Curtis Wright

Analgesic Efficacy and Safety of Morphine‐Chitosan Nasal Solution in Patients with Moderate to Severe Pain Following Orthopedic Surgery

INTRODUCTION Parenteral opioids are the standard of care for treating moderate to severe postsurgical pain. This randomized, double-blind, dose-ranging study compared the safety and efficacy of intranasal (IN) morphine with intravenous (IV) morphine and placebo. METHODS In total, 187 postbunionectomy patients with moderate to severe pain were randomized to receive IN morphine 3.75 mg, 7.5 mg, 15 mg, or 30 mg, IV morphine 7.5 mg, or placebo in the single-dose phase and IN morphine 7.5 mg or 15 mg thereafter. The primary outcome was a dose-response assessment for total pain relief based upon visual analog scales. Secondary endpoints included pain intensity, pain relief, patient global evaluation, and time to rescue medication. Safety assessments included adverse events and nasal examination. RESULTS A statistically significant linear dose response was observed over the IN morphine dose range for 4-hour total pain relief. Patients reported statistically significant pain relief and pain intensity differences following IV morphine and IN morphine at doses of 7.5 mg and greater within 30 minutes postdose, compared with placebo. Median times to rescue medication were 124 and 140 minutes for IN morphine 7.5 mg and 15 mg dosage groups, respectively, and 130 minutes for IV morphine. Local adverse events associated with IN morphine were transient and mostly mild (bad taste, nasal congestion, throat irritation, and sneezing). Systemic adverse events, regardless of route of administration, were dose-related and consistent with expected opioid effects. CONCLUSIONS By multiple measures of pain intensity and pain relief, IN morphine provides sustained analgesia in postsurgical patients and thus may offer a safe and less invasive alternative to IV morphine.

Platelet function following administration of a novel formulation of intravenous diclofenac sodium versus active comparators: a randomized, single dose, crossover study in healthy male volunteers.

STUDY OBJECTIVE To assess platelet function and safety following single-dose administration of a novel formulation of intravenous (IV) diclofenac sodium (Dyloject) 37.5 mg versus oral diclofenac 50 mg, IV ketorolac 30 mg, and oral acetylsalicylic acid (ASA) 325 mg. DESIGN Open-label, randomized, single-dose, 4-treatment crossover study. SETTING Clinical research unit. PATIENTS 30 healthy, ASA physical status I adult men. INTERVENTIONS Subjects were randomized to one of 6 treatment sequences that included 4 single-dose treatments. Study drug administration occurred on Days 1, 3, 5, and 7. MEASUREMENTS Platelet count, closure time as measured by platelet function analyzer (PFA-100), prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma concentrations of the study drugs were obtained over 24 hours after each treatment. The primary endpoint was the area under the curve for PFA collagen-epinephrine (CEPI) closure time difference from 0-6 hours post-drug administration (AUC(0-6h)). Secondary endpoints included the maximum change from baseline in PFA CEPI closure time. MAIN RESULTS AUC(0-6h) (mean ± SD) for CEPI closure time difference was significantly smaller after IV diclofenac 37.5 mg (249 ± 216 sec.hrs) than after ketorolac [and ASA (950 ± 287 sec.hrs and 834 ± 237 sec.hrs, respectively); P ≤ 0.0001 for both] but not after the oral diclofenac control (286 ± 265 sec.hrs; P = 0.40). Similarly, the maximum change from baseline in PFA CEPI closure time was lower after IV diclofenac than after ketorolac or ASA across all time intervals examined. There were no significant changes in PT or aPTT at any time point with any treatment. There was a low frequency of adverse events. CONCLUSIONS Acetylsalicylic acid and ketorolac both substantially disrupted platelet function in contrast to IV diclofenac 37.5 mg or oral diclofenac 50 mg control. Diclofenac, with its balanced COX-1 and COX-2 inhibitory profile, may pose less risk of postoperative bleeding than nonsteroidal antiinflammatory drugs (NSAIDs) such as ketorolac and ASA, which predominantly inhibit COX-1.

