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VT-1598 is a novel fungal CYP51 inhibitor and 1-tetrazole-based antifungal drug candidate with improved selectivity minimizing off-target binding to and inhibition of human CYP450 enzymes. Data are presented from this first clinical study in the evaluation of the safety and pharmacokinetic (PK) of single ascending doses of 40, 80, 160, 320, and 640 mg VT-1598, comprising a 160 mg cohort in both fasting and fed states. Eight healthy adults per dose were randomized to receive either oral VT-1598 or placebo (3:1). Over the dose range, exposures were with relatively high variation. The maximum plasma concentrations (Cmax) for VT-1598 were 31.00-279.4 ng/ml and for its primary metabolite, VT-11134, were 27.80-108.8 ng/ml. The plasma area under the concentration-time curve to the last measurable concentration (AUC0-last) for VT-1598 were 116.1-4507 ng*h/ml, and for VT-11134 were 1140-7156 ng*h/ml. The dose proportionality was inconclusive based on the results of the power model. The peak concentration time (Tmax) was 4-5 h for VT-1598 and for VT-11134. Half-life was 103-126 h for VT-11134. After food intake, Cmax of VT-1598 increased by 44% (geometric mean ratio (GMR), 1.44; 90%CI [0.691, 2.19]) and AUC0-last by 126% (GMR, 2.26; 90%CI [1.09, 3.44]), while exposure of VT-11134 was decreased 23% for Cmax (GMR, 0.77; 90%CI [0.239, 1.31]) and unchanged for AUC0-last (GMR, 1.02; 90%CI [0.701, 1.33]). Neither VT-1598 nor VT-11134 were detected in urine. No serious adverse events (AEs) or AEs leading to early termination were observed. The safety and PK profiles of VT-1598 support its further clinical development., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: The U.S. Food and Drug Administration and the government of New Zealand have proposed a reduction of the nicotine content in cigarettes to very low levels. This study examined the potential effects of this regulation in smokers with affective disorders., Methods: In a randomized controlled parallel group trial conducted at two sites in the USA (Penn State University, Hershey, PA and Massachusetts General Hospital, Boston, MA) 188 adult smokers with a current (n = 118) or lifetime (n = 70) anxiety or unipolar mood disorder, not planning to quit in the next 6 months, were randomly assigned (1:1) to smoke either Usual Nicotine Content (UNC) (11.6 mg nicotine/cigarette) research cigarettes, or Reduced Nicotine Content (RNC) research cigarettes where the nicotine content per cigarette was progressively reduced to 0.2 mg in five steps over 18 weeks. Participants were then offered the choice to either receive assistance to quit smoking, receive free research cigarettes, or resume using their own cigarette brand during a 12-week follow-up period. Main outcomes were biomarkers of nicotine and toxicant exposure, smoking behavior and dependence and severity of psychiatric symptoms. The pre-registered primary outcome was plasma cotinine., Results: A total of 143 (76.1%) randomized participants completed the randomized phase of the trial, 69 (73.4%) in the RNC group and 74 (78.8%) in the UNC group. After switching to the lowest nicotine content cigarettes, compared to smokers in the UNC group, at the last randomized visit the RNC group had significantly lower plasma cotinine (metabolite of nicotine): difference between groups, -175.7, 95% CI [-218.3, -133.1] ng/ml. Urine NNAL (metabolite of NNK, a lung carcinogen), exhaled carbon-monoxide, cigarette consumption, and cigarette dependence were also significantly lower in the RNC group than the UNC group. No between-group differences were found on a range of other biomarkers (e.g. 8-isoprostanes) or health indicators (e.g. blood pressure), or on 5 different psychiatric questionnaires, including the Kessler K6 measure of psychological distress. At the end of the subsequent 12-week treatment choice phase, those randomized to the RNC group were more likely to have quit smoking, based on initial intent-to-treat sample, n = 188 (18.1% RNC v 4.3% UNC, p = 0.004)., Conclusion: Reducing nicotine content in cigarettes to very low levels reduces some toxicant exposures and cigarette addiction and increases smoking cessation in smokers with mood and/or anxiety disorders, without worsening mental health., Trial Registration: TRN: NCT01928758, registered August 21, 2013., Competing Interests: JF has done paid consulting for pharmaceutical companies involved in producing smoking cessation medications, including GSK, Pfizer, Novartis, J&J, and Cypress Bioscience, and received a research grant from Pfizer Inc (not related to reduced nicotine cigarettes). AEE reports grant support to her institution from subcontracts from NIDA grants to Charles River Analytics and Brain Solutions LLC and consulting fees from Karuna Pharmaceuticals and Alkermes and editorial support from Pfizer for papers arising from the EAGLES trial. There are no competing interests to declare for other authors. