da-8159 and Body-Weight

Erectile dysfunction (ED) is a major complication of diabetes mellitus (DM). This study investigates the relationship between ED and the downregulation of constitutive nitric oxide synthase (cNOS) in the corpus cavernosum (CC) of diabetic rats. It also examines the effects of udenafil, a phosphodiesterase type 5 (PDE5) inhibitor, on ED and cNOS expression levels. After 16 weeks of daily oral treatment with udenafil in diabetic rats, the intracavernous pressure/mean arterial pressure (ICP/MAP) ratio was recorded to measure erectile function, and cNOS expression was measured using reverse transcriptase (RT)-PCR and immunoblots. Although the ICP/MAP ratio and the expression levels of endothelial NOS (eNOS) and neuronal NOS (nNOS) in the CC were markedly decreased in diabetic rats, long-term udenafil treatment improved the erectile function and increased cNOS expression compared with diabetic controls. These findings suggest that ED in DM is closely related to decreased cNOS expression in the CC and that udenafil has the ability to compensate for this pathological change by modulating cNOS expression. Udenafil also has an inhibitory role in cGMP (cyclic guanosine monophosphate) degradation.

Topics: Animals; Base Sequence; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Disease Models, Animal; DNA Primers; Electric Stimulation; Erectile Dysfunction; Gene Expression Regulation, Enzymologic; Male; Nitric Oxide Synthase Type I; Penis; Phosphodiesterase Inhibitors; Polymerase Chain Reaction; Pyrimidines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides

Time-averaged total body clearance (Cl) and apparent volume of distribution at steady state (V(SS)) of DA-8159 after intravenous administration to mice (30 mg/kg), rats (30 mg/kg), rabbits (30 mg/kg) and dogs (3 mg/kg) were analysed as a function of species body weight (W) using the allometric equation for interspecies scaling, and were used to predict those in humans. Significant linear relationships were obtained between log Cl (l/h) and log W (kg) (r = 0.992; p = 0.0079) and log V(SS) (l) and log W (kg) (r = 0.999; p < 0.0001). The corresponding allometric equations were Cl = 4.36 W(0.492) and V(SS) = 6.41 W(0.911). These allometric equations were extrapolated to predict the Cl and V(SS) for DA-8159 in humans based on the 70 kg body weights. In addition, concentrations in the plasma-time profile predicted using the four animal data fitted to a complex Dedrick plot of animal data. Our results indicated that the DA-8159 data obtained from four laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies.

Topics: Administration, Oral; Animals; Area Under Curve; Body Weight; Chromatography, High Pressure Liquid; Dogs; Half-Life; Humans; Injections, Intravenous; Male; Mice; Mice, Inbred ICR; Pyrimidines; Rabbits; Rats; Species Specificity; Sulfonamides

A previous study showed that DA-8159, a potent type 5 phosphodiesterase inhibitor, enhanced the relaxation of the smooth muscles in the normal rabbit corpus cavernosum. In this study, we investigated the in vitro effects of DA-8159 on cavernosal smooth muscle relaxation and the in vivo erectogenic potential in diabetic rabbits, since erectile dysfunction is a well-known sequela of diabetes mellitus. Diabetes mellitus was induced in male New Zealand White rabbits with alloxan monohydrate. Cavernosal strips from age-matched control and 8-week diabetic animals were mounted in organ baths. The relaxation responses to sodium nitroprusside (10(-9)--10(-5) M), a nitric oxide donor, were assessed in the presence or absence of DA-8159 (10(-9)--10(-6) M). For the penile erection test, DA-8159 was given orally (1-10 mg/kg) to diabetic rabbits and the length of the uncovered penile shaft was measured in a time-course manner in the presence or absence of intravenous sodium nitroprusside. The sodium nitroprusside-stimulated relaxations were significantly impaired in the corpus cavernosum from the diabetic group (IC(50)=1.07 x 10(-6) M following 8 weeks of diabetes mellitus; compared with 0.48 x 10(-6) M for age-matched controls). DA-8159 significantly and dose-dependently enhanced the sodium nitroprusside-stimulated relaxation in the diabetic groups. In addition, DA-8159 induced a dose-dependent penile erection in diabetic rabbits, which was potentiated by intravenous sodium nitroprusside. These results suggest that DA-8159 is an effective treatment for diabetic erectile dysfunction but further evaluation of the efficacy on human needs to be performed.

Topics: Animals; Area Under Curve; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Male; Muscle Relaxation; Muscle, Smooth; Nitroprusside; Penile Erection; Penis; Phenylephrine; Phosphodiesterase Inhibitors; Pyrimidines; Rabbits; Sulfonamides; Vasoconstrictor Agents; Vasodilator Agents