Single‐Dose and Multiple‐Dose Pharmacokinetics and Dose Proportionality of Intravenous and Intramuscular HPβCD‐Diclofenac (Dyloject) Compared with Other Diclofenac Formulations

To evaluate single‐ and repeated‐dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl‐β‐cyclodextrin (HPβCD)‐diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration.

Effects of Injectable HPβCD-Diclofenac on the Human Delayed Rectifier Potassium Channel Current In Vitro and on Proarrhythmic QTc In Vivo

BACKGROUND Novel formulations and administration routes of established drugs may result in higher maximum concentrations or total exposures and potentially cause previously unrecognized adverse events. OBJECTIVE This study evaluated the proarrhythmic potential of hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac, a novel injectable diclofenac formulation solubilized with hydroxypropyl-β-cyclodextrin (HPβCD), on ventricular electrical conduction in preclinical and clinical models. METHODS We assessed the effects of diclofenac, HPβCD, and HPβCD-diclofenac on the human delayed rectifier potassium channel (IKr) using human embryonic kidney (HEK) 293 cells transfected with a human ether-à-go-go-related gene (hERG) using whole-cell patch-clamp. In a single-dose, active- and placebo-controlled, 4-period crossover, thorough QT in vivo study, 70 healthy volunteers (mean age, 23.3 years; range, 18-49 years; 55.75% male) received HPβCD-diclofenac at 37.5- and 75-mg doses, inactive vehicle (placebo), and an active control (moxifloxacin). RESULTS In vitro, diclofenac produced no statistically significant effect on IKr. Significant, non-dose-dependent effects were observed in the presence of HPβCD or HPβCD-diclofenac of similar magnitude across the 300-fold dose range of concentrations tested, suggesting an artifact due to the detergent effect of HPβCD in this in vitro model. In vivo, neither HPβCD-diclofenac dose resulted in QTc prolongation ≥2 ms (≥5 ms is the threshold of clinical concern). No correlation was evident between changes in QTc and plasma concentrations of diclofenac or HPβCD. Confirming study sensitivity, moxifloxacin produced a mean QTc prolongation >10 ms. CONCLUSIONS The findings from the present study suggest that HPβCD-diclofenac does not have a dose-dependent effect in the in vitro hERG assay system and does not produce proarrhythmic QTc prolongation in vivo. ClinicalTrials.gov identifier: NCT01812538.

Anatabine Supplementation Decreases Thyroglobulin Antibodies in Patients With Chronic Lymphocytic Autoimmune (Hashimoto's) Thyroiditis: A Randomized Controlled Clinical Trial

Context: Hashimotos thyroiditis is less prevalent in tobacco smokers. Anatabine, an alkaloid found in Solanaceae plants including tobacco, has been reported to ameliorate a mouse model of Hashimotos thyroiditis. Objective: The effects of anatabine in patients with Hashimotos thyroiditis were studied. Design, Setting, Patients, and Intervention: This was a double-blind, randomized, placebo-controlled multisite study. A total of 146 patients (70 treated with anatabine and 76 with placebo) completed the study. Approximately 50% of patients in each group were taking levothyroxine. Anatabine lozenges (9–24 mg/d) or placebo, each containing vitamins A and D3, were administered orally 3 times a day for 3 months. Main Outcome Measures: Serum thyroperoxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) levels were assessed. Safety was assessed through adverse events, clinical laboratory evaluations, and vital sign measurements. Results: Anatabine-treated patients had a significant reduction in absolute serum TgAb levels from baseline by study end relative to those receiving placebo (P = .027); however, there were no significant changes or differences in treatment group means for TPOAb or TgAb levels. Mean ± SD TgAb values decreased by 46.2 ± 101.1 and 3.9 ± 83.9 World Health Organization units for the anatabine and placebo groups, respectively. Significantly more patients had a >20% drop in TgAb levels in the anatabine than placebo group (P = .023). Overall, the anatabine supplement was safe and well tolerated, although significantly (P < .05) more patients in the anatabine group reported adverse events. Conclusions: These results demonstrate an immunological effect of anatabine on TgAb levels. Further studies are warranted to determine the longer-term effects and possible actions of anatabine on the course of Hashimotos thyroiditis.