New metabolites of hongdenafil, homosildenafil and hydroxyhomosildenafil.

Recently, illegal sildenafil analogues have emerged, causing serious social issues. In spite of the importance of sildenafil analogues, their metabolic profiles or clinical effects have not been reported yet. In this study, new metabolites of illegal sildenafil analogues such as hongdenafil, homosildenafil, and hydroxyhomosildenafil were determined using liquid chromatography quadrupole-time of flight mass spectrometry (LC-Q-TOF-MS) and tandem mass spectrometry (LC-Q-TOF-MS/MS). To prepare metabolic samples, in vitro and in vivo studies were performed. For in vivo metabolites analysis, urine and feces samples of rats treated with sildenafil analogues were analyzed. For in vitro metabolites analysis, human liver microsomes incubated with sildenafil analogues were extracted and analyzed. All metabolites were characterized by LC-Q-TOF-MS and LC-Q-TOF-MS/MS. As a result, five, six, and seven metabolites were determined in hongdenafil, homosildenafil, and hydroxyhomosildenafil treated samples, respectively. These results could be applied to forensic science and other analytical fields. Moreover, these newly identified metabolites could be used as fundamental data to determine the side effect and toxicity of illegal sildenafil analogues.

Chenopodium album Linn. leaves prevent ethylene glycol-induced urolithiasis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Chenopodium album Linn. are traditionally used for correction of kidney diseases and urinary stones. The present work investigated the effect of methanolic and aqueous extracts of leaves of Chenopodium album on experimentally-induced urolithiasis in rats to substantiate its traditional use as antilithiatic agent. MATERIALS AND METHODS: The leaf extract was standardized by HPLC. Urolithiasis was induced in rats by administration of 0.75% v/v of ethylene glycol (EG) in distilled water and in addition, vehicle or methanol (CAME) or aqueous (CAAE) extract of the leaves of Chenopodium album each in the dose 100, 200 and 400mg/kg or Cystone (750mg/kg) were administered daily orally for 28 days. Urolithiasis was assessed by estimating the calcium, phosphorus, urea, uric acid, and creatinine in both urine and plasma. The volume, pH and oxalate levels were also estimated in urine. The renal oxalate content was estimated in kidney while calcium oxalate deposits were observed histologically. RESULTS: The treatment with CAME or CAAE for 28 days significantly attenuated the EG-induced elevations in the urine and plasma levels of calcium, phosphorus, urea, uric acid and creatinine along with decrease in urine volume, pH and oxalates. The treatments also decreased renal tissue oxalate and deposition of oxalate crystals in kidney due to EG treatment. The effects of CAME and CAAE were comparable to standard antilithiatic agent, cystone. The findings indicate the preventive effect of CAME and CAAE which can be due to inhibitory effect on crystallization and stone dissolution. The effect was attributed to the presence of phytochemicals like flavonoids and saponins. CONCLUSION: In conclusion, Chenopodium album leaves exhibited antilithiatic effect and validates its ethnomedicinal use in urinary disorders and kidney stones.

Daily application of alprostadil topical cream (Vitaros) does not impact vaginal pH, flora, or histology in female cynomolgus monkeys.

Topical alprostadil cream (Vitaros) is approved in Canada and Europe for the treatment of erectile dysfunction. To determine the effects on the female urogenital tract with repeated administration of the entire dose (300 µg alprostadil containing 2.5% dodecyl-2-n,n-dimethylaminopropionate hydrochloride), the vaginal pH, flora, and histology were assessed as a model for 100% transference from male to the female during unprotected sexual intercourse. Female cynomolgus monkeys were administered the entire dose of Vitaros for 14 days with a 7-day recovery. Relative to vehicle and placebo cream, the vaginal pH and microflora were determined at baseline and weekly, thereafter. Vaginal biopsies were evaluated at the end of dosing and recovery. All animals were clinically normal for the study duration, and the vaginal pH was consistent between dose groups and the dosing period. Vaginal microflora and histopathology findings of mild inflammation were generally similar across treatment groups. In conclusion, repeated vaginal exposure to Vitaros did not alter the pH, microflora, or histology after 14 daily doses, supporting the safety of Vitaros transference to the female partner.

Effect of mirabegron on plasma gonadotropic and steroidal hormone levels in rats after two weeks of oral administration.

The effects of mirabegron on plasma gonadotropic and steroidal hormone levels in rats were investigated, when administered orally once daily for two weeks to male and female rats at doses of 10, 30, and 100 mg/kg/day, in order to elucidate a potential mechanism for findings in the reproductive system observed in toxicity studies in rats. Significantly decreased body weight gain and food consumption were observed in males and females at 100 mg/kg/day on Days 1 to 4 of dosing. A significantly prolonged estrous interval was observed in females at 100 mg/kg/day and increased liver weights were noted in females at 30 mg/kg/day or greater. No histopathological changes were observed in the pituitary gland, adrenal glands, liver, testes, epididymides, prostate, seminal vesicle, ovaries, uterus, or vagina at any dose. In males, no treatment-related changes in levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, or dihydrotestosterone (DHT) were observed at any dose. Corticosterone levels in males increased in a dose-dependent manner at 30 mg/kg/day or greater. In females, no treatment-related changes in levels of LH, FSH, prolactin, estradiol, progesterone, or corticosterone were observed at any dose in any stage of the estrous cycle. Taken together, these results suggest that mirabegron has no effect on gonadotropic or sex steroidal hormone levels in either sex at doses up to 100 mg/kg/day. In contrast, adrenocortical hormone levels were increased in males at mirabegron doses of 30 mg/kg/day or greater.

Preparation, characterization and pharmacological evaluation of tolterodine hydrogels for the treatment of overactive bladder.

In this study, transdermal gel formulations for tolterodine were developed to investigate the effects of gel matrix and chemical enhancers on drug skin permeation from tolterodine hydrogels. In vitro permeation studies of tolterodine through excised mouse skin were carried out using Franz-type diffusion cells. In the optimum gel formulation, Carbopol 940 was selected as the gel matrix. Compared to gels without enhancer, tolterodine hydrogels with N-methyl pyrrolidone (NMP) showed significant enhancing effect on transdermal permeation of tolterodine (p<0.05). The results of in vitro percutaneous delivery experiment showed that the relationship of the steady accumulative percutaneous amount (Q, µg cm(-2)) of tolterodine hydrogels and time was Q4-12h=770.19t(1/2)-966.99. Tolterodine permeated at the steady-state speed of 770.19 µg cm(-2)h(-1) and its release coincided with Higuchi Equation. The pharmacokinetic properties of the optimized tolterodine formulation were studied in rabbits. The absolute bioavailability of tolterodine was 11.47%. Since the absence of hepatic first-pass metabolism, only a single active compound-tolterodine was detected in the plasma. A skin irritation study was also carried out on rabbits, and the results showed tolterodine hydrogels had no skin irritation. In the pharmacodynamic study, the significant effects of tolterodine hydrogels on the inhibition of pilocarpine-induced rat urinary bladder contraction were last to 12h, indicating that tolterodine hydrogels could produce prolonged pharmacological responses. In conclusion, tolterodine hydrogels were formulated successfully using Carbopol 940 and NMP and these results helped in finding the optimum formulation for percutaneous drug release. It is quite evident that tolterodine hydrogels may offer a possibility to avoid the first-pass effect, resulting in a single active compound of tolterodine in plasma, which may profit on the patient under the dose control and the reduction of potential adverse effect from two active compounds in the body.