A Phase I,Open-label,Single-Dose Study to Evaluate the Pharmacokinetics,Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects

Background and ObjectiveAMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects.MethodsThis was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg.ResultsFollowing oral administration, median time to maximum observed plasma concentration (t_max) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t_½) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (C_max) and AUC_∞, respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity.ConclusionAMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-022-00386-3.     

A Double-Blind,Placebo-Controlled Trial to Evaluate the Safety,Tolerability, and Pharmacokinetics of Single,Escalating Oral Doses of JDTic

Animal studies suggest that kappa opioid receptor antagonists (KORAn) potentially could treat a wide variety of addictive and depressive disorders. We assessed the KORAn JDTic for safety, tolerability, and pharmacokinetics in a double-blind, placebo-controlled, randomized trial evaluating single oral doses in healthy adult males. Predose and postdose safety assessments included orthostatic vital signs; 6-lead continuous telemetry monitoring (approximately 16 h predose to 24 h postdose); 12-lead electrocardiograms (ECGs); clinical chemistry, hematology, coagulation, and urinalysis; psychomotor functioning (using the Wayne Saccadic Fixator (WSF)); and adverse events. As a potential indicator of JDTic effects on affect, the POMS Standard instrument was administered predose and daily postdose Days 1–6. At 1 mg, 2 of the 6 JDTic (and 0/6 placebo) subjects experienced a single, asymptomatic event of multiple beats of nonsustained ventricular tachycardia (NSVT). Their events were temporally similar with respect to time postdose (and the postdose timing of an NSVT event in a monkey). These events triggered a study stopping rule. No differences were observed between the placebo and JDTic subjects with respect to clinical chemistry, hematology, coagulation, urinalysis, orthostatic vital signs, WSF, or 12-lead ECG parameters. Plasma JDTic levels were below the lower limit of quantitation (0.1 nM) in all subjects. There were no significant differences in POMS scores between the placebo and JDTic groups. Although the evidence is circumstantial, it suggests that NSVT is a potential JDTic toxicity in humans. Given the therapeutic potential of KORAn, further investigation is needed to determine whether a significant JDTic human cardiac effect indeed exists, and if so, whether it is specific to JDTic or represents a KORAn class effect.     

Absence of Pharmacokinetic and Pharmacodynamic Interactions between Almorexant and Warfarin in Healthy Subjects

Background and Objective

Almorexant is the first representative of the new class of orexin receptor antagonists, which could become a new treatment option for insomnia. The present study investigated the potential interaction between almorexant and warfarin.

Methods

In this open-label, two-way crossover, drug–drug interaction study, healthy male subjects received, in a randomized fashion, almorexant 200 mg once daily for 10 days and a single dose of 25 mg warfarin co-administered on day 5 (treatment A) and a single dose of 25 mg warfarin on day 1 (treatment B). Serial blood samples for warfarin pharmacokinetics and pharmacodynamics were drawn during both treatments.

Results

Of the 14 enrolled subjects, one withdrew due to an adverse event and 13 completed the study. Almorexant had no effect on the pharmacokinetics of warfarin. The geometric mean ratios (90 % confidence interval) for the area under the plasma concentration–time curve to infinity (AUC_0–∞) of S- and R-warfarin were 0.99 (0.89, 1.09) and 1.05 (0.95, 1.16), respectively, and for the maximum plasma concentration (C_max) were 0.99 (0.86, 1.14) and 1.00 (0.88, 1.13), respectively. The main pharmacodynamic variable was the AUC for the international normalized ratio (AUC_INR). Almorexant had no effect on this variable as demonstrated by a geometric mean ratio of 0.99 (0.82, 1.19). Secondary pharmacodynamic variables including maximum effect (E_max), the time to the maximum INR, and factor VII plasma concentrations were also not affected by almorexant.

Conclusion

No dose adjustment of warfarin is necessary when concomitantly administered with almorexant.     

Tolerability and Efficacy of Customized IncobotulinumtoxinA Injections for Essential Tremor: A Randomized,Double-Blind,Placebo-Controlled Study

In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial ({"type":"clinical-trial","attrs":{"text":"NCT02207946","term_id":"NCT02207946"}}NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn–Tolosa–Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, n = 19; placebo, n = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 (p = 0.003) and Week 8 (p = 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 (p < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 (p = 0.004) and Week 8 (p < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites.     

