Hormonal effects of CQP 201—403, a new dopamine agonist

1988 ◽  
Vol 119 (3) ◽  
pp. 452-458 ◽  
Author(s):  
R. C. Gaillard ◽  
J. Brownell
Keyword(s):  
Oral Dose ◽  
Dopamine Agonist ◽  
Single Oral Dose ◽  
Dose Range ◽  
Placebo Control ◽  
Double Blind ◽  
Duration Of Action ◽  
Suppression Effect ◽  
Hormonal Effects ◽  
Plasma Prl

Abstract. CQP 201—403 is a propylergoline derivative with strong dopamine stimulant properties in animals models. It was developed in order to meet the need for a dopamine agonist compound which would offer longer action and improved tolerability. In this study, we tested CQP 201—403 in healthy male volunteers in order to assess its PRL suppression action and other hormonal effects as well as its duration of action and tolerability. Twenty-one volunteers participated in a dose-range study conducted according to a double-blind cross-over design with placebo control. The PRL suppression effect of single oral doses ranging from 0.05 mg to 0.035 mg were investigated. The duration of action of CQP 201—403 was tested in 6 other volunteers receiving a single oral dose of 0.025 mg or placebo. Blood was sampled over 48 h for PRL and GH measurements. An endocrine profile was performed in 6 volunteers receiving either 0.025 mg CQP 201—403 as a single oral dose or placebo. Blood was sampled over 8 h for measuring plasma PRL, GH, LH, FSH, TSH and cortisol. The results show strong dose-dependent PRL suppression (P< 0.001) begining 2 h after ingestion. PRL suppression lasted for more than 24 h and the normal sleep PRL surges were abolished. GH was transiently stimulated during the first few hours; the GH sleep profile was normal. All other hormones were not affected by the administration of CQP 201—403. Tolerability was good and no drug attributable changes in safety measures occurred. This study demonstrated that CQP 201—403 is a potent and long-acting PRL suppression compound in healthy volunteers. Strong PRL suppression and optimal tolerability were achieved with the 0.025 mg dose. This new dopamine agonist promises to be a therapeutically useful dopaminomimetic compound which could probably be prescribed at a once-daily dosage.

Thorough QT Study to Evaluate the Effect of Zoliflodacin, a Novel Therapeutic for Gonorrhea, on Cardiac Repolarization in Healthy Adults

2021 ◽  
Author(s):  
Lori M. Newman ◽  
Martin Kankam ◽  
Aya Nakamura ◽  
Tom Conrad ◽  
John Mueller ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Cardiac Repolarization ◽  
Cardiac Safety ◽  
Double Blind ◽  
Thorough Qt Study ◽  
Regulatory Guidelines ◽  
Clinically Significant ◽  
The One ◽  
Global Threat

Zoliflodacin is a novel spiropyrimidinetrione antibiotic being developed as single oral dose treatment to address the growing global threat of Neisseria gonorrhoeae . To evaluate the cardiac safety of zoliflodacin, a thorough QT/QTc (TQT) study was performed in healthy subjects. In this randomized, double-blind, placebo-controlled, 4-period crossover study, 72 subjects in a fasted state received a single dose of zoliflodacin 2 g (therapeutic), zoliflodacin 4 g (supratherapeutic), placebo, and moxifloxacin 400 mg as a positive comparator. Cardiac repolarization was measured by duration of the corrected QT interval by Fridericia’s formula (QTcF). At each time point up to 24 hours after zoliflodacin administration, the upper limit of the one-sided 95% confidence interval (CI) for the placebo-corrected change from the pre-dose baseline in QTcF (ΔΔQTcF) was less than 10 ms, indicating an absence of a clinically meaningful increase in QT prolongation. The lower limit of the one-sided multiplicity-adjusted 95% CI of ΔΔQTcF for moxifloxacin was longer than 5 ms at four time points from 1-4 hours after dosing, demonstrating adequate sensitivity of the QTc measurement. There were no clinically significant effects on heart rate, PR and QRS intervals, ECG morphology, or laboratory values. Treatment-emergent adverse events (AEs) were mild or moderate in severity and transient. This was a negative TQT study according to regulatory guidelines (E14) and confirms that a single oral dose of zoliflodacin is safe and well-tolerated. These findings suggest zoliflodacin is not proarrhythmic and contribute to the favorable assessment of cardiac safety for a single oral dose of zoliflodacin.