DA-8159 (5-[2-propyloxy-5-(1-methyl-2-pyrrolidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidine-7-one, CAS 268203-93-6) is a new pyrazolopyrimidinone derivative for the treatment of erectile dysfunction. The test agent was administered by gavage at dose levels of 0, 17.5, 70, and 280 mg/kg to Sprague-Dawley male rats from 28 days before mating to the end of the mating period, and to females from 14 days before mating to day 6 of gestation. Effects of the test agent on general findings and reproductive performance of parent animals and on early embryonic development were examined. At 280 mg/kg, salivation and hair loss were observed at a high incidence in males and females, respectively. One female out of 24 died during the treatment period. A decrease in food consumption and a decrease in body weight were observed in both sexes. No treatment-related gross findings and histopathological findings were seen, except that the dead animal exhibited atrophy of the thymus. A decrease of prostate weight and an increase of liver, lung and spleen weights were seen. An increase in the period and irregularity of sexual cycle was observed. A decrease in fertility and pregnancy index was also seen. A decrease in the number of corpora lutea, implantations, and litter size was observed. There were no treatment-related changes in precoital time, mating index, sperm parameters, and serum testosterone concentration. At 17.5 mg/kg and 70 mg/kg, there were no adverse effects on all the parameters examined. Based on these results, DA-8159 induces suppressed body weight, decreased food consumption, irregularity in sexual cycle, reduced fertility, and decreased number of corpora lutea, implantations, and litter size at 280 mg/kg and no observed adverse effect levels (NOAELs) of DA-8159 are considered to be 70 mg/kg for general toxicity and reproductive capability of parent animals and for early embryonic development, respectively.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Embryo Implantation; Erectile Dysfunction; Estrous Cycle; Female; Fertility; Litter Size; Male; Organ Size; Pregnancy; Pyrimidines; Rats; Rats, Sprague-Dawley; Reproduction; Sex Characteristics; Sexual Behavior, Animal; Spermatozoa; Sulfonamides; Testosterone

The subacute toxicities (10 male and 10 female rats at each dose) and the toxicokinetics (5 male rats at each dose) of DA-8159, a new phosphodiesterase type V (PDE V) inhibitor, were evaluated after single (at day 1) and 4-week (at day 28) oral administration of the drug at doses of 0 (to serve as a control), 20, 80 and 320 mg/kg/day to rats. DA-8159 showed a decrease in body weight gain, clinical signs such as chromodacryohaemorrhoea, ptosis and decreased locomotor activity, an increase in WBC number, changes in parameters related to RBCs, an increase in organ weight of the liver, spleen and lung, and finally microscopic lesions such as cholangiofibrosis and inflammatory cell infiltration in the liver, alveolar macrophage accumulation, and inflammatory cell infiltration in the lung, an increase in bone marrow density and extrahaematopoiesis in the spleen. These changes were observed mainly at a dose of 80 mg/kg or above. While some changes were observed at a dose of 20 mg/kg, these changes were non-specific and transient since this were also observed in control rats. In addition, there was no dose-dependency in these changes. Based on these results, the NOAEL (No-Observed-Adverse-Effect-Level) for DA-8159 in rats was estimated to be 20 mg/kg/day, and the target organs were determined to be liver, bone marrow, spleen, lung and blood cells. After a 4-week oral administration, accumulation of DA-8159 was evident at a dose of 20 mg/kg/day, but was not considerable at toxic doses (80 and 320 mg/kg/day). After a single oral administration, the dose-normalized area under the plasma concentration-time curve from time zero to the last measured time, 24 h, in plasma (AUC(0-24 h)) was significantly different among the three doses (the AUC(0-24 h) based on 20 mg/kg/day was 2.33, 7.00 and 4.19 microg h/ml for 20, 80 and 320 mg/kg/day, respectively). Similar results were also obtained from DA-8164, a metabolite of DA-8159; the AUC(0-24 h) of DA-8164 after dose-normalized to 20 mg/kg/day of DA-8159 were 2.74, 5.00 and 1.68 microg h/ml, respectively.

Topics: Administration, Oral; Animals; Area Under Curve; Body Weight; Chromatography, High Pressure Liquid; Drug Administration Schedule; Female; Male; No-Observed-Adverse-Effect Level; Organ Size; Phosphodiesterase Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; Sulfonamides

The subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, were evaluated after single (at the 1st day) and 4-week (at the 28th day) oral administration of the drug, in doses of 0 (to serve as a control), 12.5, 50 and 200 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). DA-8159 had an effect on the immune-related organs (or tissues), circulatory systems, liver, adrenal glands, ovaries and pancreas. The toxic dose was 200 mg/kg and no observed adverse effect level was less than 50 mg/kg for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of DA-8159 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DA-8159 were dose-independent after single oral administration; the time to reach a peak plasma concentration (T(max)) and the dose-normalized area under the plasma concentration-time curve from time zero to 24 h in plasma (AUC(0-24 h)) were not significantly different among three doses. However, accumulation of DA-8159 after 4-week oral administration was considerable at toxic dose, 200 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC(0-24 h) value at 200 mg/kg/day (4.71 and 15.3 microg h/ml) was significantly greater than that at 12.5 mg/kg/day. After 4-week oral administration, the dose-normalized C(max) and AUC(0-24 h) at 200 mg/kg/day were significantly higher and greater, respectively, than those after a single oral administration.

Topics: Administration, Oral; Animals; Body Weight; Dogs; Erectile Dysfunction; Female; Kinetics; Male; Motor Activity; Phosphodiesterase Inhibitors; Pyrimidines; Sulfonamides