONOO(-)) is a highly reactive molecule produced by excess NO and that can posttranslationally modify and inactivate proteins, especially zinc finger transcription factors such as p53. We demonstrated previously that GBMs have evidence of tyrosine nitration, the "footprint" of peroxynitrite-mediated protein modification in vivo, and that peroxynitrite could inhibit the specific DNA binding ability of wild-type p53 protein in glioma cells in vitro. Here we show that both authentic peroxynitrite and SIN-1 (3-morpholinosydnonimine hydrochloride), a molecule that decomposes into NO and to form peroxynitrite, can inhibit wild-type p53 function in malignant glioma cells. Concentrations of peroxynitrite associated with a tumor inflammatory environment caused dysregulation of wild-type p53 transcriptional activity and downstream p21(WAF1) expression.

Behavioral effects of NMDA receptor agonists and antagonists in combination with nitric oxide-related compounds.

Responding of rats was maintained under a 120-response fixed ratio (FR) schedule of food delivery, and animals received individual and combined injections of N-methyl-D-aspartic acid (NMDA), phencyclidine hydrochloride, (+)-MK-801 hydrogen maleate (MK-801), (+/-)-2-amino-5-phosphonopentanoic acid (AP5), 7-chlorokynurenic acid (7CK), ifenprodil tartrate, N(G)-nitro-L-arginine methyl ester hydorchloride (L-NAME), 7-nitroindazole, aminoguanidine hemisulfate, L-arginine, molsidomine, sodium nitroprusside, and 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8). Behavioral suppression after NMDA was completely and dose-dependently reversed by MK-801, phencyclidine, AP5, and aminoguanidine; partially and dose-dependently attenuated by molsidomine, ifenprodil, and 7CK; and not attenuated at all by L-NAME, 7-nitroindazole, or TMB-8. These findings suggested that behavioral suppression after NMDA was associated with nitric oxide from the inducible synthase. In a second series of experiments, comparable behavioral suppression by 0.1 mg/kg MK-801, but not 3 mg/kg phencyclidine, was attenuated by nitroprusside, molsidomine, and L-arginine, suggesting that suppressions from MK-801 and phencyclidine were mediated by different final common pathways, and that behavioral suppression from MK-801, but not phencyclidine, may be associated with Ca(2+)-dependent nitric oxide.

A pilot double-blind randomized placebo-controlled study of molsidomine 16 mg once-a-day in patients suffering from stable angina pectoris: correlation between efficacy and over time plasma concentrations.

OBJECTIVES: A new once-a-day (o.a.d.) formulation of molsidomine (16 mg) was evaluated in patients with stable angina pectoris. The aims were to characterize its pharmacokinetics after a single dose, to demonstrate its clinical efficacy and safety versus placebo and to investigate correlations between pharmacokinetics and pharmacodynamics. METHODS: Forty-two patients were recruited in a double-blind, crossover, randomized placebo-controlled trial. The pharmacokinetics of molsidomine and SIN-1, its active metabolite, were determined at specific time points (3, 6, 10, 14, 18, 22 and 24 h) after the administration of a single dose of molsidomine 16 mg o.a.d. in all patients distributed into seven groups. Twenty-eight of these 42 patients showed a positive baseline cycloergometric exercise test response during the run-in placebo period and were used to compare the efficacy of molsidomine to placebo. Relationships between plasma concentration in molsidomine or SIN-1 and ischemic threshold were assessed in 16 of the 28 patients with a positive exercise test at baseline. Indeed, the censored variable ischemia-limited tolerance to exercise could not be evaluated in those patients who did not show exercise-induced ischemia anymore under molsidomine 16 mg o.a.d. Pharmacokinetic-pharmacodynamic relationships were evaluated using regression models and correlation coefficients. RESULTS: The highest average concentration in molsidomine and SIN-1 occurred after 6 h, then a plateau of 15-20 ng/ml molsidomine and 0.8-3.0 ng/ml SIN-1 was maintained for at least 8 h and the mean residual molsidomine concentration 24 h post-drug intake was around 8 ng/ml, still in the effective range of 5-10 ng/ml. A significant increase in total workload (+52 W min, P=0.009), total exercise time (+32 s, P=0.003) and time to angina (+25 s, P=0.016) was measured with molsidomine 16 mg o.a.d. relative to placebo. Using linear regression, significant correlation coefficients were determined between molsidomine plasma concentrations (but not SIN-1) and exercise test improvements (r=0.827, P<0.001 for the total workload; r=0.772, P<0.001 for the total exercise time; and r=0.566, P=0.028 for the time to 1 mm ST-segment depression). CONCLUSION: The pharmacokinetics of molsidomine 16 mg in patients with stable angina pectoris is compatible with a o.a.d. dosage regimen. This o.a.d. formulation is effective and well-tolerated, providing a 24-h therapeutic control of myocardial ischemia. A positive and significant linear relationship between molsidomine plasma concentration and the increase in exercise tolerance was observed.

