The present Phase I study investigated, for the first time, fosfomycin pharmacokinetics in humans... more 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...
Infectious Diseases in Obstetrics and Gynecology, 2020
Purpose. A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulate... more Purpose. A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulated in vaginal ovules was investigated in a randomised, double-blind, four-parallel group, tolerability, and pharmacokinetic Phase I study in healthy women. Methods. The fixed-dose combination was compared to econazole and benzydamine single-drug formulations and with placebo after daily applications for 3 consecutive days. Safety and tolerability were evaluated recording the adverse drug reactions, local and general tolerability scores, clinical laboratory assays, and vital signs. Econazole, benzydamine, and its metabolite benzydamine N-oxide pharmacokinetics were investigated after single and multiple applications. Results. Local reactions were generally absent. Pruritus and pain at the application site were infrequently reported. According to the subjects’ evaluations, the overall tolerability of the ovules was rated as excellent or good. No significant effect of any treatment on labora...
The primary objective of this single- and multiple-dose pharmacokinetic study was the investigati... more The primary objective of this single- and multiple-dose pharmacokinetic study was the investigation of rifamycin SV’s pharmacokinetic profile in plasma and urine. All the 18 enrolled healthy men and post-menopausal women received modified release tablets containing 600 mg of the oral non-absorbable antibiotic, rifamycin SV, according to a multiple dose regimen: one tablet three times a day (daily intake: 1800 mg) for 14 consecutive days. Blood sampling and urine collection were performed up to 24 h post-dose after the first dose on Days 1 and 7. On average, on Day 1, Cmax,0–24 was 5.79 ± 4.24 ng/mL and was attained in a median time of 9 h. On Day 7, all the subjects had quantifiable levels of rifamycin SV in plasma at each sampling time. After a peak concentration attained 2 h post-dose (mean ± SD concentration: 10.94 ± 16.41 ng/mL), rifamycin SV decreased in plasma to levels similar to those of Day 1. The amounts of rifamycin SV excreted in urine paralleled the plasma concentration...
The primary objective of this single- and multiple-dose pharmacokinetic study was the investigati... more The primary objective of this single- and multiple-dose pharmacokinetic study was the investigation of rifamycin SV’s pharmacokinetic profile in plasma and urine. All the 18 enrolled healthy men and post-menopausal women received modified release tablets containing 600 mg of the oral non-absorbable antibiotic, rifamycin SV, according to a multiple dose regimen: one tablet three times a day (daily intake: 1800 mg) for 14 consecutive days. Blood sampling and urine collection were performed up to 24 h post-dose after the first dose on Days 1 and 7. On average, on Day 1, Cmax,0–24 was 5.79 ± 4.24 ng/mL and was attained in a median time of 9 h. On Day 7, all the subjects had quantifiable levels of rifamycin SV in plasma at each sampling time. After a peak concentration attained 2 h post-dose (mean ± SD concentration: 10.94 ± 16.41 ng/mL), rifamycin SV decreased in plasma to levels similar to those of Day 1. The amounts of rifamycin SV excreted in urine paralleled the plasma concentration at the corresponding times. On Day 1, the total amount excreted in urine was 0.0013%, and was 0.0029% on Day 7. The study results confirmed those of the previous Phase I study: the systemic absorption of rifamycin SV was also proved negligible after 7 days of the 600 mg t.i.d. dose regimen of the newly formulated tablets, currently under development for the treatment of several small and large intestinal pathologies, including diarrhea-predominant irritable bowel syndrome, hepatic encephalopathy, and others. Registered at ClinicalTrials.gov with the identifier NCT02969252, last updated on 26JAN18.