Analgesic Efficacy and Safety Comparison of Ketorolac Tromethamine and Doleron for the Alleviation of Orthopaedic Post-Operative Pain

1989 ◽  
Vol 17 (4) ◽  
pp. 324-332 ◽  
Author(s):  
S. Johansson ◽  
G. Josefsson ◽  
J. Malstam ◽  
A. Lindstrand ◽  
A. Stenstroem
Keyword(s):  
Treatment Group ◽  
Adverse Events ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Analgesic Efficacy ◽  
Ketorolac Tromethamine ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Post Operative Pain ◽  
Parallel Group

The analgesic efficacy and safety of ketorolac tromethamine (ketorolac), a potent analgesic with anti-inflammatory and antipyretic activities, were evaluated and compared with Doleron, a combination analgesic, in 115 patients with moderate to severe orthopaedic post-operative pain. This was a randomized, double-blind (double-dummy), parallel-group comparison of a single oral dose of one capsule of 10 mg ketorolac with a single oral dose of two Doleron tablets (each tablet contained 150 mg dextropropoxyphene napsylate, 350 mg aspirin and 150 mg phenazone). During the 6 h following treatment, 80% of ketorolac treated patients and 82% of Doleron treated patients experienced adequate pain relief. There were no statistically significant differences in the overall analgesic efficacy between the treatment groups. Three patients (one on ketorolac, two on Doleron) withdrew because of adverse events (vomiting). Nausea (two patients in each treatment group), vertigo (none on ketorolac, three on Doleron) and sore throat (none on ketorolac, two on Doleron) were the only drug-related adverse events reported by more than one person in a treatment group during the trial. A total of 82% of patients given ketorolac and 76% given Doleron experienced no adverse events. A single oral dose of 10 mg ketorolac was shown to be as effective and safe as two Doleron tablets in the treatment of moderate to severe orthopaedic post-operative pain.

Netupitant/palonosetron (NEPA) for prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in multiple cycles of chemotherapy.

2015 ◽  
Vol 33 (29_suppl) ◽  
pp. 211-211
Author(s):  
Lee Steven Schwartzberg ◽  
Richard J. Gralla ◽  
Kimia Kashef ◽  
Hope Rugo
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Complete Response ◽  
Control Group ◽  
Double Blind ◽  
Report Data ◽  
Multiple Cycles ◽  
To Receive ◽  
Delayed Phase ◽  
Significant Nausea

211 Background: Prevention of CINV in the delayed phase (24-120 h post-chemotherapy) and over multiple cycles of chemotherapy remains a challenge. NEPA, a fixed combination of the NK1 receptor antagonist (RA) netupitant (300 mg) and the 5-HT3 RA palonosetron (PALO; 0.5 mg), has demonstrated efficacy in multiple studies, in both acute and delayed phases, during the first cycle of moderately or highly emetogenic chemotherapy (MEC and HEC, respectively) regimens. Two clinical trials evaluated NEPA over multiple cycles of chemotherapy. We report data for the delayed phase for each cycle. Methods: Both studies were Phase 3, double-blind, active-controlled studies. In study 1 (MEC), patients were randomized 1:1 to receive a single oral dose of NEPA (n = 724) or PALO 0.5 mg (n = 725) on Day 1; following cycle 1, patients could participate in a multi-cycle extension phase. In study 2 (MEC or HEC), patients were randomized 3:1 to receive a single oral dose of NEPA on Day 1 (n = 309) or oral aprepitant (APR) 125 mg plus oral PALO 0.5 mg on Day 1, then APR 80 mg/d on days 2 and 3 of each cycle (n = 103). In both studies, all patients also received dexamethasone. Efficacy endpoints included complete response (CR; no emesis, no rescue medication) and no significant nausea. Results: In both studies, CR rates were consistently numerically higher with NEPA (Study 1 range: 77%-89%; Study 2 range: 83%-93%) than with PALO (Study 1; range: 69%-83%) or APR/PALO (Study 2; range: 78%-88%) in each cycle up to cycle 6 (Table). In both studies, rates of no significant nausea in the NEPA group were similar to or higher than in the control group. NEPA was well tolerated in both studies; treatment-related adverse events included constipation and headache. Conclusions: These studies demonstrate sustained efficacy of NEPA (administered as a single dose on Day 1) across multiple cycles of MEC or HEC for prevention of CINV in the delayed phase. Clinical trial information: 2009-016775-30; 2010-023297-39. [Table: see text]

scholarly journals Pharmacokinetics of Ferroquine, a Novel 4-Aminoquinoline, in Asymptomatic Carriers of Plasmodium falciparum Infections