Molsidomine enhances the protective activity of valproate against pentylenetetrazole-induced seizures in mice.

Molsidomine (25 mg kg(-1)), a donor of nitric oxide, commonly used in the treatment of coronary artery disease, enhanced the protective activity of valproate against the clonic phase of pentylenetetrazole-induced seizures in mice, significantly reducing the ED(50) of valproate from 123.5 to 78 mg kg(-1). Molsidomine was found to be ineffective with respect to the protective action of clonazepam, ethosuximide and phenobarbital. Alone, molsidomine in a dose of 25 mg kg(-1) was ineffective in this model of seizures. Since N(G)-nitro-L-arginine, an inhibitor of nitric oxide synthase, failed to reverse the effect of molsidomine on valproate, an involvement of nitric oxide in the mechanism of the anticonvulsive efficacy of valproate does not seem to be probable. Molsidomine (25 mg kg(-1)) significantly elevated the free plasma level of valproate from 33.8 to 46.2 microg ml(-1). Therefore, we conclude that the interaction of molsidomine with valproate is at the pharmacokinetic level. The combination of valproate with molsidomine appears beneficial because is free from adverse effects, in terms of motor impairment and long-term memory deficit. Our results suggest that the dosage of valproate in patients with coronary artery disease treated with molsidomine should be decreased. It would allow us to reduce adverse effects of valproate.

Oxidative stress promotes the development of transformation: involvement of a potent mutagenic lipid peroxidation product, acrolein.

The effect of intracellular oxidative stress on the development of cell transformation was studied. Mouse embryo C3H/10T1/2 fibroblasts pre-treated with benzo[a] pyrene, developed transformed foci on exposure to free radical generators, such as 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) and 3-morpholinosydnonimine hydrochloride (SIN-1). These compounds generate peroxyl radicals and peroxynitrite, respectively. Neither AAPH nor SIN-1 alone induced transformation. The level of intracellular antioxidants, such as alpha-tocopherol and glutathione (GSH), decreased with time of exposure to the free radical generators, whereas the addition of exogenous alpha-tocopherol, GSH and ebselen showed a reduction in the frequency of transformation. An early event during exposure to AAPH and SIN-1 was the generation of acrolein, a highly mutagenic lipid peroxidation product, which was suppressed by the addition of alpha-tocopherol. Furthermore, it was confirmed that acrolein induced the transformation of cells which were pre-treated with benzo[a]pyrene but not of the untreated cells. These results suggest that acrolein may act as an important mediator of cell transformation under oxidative stress.

Cytotoxic effects of peroxynitrite, polymorphonuclear neutrophils, free-radical scavengers, inhibitors of myeloperoxidase, and inhibitors of nitric oxide synthase on bovine mammary secretory epithelial cells.