Contested Languages The hidden multilingualism of Europe, 2021
The present essay reports the experience of applying a web-based system of fundraising such as cr... more The present essay reports the experience of applying a web-based system of fundraising such as crowdfunding to publish a textbook for a local language (the variety of Piedmontese spoken in Biella and its neighbourhood). Piedmontese is classified as an endangered language whose number of speakers is steadily decreasing. Conversely, the mean age of speakers is increasing. Crowdfunding was chosen as a fundraising system with the aim of supporting the publication of a Piedmontese grammar and anthology. The campaign was launched on the crowdfunding platform Produzioni dal Basso on 2 September and terminated on 31 December 2015. The appeal was posted at weekly intervals on the social network Facebook starting from the day of the campaign launch. Pages specific for users with interest in Piedmontese were chosen for spreading the news. The appeal was spread also via private messages whenever possible. Meanwhile, the news was also published several times in dedicated articles by newspapers. The positive feedback by the supporters, who received copies of the book in return for contributions of a certain size, ensured the actual publication of the grammar in December 2017. In conclusion, an up-to-date system, such as that offered by the online crowdfunding platform, combined with the possibility of spreading the appeal through social networks, gained an unexpected positive feedback from the public and was able to attract the interest of a number of potential readers of the proposed text book.
Introduction
Few studies have evaluated whether the pharmacokinetics of N-acetyl-cysteine (NAC) ... more 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.
Infectious Diseases in Obstetrics and Gynecology , 2020
Purpose. A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulate... more Purpose. A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulated in vaginal ovules was investigated in a randomised, double-blind, four-parallel group, tolerability, and pharmacokinetic Phase I study in healthy women. Methods. The fixed-dose combination was compared to econazole and benzydamine single-drug formulations and with placebo after daily applications for 3 consecutive days. Safety and tolerability were evaluated recording the adverse drug reactions, local and general tolerability scores, clinical laboratory assays, and vital signs. Econazole, benzydamine, and its metabolite benzydamine N-oxide pharmacokinetics were investigated after single and multiple applications. Results. Local reactions were generally absent. Pruritus and pain at the application site were infrequently reported. According to the subjects’ evaluations, the overall tolerability of the ovules was rated as excellent or good. No significant effect of any treatment on laboratory parameters, vital signs, body weight, vaginal pH, or ECG was observed. Very low econazole, benzydamine, and benzydamine-N-oxide concentrations were measured in plasma, though quantifiable in almost all samples. Conclusion. The tested fixed-dose combination showed a good safety profile consistently with the known tolerability of both active substances. In addition, the confirmed low bioavailability of the drugs excludes the possibility of any accumulation effects and limits the risk of undesired systemic effects. This trial is registered at ClinicalTrials.gov with the identifier NCT02720783 last updated on 07 February 2017.
Background and Objective
Highly purified human menotrophin and urofollitrophin preparations obta... more 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.
Methylene blue-MMX® tablets are proposed as an aid for detection and visualisation of adenomas an... more Methylene blue-MMX® tablets are proposed as an aid for detection and visualisation of adenomas and carcinomas in patients undergoing colonoscopy, by improving their detection rate and highlighting the presence of the intestinal dysplastic lesions.
Single total doses of 100 and 200 mg were administered to healthy volunteers undergoing a bowel cleansing preparation and a full colonoscopy to investigate the colonic staining. The pharmacokinetics of methylene blue and the safety after exposure to the tablets were also investigated.
With 200 mg, the best staining, assessed as the sum of acceptable and good staining, was achieved in the ascending colon and rectosigmoid (75% subjects each), the transverse and the descending colon (approximately 63% each). Absence of staining or overstaining were reported for no colonic region of interest in any subject. Similar results were observed in the 100 mg dose group.
Methylene blue blood concentrations reached a peak (Cmax) in a median time (Tmax) of 12 h with 100 mg and 16 h with 200 mg. AUC0-t was 10.7 ± 6.7 μg/mLxh after 100 mg and 25.2 ± 7.4 μg/mLxh after 200 mg. Half-life ranged between 9 and 22 h after the lower dose and between 6 and 26 h after the higher dose. The cumulative urinary excretion was about 28% after 100 mg and about 39% after 200 mg up to 60 h post-dose.
The overall frequency of adverse events after single dose of the test product administered along with a bowel cleansing preparation was 39%, but only one was related to the test product: abnormal transaminases. The most frequent adverse event was a transient polyuria (17%). One serious adverse event (gastrointestinal haemorrhage) led the subject to study discontinuation and hospitalisation and another subject withdrew the study due to one adverse event (haematemesis). Either event was not related to methylene blue.
