SHPL-49 is an innovative glycoside derivative that is synthesized by structural modifications of salidroside，demonstrating therapeutic effects on animal models of ischemia in pre-clinical ...experiments. A phase I, single-center, randomized, double-blind, placebo-controlled, single and multiple dose administration study of SHPL-49 was conducted in healthy Chinese volunteers. In single-ascending-dose (SAD) study, 32 subjects randomized 6:2 to receive SHPL-49 (30mg, 75mg, 150mg, 300mg) or placebo with 30minutes infusion. In multiple-ascending-dose (MAD) study, subjects were randomized 6:2 to receive SHPL-49 (75mg, 150mg, 300mg) or placebo with 30minutes infusion every 8h for 7 days. Safety evaluations were conducted throughout the studies. Plasma and urine concentrations of SHPL-49 were detected and its metabolites were identified. Pharmacokinetic parameters were calculated using noncompartmental methods. SHPL-49 was generally safe and well-tolerated at single ascending doses (30 to 300mg) and multiple ascending doses (75 to 300mg). All adverse events were mild and resolved without any intervention. No serious adverse events were reported. In the SAD study, SHPL-49 exhibited dose-proportional plasma pharmacokinetics, with peak plasma concentration (Cmax) ranging from 673.83 to 6275.00ng/mL, area under the plasma concentration-time curve (AUC0–t) ranging from 338.57 to 3732.67h·ng/mL, and elimination half-life (t1/2) ranging from 0.49 to 0.67h. In the MAD, the exposure was also dose-proportional and there was no significant accumulation following multiple dosing. Four metabolites were identified in urine and plasma. SHPL-49 shows a favorable pharmacokinetic, safety, and tolerability profile in healthy Chinese volunteers following a single- and multiple-ascending- dose administration in this study. For future therapeutic investigations, it is recommended to administer SHPL-49 intravenously at 8-hour intervals with a dosage range of 150-300mg.
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•This is the first-in-human study to assess the pharmacokinetics of SHPL-49.•SHPL-49 shows a favorable pharmacokinetic, safety, and tolerability in human.•The metabolic characteristics of SHPL-49 in human were analyzed for the first time.•A dose of 150-300mg thrice daily is recommended for the phase II clinical trial.
Due to the widespread use of non-steroidal anti-inflammatory drugs (NSAIDs), the incidence of NSAID-associated adverse events has increased exponentially over the past decades. Ketoprofen (ketoprofen ...acid, KA) is a widely used NSAID and, like with other NSAIDs, its use can be associated with adverse effects that especially involve the gastrointestinal tract and the kidney. The salification of KA with L-lysine has led to the synthesis of ketoprofen lysine salt (KLS), which is characterized by higher solubility and a more rapid gastrointestinal absorption compared to KA. Previous studies have reported that KLS has also an increased gastric tolerance in vitro, and this is due to the inhibition of lipid peroxidation and reactive oxygen species scavenging effects of L-lysine. Here, we report in vivo tolerability/toxicity studies that were conducted prior seeking KLS marketing authorization, in which we compared KLS and KA safety profile, focusing in particular on the evaluation of the gastrointestinal and renal tolerability of the drugs administered orally to dogs. Our results demonstrate that KLS has an increased in vivo gastrointestinal tolerability compared to KA and show, for the first time, that KLS has also increased in vivo renal tolerability compared to KA, thus supporting the concept that L-lysine may counteract NSAID-induced oxidative stress-mediated gastrointestinal and renal injury.
•Ketoprofen L-lysine salt (KLS) has an increased in vivo gastrointestinal tolerability compared to ketoprofen acid (KA).•KLS has also increased in vivo renal tolerability compared to KA.•L-lysine may counteract gastrointestinal and renal non-steroidal anti-inflammatory drug (NSAID)-induced oxidative stress.
Single-dose intravenous (IV) injection of ketamine has shown rapid but transient antidepressant effects. The strategy of repeated-dose ketamine infusions to maintain antidepressant effects has ...received little systematic study. This study was conducted to examine the efficacy and tolerability of six ketamine infusions in Chinese patients with unipolar and bipolar depression.