Evaluation of the Safety,Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents

BackgroundTP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This study evaluated the safety, tolerability, and pharmacokinetics of orally administered TS-161 in healthy subjects.MethodsThis was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (15–400 mg TS-161) and 10-day multiple-ascending dose (50–150 mg TS-161) study in healthy subjects, conducted from June 2019 through February 2020. Plasma and urine concentrations of the prodrug and its metabolites, and cerebrospinal fluid (CSF) concentrations of the active metabolite TP0178894 were measured to evaluate the pharmacokinetic profiles after oral administration of TS-161.ResultsFollowing single and multiple doses, TP0473292 was extensively converted into its active metabolite TP0178894. Plasma concentrations of TP0178894 reached peak (C_max) within 5 hours post dose and declined with a t_1/2 <13 hours. Plasma exposures of TP0178894 increased with increasing dose. TP0178894 penetrated into CSF and reached a C_max of 9.892 ng/mL at a single dose of 100 mg, which was comparable with IC₅₀ values of antagonist activity at mGlu2/3 receptors. The most frequently observed adverse events that showed exposure-related incidence during the study were nausea, vomiting, and dizziness.ConclusionsThe mGlu2/3 receptor antagonist prodrug TP0473292 is safe and well-tolerated, is orally bioavailable in humans with extensive conversion into the active metabolite TP0178894 with sufficient CSF penetration to exert the anticipated pharmacological effects, and is a promising candidate for further clinical development in treatment of patients with depression.     

The Safety and Tolerability of Topically Delivered Kynurenic Acid in Humans. A Phase 1 Randomized Double-Blind Clinical Trial

Scarring is a consequence of biological tissue repair following trauma. Currently, there are no generally agreed ways to prevent scarring. Recently, kynurenic acid has shown to be a potent modulator of extracellular matrix deposition and remodeling. Kynurenic acid can reduce matrix deposition and other fundamental characteristics of fibrosis in vitro and in vivo. Specifically, kynurenic acid has shown to increase matrix metalloproteinase-1 activity and subsequently reduce collagen deposition in a rabbit ear scar model. In the present study kynurenic acid cream in different concentrations was topically applied on healthy skin on volunteers to assess skin reactions and skin sensitivity in both acute and chronic application settings. Skin reactions were assessed, and concentrations for kynurenic acid were assessed both form serum and urine. Results showed to acute or delayed skin reactions. Kynurenic acid was not detectable in blood at any time point, and only trace elements of kynurenic acid were found in urine. This study supports safety and tolerability of topically administered FS2 when using a liposomal, compounding base carrier.     

Pharmacokinetics,Tolerability, and Safety of the Single Oral Administration of AGSAV301 vs Exforge: A Randomized Crossover Study of Healthy Male Volunteers

Background and Objective

Valsartan, an angiotensin receptor blocker, is often used with calcium channel blockers (CCBs) such as amlodipine to control hypertension. Recently, the fixed-dose combination (FDC) of amlodipine 10 mg/valsartan 160 mg (Exforge) was approved. Amlodipine is a racemic mixture of CCB; S-amlodipine has higher activity than R-form. Therefore, AGSAV301, the FDC of S-amlodipine 5 mg/valsartan 160 mg was recently developed. The objective of this study was to compare the pharmacokinetic (PK) characteristics of S-amlodipine and valsartan when administered as one tablet each of Exforge and AGSAV301 to healthy male subjects.

Methods

This was a single-dose, randomized, open-label, two-way, two-period crossover study. Each subject received a single dose of AGSAV301 and Exforge, separated by a 3-week washout period. Plasma samples for the PK analysis of valsartan and S-amlodipine were collected at predose (0) and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, and 168 h after administration. Tolerability was also evaluated.

Results

A total of 29 subjects were enrolled; 24 completed this study. The S-amlodipine maximum plasma concentration (C _max) geometric mean ratio (GMR) between AGSAV301 and Exforge was 0.951 (90 % CI 0.983–1.014), and area under the concentration–time curve from time 0 to last measured time point (AUC_last) was 0.917 (90 % CI 0.861–0.976). The GMR of valsartan C _max was 0.994 (90 % CI 0.918–1.076), and the AUC_last was 0.927 (90 % CI 0.821–1.047). All adverse events (AEs) were resolved without sequelae; no serious AEs were reported. Two drugs showed similar tendencies to lower blood pressure in healthy subjects.