Background: Filgrastim or methionyl-granulocyte colony-stimulating factor (Met-G-CSF), is a recom... more Background: Filgrastim or methionyl-granulocyte colony-stimulating factor (Met-G-CSF), is a recombinant therapeutic protein widely used to treat severe neutropenia caused by myelosuppressive drugs in patients with nonmyeloid malignancies. In addition to its role in the regulation of granulopoiesis, treatment with G-CSF is considered the standard approach to mobilize CD34 positive (CD34 +) mononuclear cells for reconstituting hemopoietic ability for bone marrow transplantation. An intended biosimilar filgrastim (coded BK0023) was produced in GMP conditions by E.coli fermentation according to an original recombinant process and showed physico-chemical properties and purity profile similar to Neupogen®, a commercial preparation of filgrastim. The aim of the present study was to demonstrate the comparability of BK0023 to Neupogen® in terms of both in vitro biological activities and in vivo toxicology, pharmacokinetics and pharmacodynamics. Methods: Cell proliferation and radioligand binding assays were conducted in NFS-60 cells to compare the biological activity and functional interaction with the G-CSF receptor in vitro, while preclinical in vivo studies, including pharmacokinetics and pharmacodynamics after repeated dose were performed in normal and neutropenic rats. A phase I study was carried out in healthy male volunteers treated by multiple-dose subcutaneous administration of BK0023 and Neupogen® to evaluate their pharmacodynamic effects as well as their pharmacokinetic and safety profile and to demonstrate their pharmacodynamic equivalence and pharmacokinetic bioequivalence.
International Journal of Antimicrobial Agents, 2007
ABSTRACT Objective: PZ-601 (SMP-601) is a novel carbapenem with an antimicrobial spectrum that in... more ABSTRACT Objective: PZ-601 (SMP-601) is a novel carbapenem with an antimicrobial spectrum that includes multidrug-resistant Gram positive (methicillin-resistant Staphylococcus aureus, Enterococcus faecium) and extended-spectrum b-lactamase producing Gram negative organisms. We studied the pharmacokinetics and safety of single ascending doses in otherwise healthy male volunteers. Methods: Fifty-six subjects (42 PZ-601, 14 placebo) were randomised in seven cohorts (6 PZ-601, 2 placebo) to ascending doses of PZ-601: 30, 100, 300, 600, 1,000, 1,500, 2,000mg or placebo by infusion over 30 minutes. Assessments included adverse events, laboratory, ECGs and PZ-601 plasma levels and urinary excretion. Results: Adverse events were infrequently noted in 5/42 PZ-601 and in 1/14 placebo recipients. The most common events were headache (3 PZ-601, 1 placebo) and dyspepsia (1 PZ-601). There were no serious adverse events. There were no laboratory or ECG findings of clinical concern. PZ-601 exposure was linear for the administered doses with a half-life of 1.4 hours at a dose of 1,000mg. A summary of key PZ-601 pharmacokinetic parameters is presented. Conclusion: PZ-601 in single doses up to 2g was generally well-tolerated in normal healthy male subjects. These results suggest the potential for twice daily dosing and support progression to repeat dosing.
Background and objectives
The new filgrastim formulation, BK0023, whose synthesis method is pat... more 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.
Background: The non absorbable antibiotic rifamycin SV newly formulated as modified colonic relea... more Background: The non absorbable antibiotic rifamycin SV newly formulated as modified colonic release MMX® tablets was preliminarily investigated. Methods: In a multi-centre, double-blind, double-dummy, randomised, parallel group study, efficacy and safety of the 200 mg tablets were investigated vs. rifaximin 200 mg tablets in infectious diarrhoea.
Results: 22 rifamycin SV recipients (47.8%) were successes, whilst 24 (52.5%) discontinued. In the reference group 27 (50.9%) were successes, whilst 26 (49.1%) discontinued. The median time to last unformed stool was 67.5 h after rifamycin SV and 65.5 h after rifaximin. Conclusions: The efficacy of the new tablets was not significantly different from that of rifaximin administered 4 times a day for 3 days. The treatments did not differ in rate or frequency of therapeutic success. Isolates of Campylobacter jejuni and lari, Escherichia coli, Anaerobiospirillum, Salmonella enteritidis and Shigella flexneri found at pre-treatment were not retrievable after rifamycin SV.
Ralfinamide, an original Na+ channel blocker developed for the treatment of chronic pain, inhibit... more 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.
