Fosfomycin Pharmacokinetic Profile in Plasma and Urine and Quantitative Estimation in Prostate and Seminal Vesicles after One and Two Consecutive Doses of Oral Fosfomycin Trometamol in Healthy Male Volunteers.

The present Phase I study investigated, for the first time, fosfomycin pharmacokinetics in humans after two 3 g doses of fosfomycin trometamol administered 27 h apart, according to the dose regimen recommended for the prophylactic indication for transrectal prostate biopsy in adult men. Plasma, urine and seminal plasma concentrations were measured after one and two consecutive doses in 24 healthy men, representative of the target population of the prophylactic indication. Prostate and seminal vesicle concentrations were estimated based on seminal plasma concentrations using a one-step regression method. The exposure to fosfomycin was very similar in rate (Cmax, tmax) after one and two doses. The AUC showed a minimal increment. On average, the apparent volume of distribution was high (>100 L), and the mean clearance had an intermediate value. The total amount and dose fraction of fosfomycin excreted in urine showed a small increment after two doses. The renal clearance was about 5 L/h. The fosfomycin concentration in the prostate and seminal vesicles showed that the antibiotic increased on average after two consecutive doses. This result confirmed the ability of fosfomycin to distribute into the prostate and into seminal vesicles after one single dose and that a two consecutive dose regimen increases the antibiotic availability inside these peripheral tissues.

Pharmacokinetics and Safety of Single and Multiple Doses of Oral N-Acetylcysteine in Healthy Chinese and Caucasian Volunteers: An Open-Label, Phase I Clinical Study.

INTRODUCTION: Few studies have evaluated whether the pharmacokinetics of N-acetyl-cysteine (NAC) are different in Chinese and Caucasian individuals. METHODS: This single- and multiple-dose, single-centre, open-label, phase I clinical study was conducted in healthy adult volunteers. All participants received oral NAC 600-mg uncoated tablets, which were administered first as a single dose and, following a 48-h wash-out period, twice daily for 3 days. Blood and urine were collected after single- and multiple-dose NAC administration. Adverse event (AE) data were collected throughout the study. RESULTS: Fifteen Chinese and 15 Caucasian (mostly Italian) individuals (males 66.7%, mean age 36.8 years) participated in the study. Pharmacokinetic characteristics of NAC were similar in the two cohorts. Following both single- and multiple-dose administration, plasma concentration of NAC increased rapidly, reaching a peak at approximately 1.0 h. Maximum plasma concentration and extent of exposure were higher after multiple doses than after a single dose. The accumulation ratio was relatively consistent in both Chinese (mean ± standard deviation 1.5 ± 0.4) and Caucasian (1.4 ± 0.2) participants. The half-life was 15.4 h in Chinese and 18.7 h in Caucasian participants, and the fraction of NAC excreted in urine in the 36 h following administration was 3.7% in Chinese and 3.8% in Caucasian participants. Two Caucasian participants had a total of 3 AEs (headache, presyncope and dysmenorrhoea). No AEs occurred in Chinese participants. CONCLUSIONS: The pharmacokinetic characteristics of NAC are similar in healthy Chinese and Caucasian individuals after single and repeated administration. NAC has a favourable tolerability profile.

Pharmacokinetics and Pharmacodynamics of Follicle-Stimulating Hormone in Healthy Women Receiving Single and Multiple Doses of Highly Purified Human Menotrophin and Urofollitrophin.

BACKGROUND AND OBJECTIVE: Highly purified human menotrophin and urofollitrophin preparations obtained from human urine via a novel patented purification method have been tested over a timeframe of 14 years in the studies presented in this article. The objective of the studies was to investigate the pharmacokinetics and the pharmacodynamics of follicle-stimulating hormone (FSH) after single subcutaneous and intramuscular doses and multiple subcutaneous doses of the tested preparations in healthy fertile pituitary-suppressed women. DESIGNS: We performed five open, randomised, crossover, single-dose bioequivalence and/or bioavailability studies and one open, multiple-dose, pharmacokinetics and pharmacodynamics study. STUDY SUBJECTS AND TREATMENTS: The six studies included 121 healthy fertile women taking their usual combined oral contraceptives for 3 months before the study: Study 1: 300 international units (IU) of highly purified menotrophin as single subcutaneous and intramuscular doses. Study 2: 300 IU of highly purified menotrophin (test formulation vs. comparator) as single subcutaneous doses. Study 3: 300 IU of highly purified urofollitrophin (hp-FSH) (test formulation vs. comparator) as single subcutaneous doses. Study 4: 300 IU (2 × 150 IU vs. 4 × 75 IU) of hp-FSH as single subcutaneous doses. Study 5: 225 and 445 IU of hp-FSH as single subcutaneous doses. Study 6: daily 225 IU of hp-FSH as subcutaneous doses for 5 consecutive days. MAIN OUTCOME MEASURES: The main outcome measures were the FSH pharmacokinetic parameters, estradiol concentrations, and the number and size of the follicles. RESULTS: FSH after single subcutaneous and intramuscular injections of menotrophin or urofollitrophin attained a systemic peak (maximum) concentration (C max) that was on average consistent throughout the first four studies and ranged from 4.98 to 7.50 IU/L. The area under the plasma concentration-time curve (AUC) from administration to the last observed concentration time t (AUCt) ranged from 409.71 to 486.16 IU/L·h and the elimination half-life (t ½) ranged from 39.02 to 53.63 h. After multiple doses of urofollitrophin (225 IU) for 5 days, FSH attained a mean C max of 14.93 ± 2.92 IU/L and had an AUC during the time interval τ between two consecutive doses at steady state (AUCτ) of 322.59 ± 57.92 IU/L·h, which was similar to the mean AUCt after a single subcutaneous dose of 225 IU of urofollitrophin in study 5 (306.82 ± 68.37 IU/L·h). CONCLUSIONS: In our studies, the intramuscular and subcutaneous routes of menotrophin were equivalent; both menotrophin and urofollitrophin were bioequivalent to their marketed reference; FSH kinetic parameters following injection of urofollitrophin were dose proportional and independent from the administered concentration; and multiple doses of FSH increased estradiol levels and enhanced growth of follicles with a good dose-response correlation. Local tolerability was excellent throughout the six studies.