Ninety seven patients with unipolar (n = 77) and bipolar (n = 20) depression received repeated ketamine infusions (0.5 mg/kg over 40 min) with continuous vital sign monitoring. Depressive symptoms were measured by the Montgomery-Asberg Depression Rating Scale (MADRS). Suicidal ideation was assessed using the Scale for Suicidal Ideations (SSI)-part 1. Anxiety symptoms were evaluated with the 14-item Hamilton Anxiety Scale (HAMA). Adverse psychopathological and dissociative effects were assessed using the Brief Psychiatric Rating Scale (BPRS)-positive symptoms and Clinician Administered Dissociative States Scale (CADSS), respectively. Patients were assessed at baseline, 4 and 24 h, and 3, 4, 5, 6, 8, 9, 10, 11, 12, 13 and 26 days.
After six ketamine infusions, the response and remission rates were 68.0% and 50.5%, respectively. There were significant decreases in MADRS, SSI-part 1, and HAMA scores within four hours following the first ketamine infusion, and the decreases were sustained over the subsequent infusion period. The nonresponder subgroup manifested rapid significant improvement in suicidal ideations throughout the course of treatment. After the six ketamine infusions, the response was positively associated with the response at 24 h after the first infusion (OR = 8.94), personal income ≥4000 yuan/month (OR = 3.04), and no history of psychiatric hospitalization (OR = 3.41). Only CADSS scores had a mild but marginally significant increase after the first infusion but with a significant BPRS score decrease.
Six ketamine infusions were safe and effective in patients with unipolar and bipolar depression. The rapid and robust antidepressant and antisuicidal effects of ketamine infusion within four hours were sustained following the subsequent infusions.
•The strategy of repeated-dose ketamine infusions to maintain antidepressant effects has received little systematic study.•The rapid antidepressant effects of ketamine infusion within four hours were sustained following the subsequent infusions.•The response of ketamine treatment was positively associated with the response at 24h after the first infusion.
To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based ...chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016).
The PRIMA protocol was amended so newly enrolled patients received an ISD based on baseline body weight/platelet count. In this ad hoc analysis, the timing, duration, and resolution of the first occurrence of common any-grade hematologic (thrombocytopenia, anemia, neutropenia) and nonhematologic (nausea, asthenia/fatigue, constipation, insomnia, hypertension) treatment-emergent adverse events (TEAEs) were evaluated by treatment arm in the ISD safety population (data cutoff, November 17, 2021; median follow-up, 3.5 years).
Of 733 randomized patients, 255 were enrolled after the ISD protocol amendment and received ≥ 1 dose of study treatment (niraparib, 169; placebo, 86). In the niraparib arm, median times to first events were 22.0–35.0 days for hematologic TEAEs and 7.0–56.0 days for nonhematologic TEAEs. First events resolved in ≥ 89.8% of patients for hematologic TEAEs; for nonhematologic TEAEs, resolution rates ranged from 55.3% (insomnia) to 86.0% (nausea). Median durations of first hematologic TEAEs were ≤ 16.0 days, but for first nonhematologic TEAEs ranged from 18.0 days (nausea) to 134.0 days (insomnia).
The niraparib ISD was generally well tolerated and TEAEs were manageable. Common hematologic and nonhematologic TEAEs occurred early and first events of hematologic TEAEs had a short duration (≈ 2 weeks) and a high resolution rate. These findings support close monitoring immediately following niraparib initiation and may help inform patient expectations for niraparib safety.
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•Tolerability of niraparib individualized starting dose (ISD) in PRIMA/ENGOT-OV26/GOG-3012.•Evaluated timing, duration, and resolution of first occurrence of common TEAEs.•Hematologic and nonhematologic TEAEs occurred early after niraparib ISD treatment initiation.•First events of hematologic TEAEs had short durations and high rates of resolution.•Niraparib ISD was well tolerated, and common TEAEs were generally manageable.
To evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular ...degeneration (AMD).
Phase 1, open-label, single-center, first-in-human clinical study.
Adult patients (aged ≥50 years) with GA secondary to AMD in the study-treated eye (treated eye) with a best corrected visual acuity (BCVA) Snellen equivalent of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and BCVA of 20/800 or better in fellow, non-treated eye were included.