The present Phase I study investigated, for the first time, fosfomycin pharmacokinetics in humans... more 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...
Infectious Diseases in Obstetrics and Gynecology, 2020
Purpose. A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulate... more Purpose. A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulated in vaginal ovules was investigated in a randomised, double-blind, four-parallel group, tolerability, and pharmacokinetic Phase I study in healthy women. Methods. The fixed-dose combination was compared to econazole and benzydamine single-drug formulations and with placebo after daily applications for 3 consecutive days. Safety and tolerability were evaluated recording the adverse drug reactions, local and general tolerability scores, clinical laboratory assays, and vital signs. Econazole, benzydamine, and its metabolite benzydamine N-oxide pharmacokinetics were investigated after single and multiple applications. Results. Local reactions were generally absent. Pruritus and pain at the application site were infrequently reported. According to the subjects’ evaluations, the overall tolerability of the ovules was rated as excellent or good. No significant effect of any treatment on labora...
The primary objective of this single- and multiple-dose pharmacokinetic study was the investigati... more The primary objective of this single- and multiple-dose pharmacokinetic study was the investigation of rifamycin SV’s pharmacokinetic profile in plasma and urine. All the 18 enrolled healthy men and post-menopausal women received modified release tablets containing 600 mg of the oral non-absorbable antibiotic, rifamycin SV, according to a multiple dose regimen: one tablet three times a day (daily intake: 1800 mg) for 14 consecutive days. Blood sampling and urine collection were performed up to 24 h post-dose after the first dose on Days 1 and 7. On average, on Day 1, Cmax,0–24 was 5.79 ± 4.24 ng/mL and was attained in a median time of 9 h. On Day 7, all the subjects had quantifiable levels of rifamycin SV in plasma at each sampling time. After a peak concentration attained 2 h post-dose (mean ± SD concentration: 10.94 ± 16.41 ng/mL), rifamycin SV decreased in plasma to levels similar to those of Day 1. The amounts of rifamycin SV excreted in urine paralleled the plasma concentration...
The primary objective of this single- and multiple-dose pharmacokinetic study was the investigati... more The primary objective of this single- and multiple-dose pharmacokinetic study was the investigation of rifamycin SV’s pharmacokinetic profile in plasma and urine. All the 18 enrolled healthy men and post-menopausal women received modified release tablets containing 600 mg of the oral non-absorbable antibiotic, rifamycin SV, according to a multiple dose regimen: one tablet three times a day (daily intake: 1800 mg) for 14 consecutive days. Blood sampling and urine collection were performed up to 24 h post-dose after the first dose on Days 1 and 7. On average, on Day 1, Cmax,0–24 was 5.79 ± 4.24 ng/mL and was attained in a median time of 9 h. On Day 7, all the subjects had quantifiable levels of rifamycin SV in plasma at each sampling time. After a peak concentration attained 2 h post-dose (mean ± SD concentration: 10.94 ± 16.41 ng/mL), rifamycin SV decreased in plasma to levels similar to those of Day 1. The amounts of rifamycin SV excreted in urine paralleled the plasma concentration at the corresponding times. On Day 1, the total amount excreted in urine was 0.0013%, and was 0.0029% on Day 7. The study results confirmed those of the previous Phase I study: the systemic absorption of rifamycin SV was also proved negligible after 7 days of the 600 mg t.i.d. dose regimen of the newly formulated tablets, currently under development for the treatment of several small and large intestinal pathologies, including diarrhea-predominant irritable bowel syndrome, hepatic encephalopathy, and others. Registered at ClinicalTrials.gov with the identifier NCT02969252, last updated on 26JAN18.
Contested Languages The hidden multilingualism of Europe, 2021
The present essay reports the experience of applying a web-based system of fundraising such as cr... more The present essay reports the experience of applying a web-based system of fundraising such as crowdfunding to publish a textbook for a local language (the variety of Piedmontese spoken in Biella and its neighbourhood). Piedmontese is classified as an endangered language whose number of speakers is steadily decreasing. Conversely, the mean age of speakers is increasing. Crowdfunding was chosen as a fundraising system with the aim of supporting the publication of a Piedmontese grammar and anthology. The campaign was launched on the crowdfunding platform Produzioni dal Basso on 2 September and terminated on 31 December 2015. The appeal was posted at weekly intervals on the social network Facebook starting from the day of the campaign launch. Pages specific for users with interest in Piedmontese were chosen for spreading the news. The appeal was spread also via private messages whenever possible. Meanwhile, the news was also published several times in dedicated articles by newspapers. The positive feedback by the supporters, who received copies of the book in return for contributions of a certain size, ensured the actual publication of the grammar in December 2017. In conclusion, an up-to-date system, such as that offered by the online crowdfunding platform, combined with the possibility of spreading the appeal through social networks, gained an unexpected positive feedback from the public and was able to attract the interest of a number of potential readers of the proposed text book.