Conclusions

The PK profiles of AGSAV301 and Exforge were bioequivalent. Both drugs were also well tolerated, with comparable AE profiles and similar blood pressure-lowering tendencies in healthy volunteers, suggesting equivalent therapeutic indications.     

Pharmacokinetic and Pharmacodynamic Properties of a Micro-Dose Nasal Spray Formulation of Desmopressin (AV002) in Healthy Water-Loaded Subjects

Pharmaceutical Research - For some biological systems, there exist several models with somewhat different features and perspectives. We propose an evaluation method for NLME models by analyzing...     

Safety,Pharmacokinetic, and Pharmacodynamic Study of a Sublingual Formula for the Treatment of Vasovagal Syncope

BackgroundVasovagal syncope is a common cause of syncope which, if recurrent, can have multiple negative consequences such as injury and occupational disability. Various medications can be used to decrease the recurrence of vasovagal syncope but there are no drugs that can be used by patients to interrupt a perceived vasovagal episode.MethodsA phase I study was performed to evaluate the tolerability and safety of a gel formulation containing capsaicin (1 mg), phenylephrine HCL (PE) and caffeine citrate (200 mg) (CPC) in normal adult volunteers. Secondary objectives were to characterize the pharmacokinetics (PK) of the CPC formulation and the highest dose of PE needed to achieve a target increase in systolic BP of at least 40 mmHg. After receiving the first dose, a second dose of the CPC mixture was administered at 2 h. Suboptimal changes in systolic blood pressure (SBP) were noted at PE doses of 0.6, 1.2, and 1.8 mg, therefore a second cohort was studied at PE doses of 10, 20, and 30 mg. Blood samples were collected in rapid sequence and were assayed for all three drugs.ResultsA total of 17 subjects received the drug with no serious adverse effects reported. All doses were well tolerated, although the capsaicin content usually caused expected temporary oral and gastric discomfort. One subject did not complete the study because of a vasovagal reaction that was associated with the frequent blood sampling. There was a 5–25 min lag in the appearance of measurable blood concentrations of capsaicin and phenylephrine. Most subjects had baseline caffeine concentrations from dietary use, with a gradual increase noted after 15 min consistent with GI absorption. Although the intended criterion of a 40 mmHg increase in SBP was not reached, a clinically significant increase in BP for at least 15 min was noted in the six subjects who received the highest dose of PE (30 mg), with a gradual decline over the next 2 h.ConclusionThe ternary mixture of capsaicin, phenylephrine, and caffeine was well tolerated when administered as two sublingual/oral doses over a 2-h period.     

Evaluation of the Pharmacokinetics and Safety of AMG 986 Tablet and Capsule Formulations in Healthy Adult Subjects: A Phase I,Open-Label,Randomized Study

Background and objectiveAMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure. The current phase I study was conducted to evaluate the pharmacokinetics and safety of a single-dose 200-mg capsule formulation of AMG 986 relative to the tablet formulation in 12 healthy subjects.MethodsIn a two-period, two-way crossover design, eligible subjects were randomized 1:1 to tablet/capsule or capsule/tablet treatment sequences; each treatment sequence lasted for approximately 6 days and comprised six subjects.ResultsFollowing a single oral dose of AMG 986, the geometric mean maximum observed concentration (C_max) values were 9670 ng/mL and 6920 ng/mL and the geometric mean area under the curve from time zero to 120 h (AUC_0–120h) values were 68,000 ng*h/mL and 59,900 ng*h/mL for the tablet and capsule, respectively. The geometric least squares means (90% confidence interval [90% CI]) for the ratios of capsule/tablet were 0.88 (90% CI 0.81–0.96) and 0.72 (90% CI 0.57–0.91) for AUC_0–120h and C_max, respectively. AMG 986 had an acceptable safety profile; all adverse events were grade 1 or 2 in severity.ConclusionThere was a modest 12% decrease in AUC_0–120h and a 28% decrease in C_max with the AMG 986 capsule versus the tablet. These differences are not considered to be clinically relevant, suggesting the capsule formulation can be used in subsequent clinical studies of AMG 986.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-022-00388-1.     