OBJECTIVE: To determine cytotoxic effects of activated polymorphonuclear neutrophils (PMN) and peroxynitrite on bovine mammary secretory epithelial cells before and after addition of nitric oxide synthase inhibitors, myeloperoxidase (MPO) inhibitors, and free-radical scavengers. SAMPLE POPULATION: Polymorphonuclear neutrophils from 3 lactating cows. PROCEDURE: Cells from the bovine mammary epithelial cell line MAC-T were cultured. Monolayers were treated with activated bovine PMN, lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate (PMA), 3-morpholino-sydnonimine (SIN-1), 4-amino-benzoic acid hydrazide (ABAH), NG-monomethyl-L-arginine, histidine, and superoxide dismutase (SOD). At 24 hours, activity of lactate dehydrogenase in culture medium was used as a relative index of cell death. Tyrosine nitration of proteins in MAC-T cell lysates was determined by visual examination of immunoblots. RESULTS: Lipopolysaccharide, PMA, and < or = 0.1 mM SIN-1 were not toxic to MAC-T cells. Activated PMN, > or = 6 mg of histidine/ml, and 0.5 mM SIN-1 were toxic. Together, histidine and 500,000 activated PMN/ml also were toxic. NG-monomethyl-L-arginine did not have an effect, but ABAH decreased PMN-mediated cytotoxicity. Ten and 50 U of SOD/ml protected MAC-T cells from cytotoxic effects of 0.5 mM SIN-1. Compared with control samples, nitration of MAC-T tyrosine residues decreased after addition of 500,000 PMN/ml or > or = 6 mg of histidine/ml. Superoxide dismutase increased and SIN-1 decreased tyrosine nitration of MAC-T cell proteins in a dose-responsive manner. CONCLUSIONS AND CLINICAL RELEVANCE: Peroxynitrite, MPO, and histidine are toxic to mammary secretory epithelial cells. Superoxide dismutase and inhibition of MPO activity mitigate these effects. Nitration of MAC-T cell tyrosine residues may be positively associated with viability.

Prediction of the lower esophageal sphincter pressure after oral molsidomine by sydnonimine plasma concentrations.

BACKGROUND/AIMS: Recent studies suggest that endogenous nitric oxide decreases lower esophageal sphincter pressure (LESP). Substances leading to the formation of nitric oxide, such as molsidomine, decreases the human LESP. It is not yet clear whether this reduction is related to plasma concentrations of molsidomine, the nitrate-active substance sydnonimine (SIN-1) or to serum concentrations of nitrate/nitrite (NOx) as a stable end-product of volatile nitric oxide. METHODOLOGY: We performed a double blind controlled crossover trial in 8 healthy male volunteers. Plasma concentrations of molsidomine, SIN-1 and serum concentrations of NOx as well as esophageal manometry were determined. RESULTS: Mean basal LESP was significantly decreased from 25.4 +/- 2.8 mmHg to 21.9 +/- 2.7 mmHg and 21.4 +/- 2.6 mmHg 2 and 3 hours after molsidomine administration, respectively (mean +/- SEM; n = 8; p < 0.05). The maximum decrease of LESP from the baseline within 1-4 hours after molsidomine administration was 7.6 +/- 1.5 mmHg (mean +/- SEM; n = 8; p < 0.01). The decrease of the LESP correlated significantly with plasma concentrations of SIN-1 (r = -0.53; p = 0.002). NOx levels remained unchanged. CONCLUSIONS: Molsidomine decreases the LESP and plasma concentrations of the active metabolite SIN-1 may predict the potency of molsidomine to lower LESP. NOx was useless as a control metabolite to measure the LESP in response to molsidomine in healthy volunteers.

Determination of molsidomine and its active metabolite in human plasma using liquid chromatography with tandem mass spectrometric detection.