Introduction
Few studies have evaluated whether the pharmacokinetics of N-acetyl-cysteine (NAC) ... more 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.
Infectious Diseases in Obstetrics and Gynecology , 2020
Purpose. A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulate... more Purpose. A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulated in vaginal ovules was investigated in a randomised, double-blind, four-parallel group, tolerability, and pharmacokinetic Phase I study in healthy women. Methods. The fixed-dose combination was compared to econazole and benzydamine single-drug formulations and with placebo after daily applications for 3 consecutive days. Safety and tolerability were evaluated recording the adverse drug reactions, local and general tolerability scores, clinical laboratory assays, and vital signs. Econazole, benzydamine, and its metabolite benzydamine N-oxide pharmacokinetics were investigated after single and multiple applications. Results. Local reactions were generally absent. Pruritus and pain at the application site were infrequently reported. According to the subjects’ evaluations, the overall tolerability of the ovules was rated as excellent or good. No significant effect of any treatment on laboratory parameters, vital signs, body weight, vaginal pH, or ECG was observed. Very low econazole, benzydamine, and benzydamine-N-oxide concentrations were measured in plasma, though quantifiable in almost all samples. Conclusion. The tested fixed-dose combination showed a good safety profile consistently with the known tolerability of both active substances. In addition, the confirmed low bioavailability of the drugs excludes the possibility of any accumulation effects and limits the risk of undesired systemic effects. This trial is registered at ClinicalTrials.gov with the identifier NCT02720783 last updated on 07 February 2017.
Background and Objective
Highly purified human menotrophin and urofollitrophin preparations obta... more 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.
Methylene blue-MMX® tablets are proposed as an aid for detection and visualisation of adenomas an... more Methylene blue-MMX® tablets are proposed as an aid for detection and visualisation of adenomas and carcinomas in patients undergoing colonoscopy, by improving their detection rate and highlighting the presence of the intestinal dysplastic lesions.
Single total doses of 100 and 200 mg were administered to healthy volunteers undergoing a bowel cleansing preparation and a full colonoscopy to investigate the colonic staining. The pharmacokinetics of methylene blue and the safety after exposure to the tablets were also investigated.
With 200 mg, the best staining, assessed as the sum of acceptable and good staining, was achieved in the ascending colon and rectosigmoid (75% subjects each), the transverse and the descending colon (approximately 63% each). Absence of staining or overstaining were reported for no colonic region of interest in any subject. Similar results were observed in the 100 mg dose group.
Methylene blue blood concentrations reached a peak (Cmax) in a median time (Tmax) of 12 h with 100 mg and 16 h with 200 mg. AUC0-t was 10.7 ± 6.7 μg/mLxh after 100 mg and 25.2 ± 7.4 μg/mLxh after 200 mg. Half-life ranged between 9 and 22 h after the lower dose and between 6 and 26 h after the higher dose. The cumulative urinary excretion was about 28% after 100 mg and about 39% after 200 mg up to 60 h post-dose.
The overall frequency of adverse events after single dose of the test product administered along with a bowel cleansing preparation was 39%, but only one was related to the test product: abnormal transaminases. The most frequent adverse event was a transient polyuria (17%). One serious adverse event (gastrointestinal haemorrhage) led the subject to study discontinuation and hospitalisation and another subject withdrew the study due to one adverse event (haematemesis). Either event was not related to methylene blue.