Pharmacokinetics and Pharmacodynamics of Ranitidine and Famotidine in Healthy Elderly Subjects: A Double-Blind,Placebo-Controlled Comparison

The pharmacokinetics and pharmacodynamics of ranitidine and famotidine were studied in 13 healthy elderly volunteers. On 3 mornings separated by a 1-week wash-out period, each subject received a single oral dose of ranitidine 300 mg, famotidine 40 mg, and placebo in a crossover, randomized fashion with double-dummy administration. Plasma and urine concentrations of ranitidine and famotidine were determined by high-performance liquid chromatography. Intragastric pH was measured for 24-hours with an antimony probe. Famotidine's plasma half-life (4.42 hrs) was significantly longer than ranitidine's (3.14 hrs, p<0.05, paired t test). The 24-hour, area under the curve of pH profiles of the two drugs were significantly different from placebo (p<0.05, analysis of variance and Fisher PLSD test) but not from each other. The duration of effect (defined as median pH>4) was similar for ranitidine and famotidine, 10.3 and 9.9 hours, respectively (p=0.713, paired Student's t test). Thus both agents exhibited a similar duration of 24-hour antisecretory response under these study conditions.     

Topical Rapamycin Therapy to Alleviate the Cutaneous Manifestations of Tuberous Sclerosis Complex: A Double-Blind,Randomized, Controlled Trial to Evaluate the Safety and Efficacy of Topically Applied Rapamycin

Background and Objectives

Facial angiofibromas are disfiguring facial lesions, present in up to 80% of patients with tuberous sclerosis complex. Recent elucidation of the complex cell signaling pathways that are disrupted in tuberous sclerosis indicates that rapamycin may be successful in alleviating the appearance of these lesions. The objectives of the current study were to evaluate the safety of topically applied rapamycin in patients with tuberous sclerosis complex and to determine its potential effectiveness in treatment of facial angiofibromas.

Patients and Methods

The study was a prospective, randomized, double-blind, placebo-controlled study performed at the University of Texas Health Science Center at Houston. Study subjects were recruited from the patient populations at the University of Texas Tuberous Sclerosis Center of Excellence. All subjects were over the age of 13 years and had a diagnosis of tuberous sclerosis complex. Subjects were excluded if they were using any form of rapamycin or if they were pregnant. Study subjects applied the study product to their facial angiofibromas nightly for a duration of 6 months. The investigational product contained one of three doses of rapamycin compounded with Skincerity®: (i) no rapamycin; (ii) 1 mg of rapamycin per 30 cc (0.003%); or (iii) 5 mg of rapamycin per 30 cc (0.015%). Plasma rapamycin concentrations were measured monthly to test for systemic absorption. Complete blood counts were performed monthly to test for anemia, neutropenia, or thrombocytopenia. Upon completion of the trial, subjects were asked if the formulation had improved the appearance of their facial angiofibromas.

Results

Twenty-three subjects completed the study. There was no detectable systemic absorption of rapamycin (all blood concentrations were <1.0 ng/mL). There were no significant changes in white blood cell, red blood cell, or platelet counts. Seventy-three percent of subjects in the treatment arms versus 38% of subjects in the placebo arm reported a subjective improvement in the appearance of their facial angiofibromas.

Conclusion

The application of low-dose topical rapamycin (0.003–0.015%) to the face can safely decrease the appearance of facial angiofibromas in patients with tuberous sclerosis complex.

