A multiple-dose double-blind randomized study to evaluate the safety, pharmacokinetics, pharmacodynamics and analgesic efficacy of the TRPV1 antagonist JNJ-39439335 (mavatrep)

2018 ◽  
Vol 18 (2) ◽  
pp. 151-164 ◽  
Author(s):  
Prasarn Manitpisitkul ◽  
Christopher M. Flores ◽  
John A. Moyer ◽  
Gary Romano ◽  
Kevin Shalayda ◽  
...  
Keyword(s):  
Adverse Events ◽  
Knee Osteoarthritis ◽  
Multiple Dose ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Analgesic Efficacy ◽  
Heat Pain ◽  
Double Blind ◽  
Cold Pain ◽  
Thermal Burns

Abstract Background and aims: This double-blind (DB), randomized, placebo-controlled, sequential-group, multiple-ascending dose, phase 1 study evaluated safety, pharmacokinetics and pharmacodynamics of JNJ-39439335 in healthy men (part 1), and in participants with knee osteoarthritis (part 2). Methods: Both parts 1 and 2 consisted of screening (upto 21 days), 21-day DB treatment phase [eight participants/group: JNJ-39439335 (part 1: 2–50 mg; part 2: 10–50 mg): n=6; placebo: n=2] and follow-up (total study duration ~10 weeks). Results: Plasma concentrations and systemic exposure of JNJ-39439335 increased in slightly higher than dose-proportional fashion (steady-state reached by day 14). Renal excretion of JNJ-39439335 was negligible. Marked dose-related increases in pharmacodynamic heat pain assessments were observed in JNJ-39439335-treated participants, which persisted throughout the treatment with no signs of tolerance with repeated dosing. No effect on pharmacodynamic cold pain or mechanical pain assessments were seen. Effects on pharmacodynamic capsaicin-induced flare assessments in JNJ-39439335-treated participants versus placebo were consistent with effects observed with single-dose, and did not demonstrate tolerance with multiple dosing. In participants with knee osteoarthritis, significant improvements versus placebo were observed in a stair-climbing-induced pain model. All JNJ-39439335-treated participants reported ≥1 treatment-emergent adverse events (TEAE); most common (≥50% incidence) TEAEs in part 1 were feeling hot (79%), thermohypoesthesia (71%), paresthesia (58%) and feeling cold (50%), and in part 2, were minor thermal burns (50%). Conclusions: JNJ-39439335 (doses 2–50 mg) was well-tolerated, and associated with acceptable multiple-dose pharmacokinetic profile. JNJ-39439335 demonstrated sustained pharmacodynamic effects (heat pain perception, heat pain latency, capsaicin-induced flare), and an efficacy signal in participants with osteoarthritis pain. Implications: Given the efficacy signal observed and the unique safety profile, larger phase 2 studies are needed to better understand the potential of JNJ-39439335 in the treatment of chronic pain. Analgesic efficacy of lower doses administered over a longer period of time and improved patient counseling techniques to reduce the minor thermal burns can be explored to minimize the adverse events.

Tonabersat, a Gap-Junction Modulator: Efficacy and Safety in Two Randomized, Placebo-Controlled, Dose-Ranging Studies of Acute Migraineceph

Cephalalgia ◽  
2009 ◽  
Vol 29 (2_suppl) ◽  
pp. 17-27 ◽  
Author(s):  
SD Silberstein ◽  
J Schoenen ◽  
H Göbel ◽  
HC Diener ◽  
AH Elkind ◽  
...  
Keyword(s):  
Adverse Events ◽  
North American ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Plasma Concentrations ◽  
International Study ◽  
Maximum Plasma ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Dose Ranging

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.

scholarly journals Lack of Analgesia by Oral Standardized Cannabis Extract on Acute Inflammatory Pain and Hyperalgesia in Volunteers

2008 ◽  
Vol 109 (1) ◽  
pp. 101-110 ◽  
Author(s):  
Birgit Kraft ◽  
Nathalie A. Frickey ◽  
Rainer M. Kaufmann ◽  
Marcus Reif ◽  
Richard Frey ◽  
...  
Keyword(s):  
Inflammatory Pain ◽  
Animal Studies ◽  
Analgesic Efficacy ◽  
Spontaneous Pain ◽  
Heat Pain ◽  
Secondary Hyperalgesia ◽  
Double Blind ◽  
Pain Thresholds ◽  
Healthy Female ◽  
Cannabis Extract

Background Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with Delta-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia. Methods The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing Delta-tetrahydrocannabinol-standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain. Results Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered. Conclusion To conclude, no analgesic or antihyperalgesic activity of cannabis extract was found in the experiments. Moreover, the results even point to the development of a hyperalgesic state under cannabinoids. Together with previous data, the current results suggest that cannabinoids are not effective analgesics for the treatment of acute nociceptive pain in humans.