Background: Filgrastim or methionyl-granulocyte colony-stimulating factor (Met-G-CSF), is a recom... more Background: Filgrastim or methionyl-granulocyte colony-stimulating factor (Met-G-CSF), is a recombinant therapeutic protein widely used to treat severe neutropenia caused by myelosuppressive drugs in patients with nonmyeloid malignancies. In addition to its role in the regulation of granulopoiesis, treatment with G-CSF is considered the standard approach to mobilize CD34 positive (CD34 +) mononuclear cells for reconstituting hemopoietic ability for bone marrow transplantation. An intended biosimilar filgrastim (coded BK0023) was produced in GMP conditions by E.coli fermentation according to an original recombinant process and showed physico-chemical properties and purity profile similar to Neupogen®, a commercial preparation of filgrastim. The aim of the present study was to demonstrate the comparability of BK0023 to Neupogen® in terms of both in vitro biological activities and in vivo toxicology, pharmacokinetics and pharmacodynamics. Methods: Cell proliferation and radioligand binding assays were conducted in NFS-60 cells to compare the biological activity and functional interaction with the G-CSF receptor in vitro, while preclinical in vivo studies, including pharmacokinetics and pharmacodynamics after repeated dose were performed in normal and neutropenic rats. A phase I study was carried out in healthy male volunteers treated by multiple-dose subcutaneous administration of BK0023 and Neupogen® to evaluate their pharmacodynamic effects as well as their pharmacokinetic and safety profile and to demonstrate their pharmacodynamic equivalence and pharmacokinetic bioequivalence.
International Journal of Antimicrobial Agents, 2007
ABSTRACT Objective: PZ-601 (SMP-601) is a novel carbapenem with an antimicrobial spectrum that in... more ABSTRACT Objective: PZ-601 (SMP-601) is a novel carbapenem with an antimicrobial spectrum that includes multidrug-resistant Gram positive (methicillin-resistant Staphylococcus aureus, Enterococcus faecium) and extended-spectrum b-lactamase producing Gram negative organisms. We studied the pharmacokinetics and safety of single ascending doses in otherwise healthy male volunteers. Methods: Fifty-six subjects (42 PZ-601, 14 placebo) were randomised in seven cohorts (6 PZ-601, 2 placebo) to ascending doses of PZ-601: 30, 100, 300, 600, 1,000, 1,500, 2,000mg or placebo by infusion over 30 minutes. Assessments included adverse events, laboratory, ECGs and PZ-601 plasma levels and urinary excretion. Results: Adverse events were infrequently noted in 5/42 PZ-601 and in 1/14 placebo recipients. The most common events were headache (3 PZ-601, 1 placebo) and dyspepsia (1 PZ-601). There were no serious adverse events. There were no laboratory or ECG findings of clinical concern. PZ-601 exposure was linear for the administered doses with a half-life of 1.4 hours at a dose of 1,000mg. A summary of key PZ-601 pharmacokinetic parameters is presented. Conclusion: PZ-601 in single doses up to 2g was generally well-tolerated in normal healthy male subjects. These results suggest the potential for twice daily dosing and support progression to repeat dosing.
Background and objectives
The new filgrastim formulation, BK0023, whose synthesis method is pat... more 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.
Background: The non absorbable antibiotic rifamycin SV newly formulated as modified colonic relea... more Background: The non absorbable antibiotic rifamycin SV newly formulated as modified colonic release MMX® tablets was preliminarily investigated. Methods: In a multi-centre, double-blind, double-dummy, randomised, parallel group study, efficacy and safety of the 200 mg tablets were investigated vs. rifaximin 200 mg tablets in infectious diarrhoea.
Results: 22 rifamycin SV recipients (47.8%) were successes, whilst 24 (52.5%) discontinued. In the reference group 27 (50.9%) were successes, whilst 26 (49.1%) discontinued. The median time to last unformed stool was 67.5 h after rifamycin SV and 65.5 h after rifaximin. Conclusions: The efficacy of the new tablets was not significantly different from that of rifaximin administered 4 times a day for 3 days. The treatments did not differ in rate or frequency of therapeutic success. Isolates of Campylobacter jejuni and lari, Escherichia coli, Anaerobiospirillum, Salmonella enteritidis and Shigella flexneri found at pre-treatment were not retrievable after rifamycin SV.
Ralfinamide, an original Na+ channel blocker developed for the treatment of chronic pain, inhibit... more 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.
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Papers by Andrea Di Stefano
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.
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.