Trial Registration

ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01031901","term_id":"NCT01031901"}}NCT01031901Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder characterized by the formation of benign tumors in multiple organ systems. Facial angiofibromas appear as red or pink papules over the central face, especially on the nasolabial folds, cheeks, and chin,[1] in people with TSC. Lesions arise in early childhood and are present in up to 80% of TSC patients.[1,2] In some patients, the lesions become confluent and can result in severe disfigurement. Although multiple treatments have been developed to alleviate the appearance of facial angiofibromas – curettage, cryosurgery, chemical peels, dermabrasion, shave excisions, and laser therapy[3–8] – these are uncomfortable and need to be repeated at periodic intervals to treat recurrence.[9]In patients with TSC, the mammalian target of rapamycin (mTOR) is aberrantly activated in fibroblast-like cells located within the dermal layer of the skin. These cells produce an epidermal growth factor, epiregulin, which stimulates epidermal cell proliferation.[10] Epidermal cells are produced at a faster rate than the ability to slough the dead cells from the skin surface.[11] This overproduction of skin cells, in conjunction with angiogenesis, results in the initial appearance and continued progression of facial angiofibromas over time.Recent elucidation of the complex signaling relationship between the tuberous sclerosis 1 (TSC1) and tuberous sclerosis 2 (TSC2) gene products and mTOR has led to an explosion of research related to the use of mTOR inhibitors, such as rapamycin, in TSC. These mTOR inhibitors are showing promise in treating multiple tumor types, including renal angiomyolipomas (AMLs), sub-ependymal giant cell astrocytomas (SEGAs), and lymphangioleiomyomatosis (LAM).[12–15]Rapamycin is a naturally occurring antifungal macrolide, first isolated from Streptomyces hygroscopicus in 1965. Rapamycin binds with high specificity to mTOR, and binding results in inhibition of mTOR activity and ultimately in downregulation of cell growth.[16] Rapamycin has a molecular weight of 914.2 grams/mol, allowing for its absorption through the superficial layers of the epidermis to the deep dermal layer implicated in the development of facial angiofibromas.The primary goal of this study was to evaluate the safety of topical rapamycin (0.003% and 0.015%) in patients with TSC. The secondary goal of this study was to evaluate the efficacy of the topical product for treatment of facial angiofibromas.     

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Fimasartan Following Single and Repeated Oral Administration in the Fasted and Fed States in Healthy Subjects

Background and Objectives

Fimasartan (BR-A-657) is a novel, non-peptide angiotensin II receptor antagonist with a selective type I receptor blockade effect. Two first-in-human studies investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of fimasartan.

Methods

Fasted single oral tablet doses of fimasartan 20–480mg or placebo were administered to 40 healthy male subjects (aged 19–54 years) in a double-blind, randomized, sequential-group design. Subjects receiving fimasartan 240mg also received the same treatment in the fed state after an interval of 7 days. In another study, oral tablet doses of fimasartan 120 and 360mg or placebo were given once daily for 7 days to groups of eight fasted healthy male subjects (aged 20–55 years) in a double-blind, randomized, sequential-group design. Safety and tolerability were assessed. The PK and PD of fimasartan were also evaluated and compared for the different doses.

Results

Fimasartan was safe and well tolerated, but with an increased incidence of low BP and postural dizziness for the 360mg dose after repeated administration. Fimasartan produced increases in plasma renin activity, angiotensin I and II, which were not dose dependent. Maximal increases occurred between 6 and 8 hours post-dose, lasting up to 48 hours. Fimasartan was absorbed rapidly after all doses and had a multiphasic distribution. Two peaks in the plasma concentration-time profile were observed in most subjects. Steady state was achieved after three doses, and accumulation was minimal after repeated doses for 7 days (24–30%). The effective half-life ranged from 9.84 to 13.2 hours. The systemic exposure of fimasartan was dose proportional, and no marked food effect was noted after administration of 240mg in the fed state. Urinary excretion of fimasartan was very low (1.74–2.51%), suggesting non-renal elimination.

Conclusion

Fimasartan had a good safety profile and was well tolerated after fasted single oral doses of 20–480mg, a fed single oral dose of 240mg, and fasted repeated oral doses of 120 and 360mg in healthy subjects. In addition, the PK and PD of fimasartan in this population were well characterized. Further studies are needed to evaluate the safety, efficacy, and dose-response relationship of fimasartan in patients with hypertension.     

Effects of Short-Term Varenicline Administration on Emotional and Cognitive Processing in Healthy,Non-Smoking Adults: A Randomized,Double-Blind,Study

Varenicline is an effective and increasingly prescribed drug for smoking cessation, but has been associated with depressive symptoms and suicidal behavior. However, it remains unclear whether those changes in mood and behavior are directly related to varenicline use, or caused by smoking cessation itself or reflects depression and suicidality rates in smokers, independent of treatment. To investigate the influence of varenicline on mood and behavior independent of smoking and smoking cessation, we assessed the effects of varenicline on emotional processing (a biomarker of depressogenic effects), emotion-potentiated startle reactivity, impulsivity (linked with suicidal behavior), and cognitive performance in non-smoking subjects. We used a randomized, double-blind design, in which we administered varenicline or placebo to healthy subjects over 7 days (0.5 mg/day first 3 days, then 1 mg/day). Cognitive and emotional processing was assessed by a battery of computerized tasks and recording of emotion-potentiated startle response. A total of 41 subjects were randomized, with 38 subjects included in the analysis. The varenicline group did not differ from placebo in terms of negative biases in emotional processing or mood. However, compared with placebo, the varenicline group scored higher on working and declarative memory. In conclusion, short-term varenicline use did not influence negative biases in emotional processing or impulsivity in non-smoking subjects, thereby not supporting direct depressogenic or suicidal risk behavior-inducing effects. In contrast, varenicline may have cognitive-enhancing effects.     