Safety and Efficacy of the Cyclooxygenase-2 Inhibitors Parecoxib and Valdecoxib after Noncardiac Surgery

2006 ◽  
Vol 104 (3) ◽  
pp. 518-526 ◽  
Author(s):  
Nancy A. Nussmeier ◽  
Andrew A. Whelton ◽  
Mark T. Brown ◽  
Girish P. Joshi ◽  
Richard M. Langford ◽  
...  
Keyword(s):  
Adverse Events ◽  
Artery Bypass ◽  
Opioid Analgesic ◽  
Analgesic Efficacy ◽  
Noncardiac Surgery ◽  
Double Blind ◽  
Related Symptom ◽  
Pain Ratings ◽  
Gastroduodenal Ulceration

Background Valdecoxib and its intravenous prodrug parecoxib are reported to increase thromboembolic risk after coronary artery bypass grafting. The authors conducted a randomized trial to examine their safety and analgesic efficacy in patients recovering from major noncardiac surgical procedures. Methods The trial was randomized and double-blind, with 10 days of treatment and 30 days of follow-up. Patients (n = 1,062) received either parenteral parecoxib for 3 days and oral valdecoxib for the rest of the treatment period or placebo medications throughout. The frequency of predefined adjudicated postrandomization adverse events, including cardiovascular thromboembolism, renal dysfunction, gastroduodenal ulceration, and wound-healing complications, was assessed in each group. Secondary efficacy endpoints included patients' pain ratings, opioid analgesic consumption (recorded as morphine equivalents), and reports of opioid-related adverse effects. Results Predefined adjudicated adverse events had similar frequencies among patients who received parecoxib and valdecoxib (2.7%) and placebo patients (3.2%) (P = 0.58), including cardiovascular thromboembolic events (1.0% in each group; P = 1.0). Placebo patients consumed more morphine equivalents (66.2 +/- 92.4 mg) than did patients receiving parecoxib and valdecoxib (43.2 +/- 65.7 mg) (P < 0.001). Placebo patients had higher mean pain ratings on each of study days 2-10 (P < 0.01) and reported more opioid-related symptom distress on days 2-6 (P < 0.01). Conclusions Parecoxib and valdecoxib are useful adjuncts to opioids for the treatment of postoperative pain in noncardiac surgical patients. Further study will be required to determine the safety profile of parecoxib and valdecoxib administered to patients with known atherosclerotic disease after noncardiac surgery.

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.

Combined nitrous oxide 70% with intranasal fentanyl for procedural analgosedation in children: a prospective, randomised, double-blind, placebo-controlled trial

2019 ◽  
Vol 36 (3) ◽  
pp. 142-147 ◽  
Author(s):  
Michelle Seiler ◽  
Georg Staubli ◽  
Markus A. Landolt
Keyword(s):  
Nitrous Oxide ◽  
Adverse Events ◽  
Scale Score ◽  
Controlled Trial ◽  
Analgesic Efficacy ◽  
Pain Scale ◽  
Double Blind Study ◽  
Double Blind ◽  
Significant Group ◽  
Registration Number

ObjectiveNitrous oxide 70% (N2O 70%) is an excellent medication for procedural analgosedation (PAS), yet the limit of its analgesic power remains uncertain; therefore, a combination with intranasal fentanyl (INF) was suggested. However, this combination seems to result in a higher rate of vomiting and deeper sedation. This study aimed at assessing the analgesic efficacy, sedation depth and rate of adverse events of PAS with N2O 70% with and without INF.MethodsPatients aged 2–16 years who qualified for PAS with N2O 70% were randomly assigned to receive either INF or placebo prior to N2O inhalation in this randomised, double-blind study, which was performed in a tertiary children’s hospital ED between September 2015 and October 2017. Behaviour during the procedure was evaluated using the Face, Leg, Activity, Cry and Consolability (FLACC) scale and the Modified Behavioural Pain Scale (MBPS); analgesic efficacy was assessed with a self-reported pain scale. Sedation depth using the validated University of Michigan Sedation Scale and adverse events in the ED and during the following 12 hours were documented.ResultsA total of 402 patients were included; 3 did not tolerate N2O and therefore had to be excluded. Overall, 399 patients were analysed, of whom 201 (50.4%) received INF. No significant group differences with regard to FLACC scale score, self-reported pain, MBPS score and sedation depth were found. In addition, the two groups did not differ with regard to all types of adverse events.ConclusionCombining N2O 70% with INF resulted in no differences with regard to FLACC scale score, self-reported pain, MBPS score, patient and parental satisfaction rate, sedation depth, and adverse events.Trial registration numberNCT02533908