Pharmacokinetic studies of molsidomine require a sensitive analytical method to allow the determination of concentrations of this compound and its active metabolite 3-morpholinosydnonimine (Sin-1) in the ng/ml range in plasma. The method developed is based on on-line LC-MS-MS using pneumatically assisted electrospray ionisation as an interface, preceded by off-line solid-phase extraction (SPE) on disposable extraction cartridges (DECs). The SPE operations were performed automatically by means of a sample processor equipped with a robotic arm (automated sample preparation with extraction cartridges; ASPEC system). The DEC, filled with phenyl-modified silica, was first conditioned with methanol and water. The washing step was performed with water. Finally, the analytes were successively eluted with methanol containing formic acid (0.2%) and water. The liquid chromatographic separation of molsidomine and Sin-1 was achieved on an RP-8 stationary phase (5 microns). The mobile phase was a mixture of methanol-water-formic acid (65:35:0.1, v/v/v). The HPLC system was then coupled to a MS-MS system with an atmospheric pressure ionisation interface in the positive ion mode. The chromatographed analytes were detected in the multiple reaction monitoring mode. The MS-MS ion transitions monitored were (m/z) 243-->86 for molsidomine and 171-->86 for Sin-1. The method developed was validated. The absolute recoveries evaluated over the whole concentration range were 74 +/- 3 and 55 +/- 5% for molsidomine and Sin-1, respectively. The method was found to be linear in the 0.5-50 ng/ml concentration range for the two analytes (r2 = 0.999 for both molsidomine and Sin-1). The mean RSD values for repeatability and intermediate precision were 3.4 and 4.8% for moldsidomine and 3.1-7.7% for the metabolite. The method developed was successfully used to investigate the bioequivalence of oral doses of molsidomine between a generic tablet and a reference product.

Clinical pharmacokinetics of vasodilators. Part II.

Stimulating cardiac beta 1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. beta 1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of beta-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast-fed infants, combined with more women delaying pregnancy until their fourth decade, has entailed an increase in the need for hypertension management during lactation. Low dose hydrochlorothiazide, propranolol, nifedipine and enalapril or captopril do not pose enough of a risk of preclude breastfeeding in this group. The most frequently used antihypertensive agents during pregnancy are methyldopa, labetalol and calcium channel antagonists. Methyldopa and beta-blockers are the drugs of choice for treating mild to moderate hypertension. Prazosin and hydralazine are used to treat moderate to severe hypertension and hydralazine, urapidil or labetalol are used to treat hypertensive emergencies. The use of overly aggressive antihypertensive therapy during pregnancy should be avoided so that adequate uteroplacental blood flow is maintained. Methyldopa is the only drug accepted for use during the first trimester of pregnancy.

Efficiency of aerosolized nitric oxide donor drugs to achieve sustained pulmonary vasodilation.

Inhalation of nitric oxide (NO) causes selective pulmonary vasodilation, but demands continuous supply of the gaseous agent. We investigated the suitability of aerosolization of NO-donor drugs for achieving sustained reduction of pulmonary vascular tone. In buffer-perfused rabbit lungs, stable pulmonary hypertension was achieved by continuous infusion of the thromboxane-analogue U46619. The NO-donor drugs molsidomine, 3-morpholinosydnone-imine (SIN-1), sodium nitroprusside (SNP) and glyceryl-trinitrate reduced the pulmonary hypertension in a dose-dependent fashion, whether admixed to the perfusate or inhaled as alveolar-accessible aerosol particles (aerosolization time 3-6 min), with an efficiency ranking of SNP > SIN-1 >> molsidomine and glyceryl-trinitrate. Notably, nearly identical dose-response curves were obtained when corresponding molar quantities of the most potent agents, SNP and SIN-1, were applied either via transbronchial or via intravascular routes, with respect to rapidity of onset, extent (pressure reduction to near baseline) and duration (>90 min) of vasorelaxation. Appearance of sydnonimines in the perfusate after aerosolization and reduction of SIN-1 efficacy when nebulized in nonrecirculatingly perfused lungs demonstrated substantial entry of this prodrug into the vascular space after alveolar deposition. In contrast, undiminished vasodilatory efficacy of aerosolized SNP under conditions of non-recirculating perfusion suggested predominant efficacy via local NO release for this agent. We conclude that short aerosolization maneuvers of NO-donor drugs are suitable to achieve dose-dependent, extensive and sustained vasodilation in the pulmonary circulation, thus offering a new therapeutic approach in pulmonary hypertension.

Mode of cytostatic action of mesoionic oxatriazole nitric oxide donors in proliferating human hematopoietic cells.

