A reliable method to quantify sildenafil and its metabolite N-demethylsildenafil by HPLC in plasma of children.

The aim of this study was to develop a simple method for quantifying plasma levels of sildenafil and its metabolite by liquid chromatography with a C18 reverse-phase column and UV detection. For both compounds, linearity was assessed in the range from 10 and 1 000 ng · ml-1 and had correlation coefficients of r=0.995 and r=0.997 for sildenafil and its metabolite, respectively. The inter- and intra-day coefficients of variation was<5.3%. The limits of detection and quantification were 1 and 10 ng · ml-1. Drug levels were determined satisfactorily in two patients. A simple and reliable method was developed for use in children with Pulmonary Arterial Hypertension under treatment with sildenafil.

Comparison of fasting bioavailability among 100-mg commercial, 100-mg generic, and 50-mg chewable generic sildenafil tablets in healthy male Mexican volunteers: a single-dose, 3-period, crossover study.

BACKGROUND: Sildenafil citrate (SIL) was the first oral drug registered in Mexico for the treatment of erectile dysfunction. However, succinct pharmacokinetic data are available in the Mexican population. OBJECTIVE: The goals of the present work were: (1) to design a specific method to quantify SIL plasma levels by using UPLC-MS/MS; (2) to compare oral SIL bioavailability in Mexican men with pharmacokinetic data in other populations; (3) to fulfill local regulatory requests; and (4) to describe the relative tolerability of a new 50-mg chewable tablet. METHODS: This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy male volunteers. In each period, subjects received single oral doses of 100 mg of sildenafil (1 commercial [reference(⁎)], 1 generic [test 1(†)], or 2 chewable generic tablets [test 2(‡)]), with a 4-day washout period between each dose. Serial blood samples were collected for up to 24 hours. SIL was measured in heparinized plasma by using a validated UPLC-MS/MS method. Pharmacokinetic parameters included C(max), T(max), AUC(0-24), and AUC(0-∞). Bioequivalence was established if 90% CIs for mean test:reference ratios of log-transformed C(max) and AUC fell within the range of 0.80 to 1.25. Tolerability was assessed on the basis of a clinical interview with the subject and monitoring of vital signs. RESULTS: Demographic data showed a homogeneous population. Validation of analytical method proved to be linear within the range of 1 to 1000 ng/mL, with selectivity, accuracy, and precision. 90% CIs for test 1:reference ratios were 86.52 to 113.56, 94.75 to 108.84, and 94.97 to 108.82 for the logarithm parameters C(max), AUC(0-24), and AUC(0-∞), respectively. The 90% CIs for the test 2:reference ratios were 82.14 to 107.24, 98.26 to 112.56, and 99.19 to 113.34 for C(max), AUC(0-24), and AUC(0-∞). Regarding relative tolerability, slight cephalea was the most common adverse effect. CONCLUSIONS: The developed analytical method was validated in compliance with local requirements and was useful for sildenafil measurement. This single-dose study under fasting conditions suggests that both test products met the Mexican regulatory criteria for assuming bioequivalence in these healthy, male Mexican volunteers. The clinical data suggest that the chewable tablets were well tolerated by volunteers.

Validation of an HPLC method for sildenafil citrate analysis in human plasma samples.

A simple, precise, rapid and accurate HPLC method for the determination of sildenafil citrate (SLD) in human plasma has been developed based on previous reports, to offer an alternative way to detect and quantify SLD and also to improve some characteristics of the validation process. Chromatography was carried out on a C18 reversed-phase column, using a mixture of acetonitrile: ammonium acetate (0.3 M pH 6.8) (1:1 v/v) as the mobile phase at a flow of 0.750 mL/min. Diazepam was used as an internal standard (IS) and detection was by UV at 240 nm. Samples were extracted with 200 microl of 0.1 M Na2CO3 and 5 mL of diethyl ether: dichloromethane (60:40). Retention times of SLD and IS were 4.8 and 7.1 min, respectively; total run time was 10 min. The linear range of SLD was found to be 20 - 1000 ng/mL. Limit of quantitation (LOQ) and limit of detection (LOD) were calculated to be 10 and 20 ng/mL, respectively. An improved percentage recovery of analyte is reported, showing a fast and reproducible approach to detect SLD in plasma human sample. The method was validated for its linearity, precision, accuracy, recovery, stability and specificity.

Evaluation of the adverse effects of oral firocoxib in healthy dogs.