Comparative Analgesic and Mental Effects of Increasing Plasma Concentrations of Dexmedetomidine and Alfentanil in Humans

2004 ◽  
Vol 101 (3) ◽  
pp. 744-752 ◽  
Author(s):  
Martin S. Angst ◽  
Bhamini Ramaswamy ◽  
M Frances Davies ◽  
Mervyn Maze
Keyword(s):  
Plasma Concentration ◽  
Receptor Agonist ◽  
Plasma Concentrations ◽  
Analgesic Efficacy ◽  
Intrathecal Administration ◽  
Experimental Models ◽  
Sedation Score ◽  
Systemic Administration ◽  
Double Blind ◽  
Cognitive Speed

Background In animals, systemic and intrathecal administration of the alpha2 -adrenergic receptor agonist dexmedetomidine results in robust antinociceptive effects in models of heat pain. In humans, systemically administered dexmedetomidine is approved for sedating patients in the intensive care unit. However, whether systemic administration of dexmedetomidine in humans produces significant analgesia at doses causing sedation but not unconsciousness remains controversial. Methods This study in human volunteers used a placebo-controlled, double-blind, and randomized design to examine whether dexmedetomidine at doses causing mild to severe sedation produces analgesia in experimental models of heat and electrical pain. Results were compared to the effects of the mu-opioid receptor agonist alfentanil. A computer-controlled infusion provided four median step-up plasma concentrations of dexmedetomidine (0.09, 0.24, 0.54, and 1.23 ng/ml) and alfentanil (13.4, 33.8, 67.8, and 126.1 ng/ml). Results Sedative and cognitive effects of dexmedetomidine were dose-dependent, resulting in a median sedation score of 95 of 100 and slowing of cognitive speed (reaction time, trail-making test) by a factor of about two at the highest plasma concentration. Dexmedetomidine did not attenuate heat or electrical pain. Alfentanil caused severe sedation (median sedation score 88 of 100) and slowed cognitive speed by a factor of approximately 1.4 at the highest plasma concentration. Alfentanil attenuated heat and electrical pain dose dependently. Conclusion This study documents that systemic dexmedetomidine lacks analgesic efficacy for heat and electrical pain at doses causing mild to severe sedation. These results provide further evidence suggesting that systemic administration of dexmedetomidine lacks broad analgesic activity in models of acute pain at doses not rendering humans unconscious.

scholarly journals A phase 2 study of the inhaled pan-JAK inhibitor TD-0903 in severe COVID-19: Part 1

2021 ◽  
Author(s):  
Dave Singh ◽  
Maxim Bogus ◽  
Valentyn Moskalenko ◽  
Robert Lord ◽  
Edmund J. Moran ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Hospitalized Patients ◽  
Janus Kinase ◽  
The Novel ◽  
Jak Inhibitor ◽  
Phase 2 ◽  
Double Blind ◽  
Phase 2 Trial ◽  
Hospitalised Patients

AbstractBackgroundLung-targeted anti-inflammatory therapy could potentially improve outcomes in patients with COVID-19. The novel inhaled pan-Janus kinase (JAK) inhibitor TD-0903 was designed to optimise delivery to the lungs while limiting systemic exposure. Here, we report results from the completed Part 1 of a 2-part phase 2 trial (NCT04402866) in hospitalised patients with severe COVID-19.MethodsPart 1 explored 3 doses of TD-0903 (1, 3, and 10 mg once-daily for 7 days) and placebo in a randomised, double-blind, ascending-dose study. Each dose cohort comprised 8 hospitalized patients (6:2 TD-0903:placebo) with PCR-confirmed COVID-19 requiring supplemental oxygen and receiving background standard-of-care therapy. Key objectives included safety and tolerability, pharmacokinetics, and oxygen saturation/fraction of inspired oxygen ratio; clinical outcomes were also explored. Data were summarised as descriptive statistics.ResultsTwenty-five patients were randomised to receive TD-0903 1 mg (n = 6), 3 mg (n = 7), 10 mg (n = 6), or placebo (n = 6). Almost all patients (92%) received background dexamethasone; 3 (12%) received remdesivir. TD-0903 was generally well tolerated with no drug-related serious adverse events. Low plasma concentrations of TD-0903 were observed at all doses. Clinically favourable numerical trends in patients receiving TD-0903 vs placebo included improved 8-point clinical status, shortened hospitalisation, improved oxygenation, and fewer deaths.ConclusionsIn Part 1 of this phase 2 trial, the novel inhaled JAK inhibitor TD-0903 showed potential for treatment of patients with severe COVID-19. TD-0903 3 mg is being evaluated in Part 2 of the randomised, double-blind, parallel-group trial in 198 hospitalized patients with COVID-19.