Patients (N=17) were sequentially enrolled into low (3.56×1010 viral genome vg/eye; n=3), intermediate (1.07×1011 vg/eye; n=3), and high (3.56×1011 vg/eye; n=11) dose cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months.
Safety and tolerability outcomes included assessment of ocular and non-ocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate.
Baseline patient characteristics were consistent with the disease under study, and all enrolled patients had foveal center–involved GA. JNJ-1887 was well tolerated across all cohorts, with no dose-limiting AEs. There were no serious or systemic AEs related to study intervention. Overall, 5/17 (29%) patients experienced 6 events of mild ocular inflammation related to study treatment; exam findings in all resolved, and AEs resolved in 4 of 5 patients following topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. GA lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0-6 to 0.056 mm at months 18-24.
All 3 studied doses of JNJ-1887 had a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted.
Resumen: Introducción y objetivo: La endoscopia transnasal (ETN) ha probado su utilidad diagnóstica; sin embargo, no se ha aceptado de manera generalizada debido a que se realiza sin sedación y no se ...han llevado a cabo estudios que reporten el uso de métodos que mejoren su tolerabilidad. El objetivo fue evaluar la tolerabilidad de la ETN cuando se realiza de manera simultánea con un dispositivo audiovisual como distractor. Métodos: Se evaluaron 50 pacientes y 10 de ellos rechazaron participar. El procedimiento se explicó utilizando un dispositivo audiovisual. Antes de la aleatorización se aplicaron escalas de ansiedad y depresión. Los pacientes se dividieron en 2 grupos: grupo i (utilizando un dispositivo audiovisual durante el procedimiento) y grupo ii (sin dispositivo). Se utilizaron escalas numéricas de ansiedad y dolor. Se monitorizaron signos vitales antes, durante y después de la endoscopia. Se aplicó una escala de satisfacción al final del estudio y 24 horas después. Resultados: El promedio de edad fue 41.6 años y 35 (87.5%) pacientes fueron de sexo femenino. La indicación más frecuente para ETN fue enfermedad por reflujo gastroesofágico refractario. No se encontraron comorbilidades significativas y ningún participante contaba con puntuación de ansiedad o depresión significativa. Un paciente del grupo ii no toleró la ETN debido a dolor nasal. No se encontró diferencia significativa en niveles de ansiedad y dolor, signos vitales y escala de satisfacción entre grupos. Conclusiones: Nuestro estudio mostró que la ETN es bien tolerada y tiene un porcentaje alto de aceptación en nuestros pacientes. El uso de dispositivos audiovisuales distractores no incrementó la tolerancia al procedimiento endoscópico. Abstract: Introduction and objective: Transnasal endoscopy (TNE) has proven its diagnostic utility, but it has not been widely accepted given that it is performed without sedation. There are no previous studies on the use of methods to improve its tolerability. Our aim was to evaluate the tolerability of TNE, when simultaneously performed with an audiovisual device as a distractor. Methods: We evaluated 50 patients, 10 of whom did not agree to participate. The performance of the procedure was explained, using an audiovisual device. Before randomization, we applied anxiety and depression scores. Patients were divided into 2 groups: Group I (using an audiovisual device during the procedure) and Group II (without a device). Anxiety and numeric pain rating scales were used, and vital signs were monitored and recorded before, during, and after the endoscopy. An overall procedure satisfaction score was applied at the end of the study and 24 h later. Results: Mean age was 41.6 years and 35 of the patients were women (87.5%). The most frequent indication for TNE was refractory gastroesophageal reflux disease. There were no severe comorbidities, and none of the patients had a significant anxiety or depression score. One patient in Group II did not tolerate TNE due to nasal pain. There was no statistically significant difference between groups, regarding anxiety, pain, vital signs, and satisfaction scale. Conclusion: Our study showed that TNE was well tolerated and had a high acceptance rate in our patients. The use of distracting audiovisual devices did not increase tolerance to the endoscopic procedure.
Molnupiravir, EIDD-2801/MK-4482, the prodrug of the active antiviral ribonucleoside analog ß-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses including severe acute ...respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and seasonal and pandemic influenza viruses.Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics.EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure.Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.
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