This study evaluated the adverse effects of oral firocoxib in dogs. Six dogs (20.2+/-6.3 kg) were studied. Values for complete blood count (CBC), serum urea, creatinine, alanine transaminase, alanine phosphatase, gamma-glutamyl transferase, occult blood in feces, platelet aggregation, and buccal mucosal bleeding time were measured before and 7, 14, 21, and 29 days after SID treatment with firocoxib 5.3+/-0.34 mg/kg (FG) or lactose 1 mg/kg (LG) for 28 days, in a randomized crossover study. Gastrointestinal (GI) tract endoscopy was performed before treatment began and at 29 days. Lesions were scored from grade 0 to 6. Data were analyzed using anova and paired t-tests (P<0.05). None of the dogs presented adverse clinical effects. There were no significant changes in CBC, biochemical profiles within groups, or differences between groups. Pretreatment mean+/-SD bleeding time (LG, 70.7+/-32.1 sec; FG, 75.8+/-38.1 sec) and platelet aggregation (LG, 86.4+/-10.2%; FG, 85.6+/-9.2%) were not significantly different from readings at 29 days (LG, 95.2+/-25 sec; FG, 91.7+/-24 sec and LG, 73.2+/-15.1%; FG, 84+/-10.3%) nor the groups were different. None of the dogs had positive fecal occult blood tests, and endoscopic lesion scores were grade 0 both before treatment and at 29 days. Administration of firocoxib did not cause any adverse effects on GI, or hematological or serum biochemical variables and appears to have been well tolerated by dogs.

Protective effects of etoricoxib, a selective inhibitor of cyclooxygenase-2, in experimental periodontitis in rats.

BACKGROUND: The purpose of the present study was to evaluate the effect of a potent selective cyclooxygenase-2 (COX-2) inhibitor, etoricoxib, on the prevention of alveolar bone loss in experimental periodontitis induced in rats. METHODS: Ninety Wistar rats were separated into three experimental groups. Cotton ligatures were placed at the gingival margin level of lower right first molars. The rats were randomly assigned to one of the following groups: control received a daily oral dose of 1 ml/kg of saline solution; Eto1 received 6 mg/kg of etoricoxib; Eto2 received 12 mg/kg of etoricoxib. Serum levels of etoricoxib and white blood cells were determined. Standardized digital radiographs were taken after death at 3, 5, 10, 18 and 30 days to measure the amount of bone loss at the mesial root surface of the first molar tooth in each rat. RESULTS: One-way analysis of variance (anova) indicated that groups treated with both doses of etoricoxib had significantly (p < 0.05) less alveolar bone loss when compared to controls. Furthermore, etoricoxib treatment significantly inhibited the leukocytosis observed 3 days after the induction of periodontitis. CONCLUSION: These data provide evidence that systemic therapy with etoricoxib can retard alveolar bone loss in a ligature-induced periodontitis model in rats.

Chromosomal aberrations in leucocyte metaphases of leprosy patients under dapsone therapy

Chromosome analyses were made on leukocyte metaphases of 18 leprosy patients who were ingesting daily doses of 50 mg or 100 mg of DDS and of 40 healthy individuals used for control. These analyses have shown that the proportion of numerical chromosomal aberrations in the leukocyte metaphases of the leprosy patients did not differ significantly from that observed in the cells of the controls. In contrast, the frequency of cells with chromatid or chromosome breaks and gaps was significantly increased in the leukocytesof leprosy patients. Multiple regression analysis applied to the data recorded has shown that the increase of breaks and gaps in the chromosomes of leprosy patients can not be attributed to age, years under sulfonetherapy or to concentration of DDS in blood.

The action of diasone in the treatment of leprosy: preliminary report

The action of the oral administration of diasone has been studied in a group of advanced cases of leprosy of whom almost all had previously been treated with chaulmoogra oil. The drug was given for periods of 8 weeks with a daily dosage varying between 1 and 3 Grams according to individual tolerance; between each period or course of treatment there was a 4 weeks' interval. Anemia (82 per cent), asthenia and depression (88 per cent), headache (74 per cent) were noted as signs of intolerance. There were no grave consequences and intolerance was readily treated with liver extract, iron, and vitamin B complex. Activity of the drug was shown by softening, ulceration, and re-absorption of leprous nodules, healing of ulcers, and re-absorption of deep lepromatous infiltrations. Bacteriologically, granulation of the bacilli was observed but in no case had bacilli completely disappeared from the lesions. The improvement noted was greater the longer and more concentrated the treatment. The results found after 8 months trial were the following: in 5 cases treated for 3 periods, 100 per cent improved; in 11 cases treated for 2 periods, 63.6 per cent improved; in 26 cases after only 1 period of treatment, 50 per cent improved. Thus of 42 patients who had completed 1 to 3 periods of treatment, 59.5 per cent showed improvement. Finally it may be stated that diasone has proved to be effective in the treatment of leprosy in a series of 42 patients observed for 8 months. Further experimental treatment should be carried out so that definite conclusions based on greater experience can be obtained.