A Randomized,Double-Blind Placebo Controlled Cross-Over Study to Investigate the Effects of RW94 on the Absorption of Dietary Fat in Healthy Volunteers

Summary

RW94 is a permitted additive in the food industry, which precipitates fatty acids in vitro. In vivo, this could result in reduced fatty acid absorption by the body, and may, therefore, influence the amount of fat excreted in the faeces. An investigation into the effects of RW94 on bodily fat absorption and excretion was undertaken. The safety, tolerability and efficacy of the product was compared with placebo in a group of 12 healthy volunteers, randomly assigned to receive either RW94 or placebo for a period of four days when dietary fat intake was controlled. After a 10-day washout period, the randomly assigned groups were crossed over to receive placebo and RW94, respectively, for a second 4-day period, when fat intake was similarly controlled.

Five grams of RW94 administered orally 30?min after each meal resulted in a statistically significant increase in the amount of excreted faecal lipids compared with placebo (p < 0.05). Following high fat intake, total blood cholesterol was predictably raised in both placebo and RW94 groups, but was less markedly raised with RW94 than placebo. All subjects lost body weight during the study, but the loss while consuming RW94 was significantly greater (p < 0.05) than while consuming placebo. All subjects found the treatments acceptable, though an increased incidence of flatulence, rumbling stomach and abdominal discomfort was noted with RW94 compared with placebo. RW94 was comparable with placebo in respect of safety.     

A Double-Blind Study Comparing Two Single-Dose Regimens of Ketorolac with Diclofenac in Pain Due to Cancer

Study Objective . To compare the analgesic efficacy and safety of two single doses of ketorolac with diclofenac in acute cancer pain. Design . Double-blind, randomized, clinical study. Setting . Hospital-based clinical research center. Subjects . One hundred eighty patients suffering acute, moderate, or severe cancer pain. Interventions . A single intramuscular injection of ketorolac 10 or 30 mg or diclofenac 75 mg. Measurements and Main Results . Pain intensity was assessed 30 minutes and 1, 2, 3, 4, 5, and 6 hours after injection or until rescue drug administration. In approximately 70% of patients all treatments provided prompt sustained pain relief throughout the 6-hour observation period. There were no statistically significant differences in any of the analyzed efficacy measures among the three groups. Conclusion . Intramuscular ketorolac 10 mg is adequate to relieve cancer pain, and is equivalent to ketorolac 30 mg and to diclofenac 75 mg.     

Double-Blind Randomized Controlled Pilot Study of the Efficacy and Tolerability of Pirlindole,a Reversible Inhibitor of Monoamine Oxidase A,and Mianserin,in the Treatment of Depression

This double-blind randomized pilot study aimed to compare the efficacy and the tolerability of pirlindole (150–225 mg/day), a reversible inhibitor of monoamine oxidase A, and mianserin (60–90 mg/day) in the treatment of major depression. Forty patients were included in the trial (20 pirlindole and 20 mianserin) and 38 patients (18 pirlindole and 20 mianserin) completed the whole study (28 days of administration). Both treatments exhibited highly significant improvements in the Hamilton Depression Rating Scale score (HDRS), the Hamilton Anxiety Rating Scale score (HARS) and the Beck auto-evaluation scale score (BECK) from day 7 up to day 28. The evolution of the HDRS score in the two groups did not differ significantly. The evolution of the HARS and BECK scores taken separately and the evolution of the combined total score (HDRS + HARS + BECK) significantly differed between the two groups, pirlindole producing a significantly higher decrease than mianserin in the two separate scores on day 28 and on days 21 and 28 in the case of the combined total score. Two patients experienced adverse reactions, one in the pirlindole group complained of sleep disturbances and one in the mianserin group suffered from dry mouth. The results of this study attest to the efficacy and tolerability of pirlindole in the treatment of depression. © 1997 John Wiley & Sons, Ltd.