Single total doses of 100 and 200 mg were administered to healthy volunteers undergoing a bowel cleansing preparation and a full colonoscopy to investigate the colonic staining. The pharmacokinetics of methylene blue and the safety after exposure to the tablets were also investigated.
With 200 mg, the best staining, assessed as the sum of acceptable and good staining, was achieved in the ascending colon and rectosigmoid (75% subjects each), the transverse and the descending colon (approximately 63% each). Absence of staining or overstaining were reported for no colonic region of interest in any subject. Similar results were observed in the 100 mg dose group.
Methylene blue blood concentrations reached a peak (Cmax) in a median time (Tmax) of 12 h with 100 mg and 16 h with 200 mg. AUC0-t was 10.7 ± 6.7 μg/mLxh after 100 mg and 25.2 ± 7.4 μg/mLxh after 200 mg. Half-life ranged between 9 and 22 h after the lower dose and between 6 and 26 h after the higher dose. The cumulative urinary excretion was about 28% after 100 mg and about 39% after 200 mg up to 60 h post-dose.
The overall frequency of adverse events after single dose of the test product administered along with a bowel cleansing preparation was 39%, but only one was related to the test product: abnormal transaminases. The most frequent adverse event was a transient polyuria (17%). One serious adverse event (gastrointestinal haemorrhage) led the subject to study discontinuation and hospitalisation and another subject withdrew the study due to one adverse event (haematemesis). Either event was not related to methylene blue.
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.
Results: 22 rifamycin SV recipients (47.8%) were successes, whilst 24 (52.5%) discontinued. In the reference group 27 (50.9%) were successes, whilst 26 (49.1%) discontinued. The median time to last unformed stool was 67.5 h after rifamycin SV and 65.5 h after rifaximin. Conclusions: The efficacy of the new tablets was not significantly different from that of rifaximin administered 4 times a day for 3 days. The treatments did not differ in rate or frequency of therapeutic success. Isolates of Campylobacter jejuni and lari, Escherichia coli, Anaerobiospirillum, Salmonella enteritidis and Shigella flexneri found at pre-treatment were not retrievable after rifamycin SV.
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.
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.
Single total doses of 100 and 200 mg were administered to healthy volunteers undergoing a bowel cleansing preparation and a full colonoscopy to investigate the colonic staining. The pharmacokinetics of methylene blue and the safety after exposure to the tablets were also investigated.
With 200 mg, the best staining, assessed as the sum of acceptable and good staining, was achieved in the ascending colon and rectosigmoid (75% subjects each), the transverse and the descending colon (approximately 63% each). Absence of staining or overstaining were reported for no colonic region of interest in any subject. Similar results were observed in the 100 mg dose group.
Methylene blue blood concentrations reached a peak (Cmax) in a median time (Tmax) of 12 h with 100 mg and 16 h with 200 mg. AUC0-t was 10.7 ± 6.7 μg/mLxh after 100 mg and 25.2 ± 7.4 μg/mLxh after 200 mg. Half-life ranged between 9 and 22 h after the lower dose and between 6 and 26 h after the higher dose. The cumulative urinary excretion was about 28% after 100 mg and about 39% after 200 mg up to 60 h post-dose.
The overall frequency of adverse events after single dose of the test product administered along with a bowel cleansing preparation was 39%, but only one was related to the test product: abnormal transaminases. The most frequent adverse event was a transient polyuria (17%). One serious adverse event (gastrointestinal haemorrhage) led the subject to study discontinuation and hospitalisation and another subject withdrew the study due to one adverse event (haematemesis). Either event was not related to methylene blue.
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.
Results: 22 rifamycin SV recipients (47.8%) were successes, whilst 24 (52.5%) discontinued. In the reference group 27 (50.9%) were successes, whilst 26 (49.1%) discontinued. The median time to last unformed stool was 67.5 h after rifamycin SV and 65.5 h after rifaximin. Conclusions: The efficacy of the new tablets was not significantly different from that of rifaximin administered 4 times a day for 3 days. The treatments did not differ in rate or frequency of therapeutic success. Isolates of Campylobacter jejuni and lari, Escherichia coli, Anaerobiospirillum, Salmonella enteritidis and Shigella flexneri found at pre-treatment were not retrievable after rifamycin SV.