The cytopathological effects of the novel nitric oxide (NO)-releasing, mesoionic 3-aryl-substituted oxatriazole-5-imine derivatives GEA 3162 and GEA 3175, and a reference NO donor SIN-1 were investigated in proliferating human hematopoietic cells. The GEA compounds (10-50 microM) induced rapid surface changes, which progressed as peculiar deep indentations and strictures in human leukemic T cells (MOLT-3) in 30 min. An excess of red cells partially prevented these surface changes. GEA 3162-treated MOLT-3 cells became permeable to ethidium bromide and lost their ability to be stained by acridine orange after 5 h of exposure. GEA 3162 and GEA 3175 suppressed thymidine and uridine incorporation in a dose-dependent manner, reflecting the inhibition of DNA and RNA synthesis respectively. In addition, the GEA compounds inhibited the growth of human bone marrow stem cells, CFU-GM colonies being more susceptible to the cytostatic action than BFU-E. The reference compound SIN-1 had comparative cytostatic effects at ten times greater concentrations (500 microM). We conclude that NO-releasing mesoionic oxatriazole derivatives have cytostatic action against human malignant and non-malignant hematopoietic cells, supporting the value of NO-releasing and NO-inducing compounds as anti-cancer agents.

Clinical pharmacokinetics of molsidomine.

Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t-1/2) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight. Single-dose studies (1, 2 and 4 mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2 mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4 mg 4 times daily for 4 weeks) do not show any accumulation of the drug. A study in young and elderly individuals indicated that the first-pass effect is decreased and t-1/2 prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds. A linear dose-effect relationship is observed with counterclockwise hysteresis, i.e. a greater effect associated with the decrease of plasma concentrations than during their increase, which may be at least partly due to the metabolic delay in the formation of NO from SIN-1. Accordingly, the duration of action of molsidomine is longer than would be expected on the basis of the elimination half-life. The pharmacokinetics of molsidomine support the recommended dosages for use in angina pectoris.

In-vivo and in-vitro correlation for delayed-release behaviour of a molsidomine/O-carboxymethyl-O-ethyl-beta-cyclodextrin complex in gastric acidity-controlled dogs.

The in-vivo absorption behaviour of molsidomine from the delayed-release tablets of an O-carboxymethyl-O-ethyl-beta-cyclodextrin complex was investigated using gastric acidity-controlled dogs under fasted and non-fasted conditions. The in-vitro release profiles were generated by changing the pH of the dissolution medium at different rotation paddle speeds. The absorptivity of molsidomine in the high acidity dog was correlated with the pH-changed release profile (pH 1.2 to 7.0 after 2 h), whereas that in the low acidity dog was correlated with the release profile at a constant pH of 7.0. The absorption in fasted dogs was well correlated with the in-vitro release at the low-rotation paddle speed (< 5 rev min-1), whereas that in the non-fasted dogs was correlated with that of high rotation (100 rev min-1). The present results suggested that the in-vivo delayed-release behaviour of the complex is predictable from the in-vitro release profiles generated using pH-variable dissolution testing apparatus at different rotation speeds of the paddle.

Peracylated beta-cyclodextrins as novel sustained-release carriers for a water-soluble drug, molsidomine.

Peracylated beta-cyclodextrins with different alkyl chains (acetyl-octanoyl) were prepared by acylating all hydroxyl groups of beta-cyclodextrin (beta-CyD), and their physical properties were evaluated. These hydrophobic beta-CyDs decreased the release rate of molsidomine, a peripheral vasodilator, in proportion to the lengthening of alkyl chain and suppressed a peak plasma level of molsidomine following oral administration of peracylated beta-CyD complexes to dogs. Among the peracylated beta-CyDs tested, perbutanoyl-beta-CyD maintained sufficient plasma drug levels for a long period of time, while other peracylated beta-CyDs having shorter or longer chains were inappropriate to control the in-vivo release behaviour of molsidomine. The prominent retarding effect of perbutanoyl-beta-CyD was ascribable to the appropriate mucoadhesive property and hydrophobicity, compared with other peracylated beta-CyDs. The present results suggest that perbutanoyl-beta-CyD is particularly useful in modifying the release rate of water-soluble drugs as a novel slow-release carrier.