scholarly journals A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Ascending Dose and Food Effect Study to Evaluate the Tolerance, Pharmacokinetics of Jaktinib, a New Selective Janus Kinase Inhibitor in Healthy Chinese Volunteers

2020 ◽  
Vol 11 ◽  
Author(s):  
Jingrui Liu ◽  
Binhua Lv ◽  
Hewen Yin ◽  
Xiaoxue Zhu ◽  
Haijing Wei ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Phase I ◽  
Multiple Dose ◽  
Food Effect ◽  
Effect Study ◽  
Janus Kinase ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Healthy Chinese

Background: Jaktinib is a novel selective janus kinase 1/2 inhibitor. The phase I first-in-human study evaluated the tolerance and pharmacokinetics of jaktinib in healthy Chinese subjects.Methods: A randomized, double-blind, placebo-controlled study were designed. A total of 126 healthy subjects were enrolled into the single ascending dose, multiple ascending dose and food effect study. Safety endpoints included adverse events, abnormal vital signs, 12-lead ECGs, abdominal ultrasound, chest x-ray, physical examination and clinical laboratory tests. Blood, urine and feces samples were collected at predetermined time points for pharmacokinetic analysis of jaktinib, the metabolites ZG0244 and ZG0245, which are formed by oxidation or hydrolysis metabolic pathway, respectively.Results: Jaktinib was absorbed with a median time to peak plasma concentration of 1.25–3.5 h and was eliminated with a half-life of 2.952–9.040 h. Linear pharmacokinetic characteristic was presented over the dose range from 25 to 400 mg. No obvious accumulation was observed after multiple doses for 10 days. Administration after a high-fat breakfast significantly increased the absorption of jaktinib. The accumulated fraction of jaktinib and the determined metabolites excreted in urine and feces was 19.478%. Jaktinib was well tolerated in all single dose cohorts. In multiple dose cohorts, 200 mg q24 h method was evaluated as maximally tolerated dose. Neutropenia, diarrhea, dizziness and headache were the most frequently reported treatment related adverse events. No deaths, serious or Grade ≥4 adverse events was developed.Conclusion: Jaktinib was well tolerated when single dose ranging from 25 to 400 mg and multiple dose up to 200 mg q24 h. The safety and pharmacokinetic characteristics support the next trial in myelofibrosis patients.

scholarly journals Single- and Multiple-Dose Study To Determine the Safety, Tolerability, Pharmacokinetics, and Food Effect of Oral MRX-I versus Linezolid in Healthy Adult Subjects

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Paul B. Eckburg ◽  
Yigong Ge ◽  
Barry Hafkin
Keyword(s):  
Adverse Events ◽  
Multiple Dose ◽  
Bacterial Infections ◽  
Food Effect ◽  
Phase 1 ◽  
Drug Discontinuation ◽  
The Novel ◽  
Double Blind ◽  
Dose Study ◽  
To Receive

ABSTRACT A multipart phase 1 study was conducted to determine the safety, tolerability, pharmacokinetics, and food effect of the novel oral oxazolidinone, MRX-I, in healthy adults, as well as the tolerability of longer-term exposure of both oral MRX-I and linezolid. Thirty subjects in part 1 received single ascending doses of MRX-I or placebo under fasting or fed condition in a double-blind crossover design. Twelve subjects in part 2 received MRX-I at 800 mg every 12 h (q12h) for 14 days in a double-blind, placebo-controlled design. In part 3, 24 subjects were randomized to receive 28 days of MRX-I at 800 mg q12h or oral linezolid at 600 mg q12h for 28 days in a double-blind, double-dummy design. Oral MRX-I was associated with a greater bioavailability and exposure when administered with food, and minimal accumulation of MRX-I occurred after multiple-dose administration. Oral MRX-I was well tolerated at single doses of up to 1,200 and 800 mg q12h for up to 28 days; all adverse events were mild to moderate in severity, and there was no drug discontinuation due to adverse events. These data support further clinical development of oral MRX-I in the treatment of resistant Gram-positive bacterial infections.

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