Recombinant filgrastim (BK0023) pharmacodynamics and pharmacokinetics after single and multiple escalating doses in an equivalence study in healthy men.

BACKGROUND AND OBJECTIVES: The new filgrastim formulation, BK0023, whose synthesis method is patented, was tested in a phase I clinical study that was aimed at investigating the pharmacodynamic and pharmacokinetic equivalence and the safety of BK0023 in healthy male subjects. METHODS: Single and multiple escalating doses were administered to healthy male volunteers according to a double-blind, randomised, two-way crossover design. Thirty-two subjects received subcutaneous filgrastim 2.5 µg/kg/day for 7 consecutive days in each period, 36 subjects received 5 µg/kg/day for 7 days in each period, and 22 subjects received 10 µg/kg/day for 5 days. Absolute neutrophil count (ANC) and CD34+ cell count were measured in whole blood as primary and secondary pharmacodynamic parameters. Filgrastim concentrations were measured in serum to calculate the primary pharmacokinetic parameters. RESULTS: The maximum ANC and the area under the curve of the ANC after the first dose and to the end of treatment satisfied the equivalence criterion (95 % confidence intervals within 85-115 or 85-117 % in case of log-transformation). At all three dose regimens, BK0023 was also bioequivalent to the reference product in terms of pharmacokinetic profile of serum filgrastim. The frequency of the treatment-emergent adverse events did not differ significantly between treatments, with the most frequent untoward effects being back and bone pain. CONCLUSIONS: Equivalence could be established using both the baseline-adjusted values and the original unadjusted values. The tested formulation at all three dose regimens was also bioequivalent to the reference product in terms of pharmacokinetic profile.

Antiviral activity of mycophenolic acid derivatives in plants.

KEYWORDS: antiviral agents; chemotherapy; polyamidoamine; multivalency.

Pressor response to oral tyramine and monoamine oxidase inhibition during treatment with ralfinamide (NW-1029).

Ralfinamide, an original Na(+) channel blocker developed for the treatment of chronic pain, inhibits monoamineoxidase-B with no apparent effect on monoamineoxidase-A. To evaluate the pressor response to oral tyramine under fasting conditions during treatment with ralfinamide in healthy normotensive subjects. Ten women and 10 men aged 52.9 ± 5.5, sensitive to the oral tyramine pressor effect in the dose range 200-400 mg, received ralfinamide 320 mg daily during 7 days of confinement. Starting on day 5, ascending doses of tyramine 50, 100 and 200 mg were daily administered to subjects, who had responded to 200 mg at screening, and 100, 200 and 400 mg to the 400 mg responders. Vital parameters were monitored. The systolic blood pressure peak (ΔSBP), the time to achieve the peak (Δt) and the area under the pressure curve (over baseline) were calculated. ΔSBP ≥ 30 mmHg were measured for one subject with tyramine 200 mg and for 11 subjects with 400 mg, whilst ΔSBP was <30 mmHg for eight subjects at all the tested doses. ΔSBP, Δt and AUC after co-treatment with ralfinamide and tyramine were not significantly different from those measured after tyramine alone. Ralfinamide did not potentiate the pressor response to single oral doses of tyramine from 50 to 400 mg. These preliminary results give an evidence for the specificity of ralfinamide for MAO-B in comparison with MAO-A, analogously to the observations previously done for safinamide. Dietary tyramine restrictions may not be necessary in neuropathic pain patients receiving ralfinamide as a therapy.

[Rare localization of melanoma in a case of pharyngeal cancer]. / Rara localizzazione di un caso di melanoma a livello del faringe.

The authors report a rare case of pharyngeal malignant melanoma, underlining the necessity of early diagnosis, in order to achieve the best possible prognosis preventing metastatic spreading. Unusual locations of MM are discussed, with emphasis on those that do not allow an early detection of the disease.