2012 ◽  
Vol 56 (6) ◽  
pp. 3165-3173 ◽  
Author(s):  
Christian Supan ◽  
Ghyslain Mombo-Ngoma ◽  
Matthias P. Dal-Bianco ◽  
Carmen L. Ospina Salazar ◽  
Saadou Issifou ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Oral Dose ◽  
Dose Range ◽  
Young Male ◽  
Double Blind ◽  
Time Curve ◽  
Blood Concentrations ◽  
Content Type ◽  
Dose Linearity ◽  
Dose Study

ABSTRACTFerroquine (SSR97193), a ferrocene-quinoline conjugate, is a promising novel antimalarial currently undergoing clinical evaluation. This study characterizes its pharmacokinetic properties. Young male African volunteers with asymptomaticPlasmodium falciparuminfection were administered a single oral dose (n= 40) or a repeated oral dose (n= 26) given over 3 days of ferroquine in two dose-escalation, double-blind, randomized, placebo-controlled clinical trials. In addition, a food interaction study was performed in a subsample of participants (n= 16). The studies were carried out in Lambaréné, Gabon. After single-dose administration of ferroquine, dose linearity was demonstrated in a dose range of 400 to 1,200 mg for maximum mean blood concentrations ([Cmax] 82 to 270 ng/ml) and in a dose range of 400 to 1,600 mg for overall exposure to ferroquine (area under the concentration-time curve [AUC], 13,100 to 49,200 ng · h/ml). Overall mean estimate for blood apparent terminal half-life of ferroquine was 16 days and 31 days for its active and major metabolite desmethylferroquine (SSR97213). In the 3-day repeated-dose study,Cmaxand overall cumulated exposure to ferroquine (AUCcum) increased in proportion with the dose from day 1 to day 3 between 400 and 800 mg. No major food effect on ferroquine pharmacokinetics was observed after single administration of 100 mg of ferroquine except for a slight delay of time to maximum blood concentration (tmax) by approximately 3 h. The pharmacokinetics of ferroquine and its active main metabolite are characterized by sustained levels in blood, and the properties of ferroquine as a partner drug in antimalarial combination therapy should be evaluated.

scholarly journals Pharmacodynamic Evaluation of Dosing, Bacterial Kill, and Resistance Suppression for Zoliflodacin Against Neisseria gonorrhoeae in a Dynamic Hollow Fiber Infection Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Susanne Jacobsson ◽  
Daniel Golparian ◽  
Joakim Oxelbark ◽  
Emilie Alirol ◽  
Francois Franceschi ◽  
...  
Keyword(s):  
Single Dose ◽  
Oral Dose ◽  
Neisseria Gonorrhoeae ◽  
Single Oral Dose ◽  
Hollow Fiber ◽  
Dose Range ◽  
World Health ◽  
Dose Fractionation ◽  
Infection Model ◽  
Pharmacokinetic Data

Antimicrobial resistance in Neisseria gonorrhoeae is threatening the treatment and control of gonorrhea globally, and new treatment options are imperative. Utilizing our dynamic in vitro hollow fiber infection model (HFIM), we examined the pharmacodynamics of the first-in-class spiropyrimidinetrione (DNA gyrase B inhibitors), zoliflodacin, against the N. gonorrhoeae reference strains World Health Organization F (susceptible to all relevant antimicrobials) and WHO X (extensively drug resistant, including resistance to ceftriaxone) over 7 days. Dose-range experiments with both strains, simulating zoliflodacin single oral dose regimens of 0.5–8 g, and dose-fractionation experiments with WHO X, simulating zoliflodacin oral dose therapy with 1–4 g administered as q12 h and q8 h for 24 h, were performed. A kill-rate constant that reflected a rapid bacterial kill during the first 6.5 h for both strains and all zoliflodacin doses was identified. In the dose-range experiments, the zoliflodacin 2–8 g single-dose treatments successfully eradicated both WHO strains, and resistance to zoliflodacin was not observed. However, zoliflodacin as a single 0.5 g dose failed to eradicate both WHO strains, and a 1 g single dose failed to eradicate WHO X in one of two experiments. The zoliflodacin 1 g/day regimen also failed to eradicate WHO X when administered as two and three divided doses given at q12 h and q8 h in the dose-fractionation studies, respectively. All failed regimens selected for zoliflodacin-resistant mutants. In conclusion, these data demonstrate that zoliflodacin should be administered at &gt;2 g as a single oral dose to provide effective killing and resistance suppression of N. gonorrhoeae. Future studies providing pharmacokinetic data for zoliflodacin (and other gonorrhea therapeutic antimicrobials) in urogenital and extragenital infection sites, particularly in the pharynx, and evaluation of gonococcal strains with different gyrB mutations would be important.

Sign in / Sign up

Export Citation Format

Share Document