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Many smokers report attempting to quit each year, yet most relapse, in part due to exposure to smoking-related cues. It is hypothesized that extinction of the cue-drug association could be facilitated through random nicotine delivery (RND), thus making it easier for smokers to quit. The current study aimed to evaluate the effects of RND on smoking cessation-related outcomes including cigarettes per day (CPD) and exhaled carbon monoxide (CO)., Methods: Participants were current smokers (>9 CPD) interested in quitting. Novel trans-mucosal, orally dissolving nicotine films, developed by Bionex Pharmaceuticals, were used in the study. The pharmacokinetic profile of these films was assessed in single (Experiment 1) and multiple-dose (Experiment 2) administrations prior to the smoking cessation study (Experiment 3). In Experiment 3, participants were randomized 1:1:1 to recieve 4 nicotine films per day of either: placebo delivery (0 mg), steady-state delivery (2 mg), or random nicotine delivery (RND) (0 mg or 4 mg). After two weeks, participants were advised to quit (target quit date, TQD) and were followed up 4 weeks later to collect CPD and CO and to measure dependence (Penn State Cigarette Dependence Index; PSCDI) and craving (Questionnaire of Smoking Urges; QSU-Brief). Means and frequencies were used to describe the data and repeated measures ANOVA was used to determine differences between groups., Results: The pharmacokinetic studies (Experiment 1 and 2) demonstrated that the films designed for this study delivered nicotine as expected, with the 4 mg film delivering a nicotine boost of approximately 12.4 ng/mL across both the single and the multiple dose administration studies. The films reduced craving for a cigarette and were well-tolerated, overall, and caused no changes in blood pressure or heart rate. Using these films in the cessation study (Experiment 3) (n = 45), there was a significant overall reduction in cigarettes smoked per day (CPD) and in exhaled CO, with no significant differences across groups (placebo, steady-state, RND). In addition, there were no group differences in dependence or craving. Adverse events included heartburn, hiccups, nausea, and to a lesser extent, vomiting and anxiety and there were no differences across groups., Conclusion: Overall, this pilot study found that RND via orally dissolving films was feasible and well tolerated by participants. However, RND participants did not experience a greater reduction in self-reported CPD and exhaled CO, compared with participants in the steady-state and placebo delivery groups. Future studies to evaluate optimal RND parameters with larger sample sizes are needed to fully understand the effect of RND on smoking cessation-related outcomes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: The extent to which use of electronic nicotine delivery systems (ENDS) for smoking reduction leads to cigarette abstinence in smokers with no plans to quit smoking is unclear. This exploratory analysis examined the effects of ENDS delivering different amounts of nicotine on cigarette abstinence up to 24-week follow-up, in comparison to placebo or a behavioral substitute., Methods: This four-arm parallel-group, randomized, placebo-controlled trial took place at two academic medical centers in the United States (Penn State Hershey and Virginia Commonwealth University). Participants were current adult smokers (N = 520) interested in reducing but not planning to quit. They received brief advice and were randomized to one of four 24-week conditions, receiving either an eGo-style ENDS paired with 0, 8, or 36 mg/ml nicotine liquid (double-blind) or a cigarette-shaped tube, as a cigarette substitute (CS). Self-reported daily cigarette consumption and exhaled carbon monoxide (CO) were measured at all study visits. Outcomes included intent-to-treat, self-reported 7-day cigarette abstinence, biochemically confirmed by exhaled CO at 24 weeks after randomization., Results: At 24 weeks, significantly more participants in the 36 mg/ml condition (14/130, 10.8%) than in the 0 mg/ml condition (1/130, 0.8%) and the CS condition (4/130, 3.1%) were abstinent (relative risk = 14 [95% CI = 1.9-104.9] and 3.5 [95% CI = 1.2-10.4], respectively). The abstinence rate in the 8 mg/ml condition was 4.6% (6/130)., Conclusions: When smokers seeking to reduce smoking tried ENDS, few quit smoking in the short term. However, if smokers continued to use an ENDS with cigarette-like nicotine delivery, a greater proportion completely switched to ENDS, as compared with placebo or a cigarette substitute., Implications: The extent to which use of electronic nicotine delivery systems (ENDS) for smoking reduction leads to cigarette abstinence in smokers with no plans to quit smoking was unclear. This randomized trial found that ENDS with nicotine delivery approaching that of a cigarette are more effective in helping ambivalent smokers to quit cigarette smoking., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Varenicline is a safe and effective aid to smoking cessation but most trials have involved frequent visits or intensive behavioral support unlike that typically provided in primary care. The current study examined if motivational text messages, sent via cellphone, would increase quit rates in smokers being treated with varenicline and 3 brief sessions in a family practice setting., Methods: This study was a randomized controlled, parallel-group smoking cessation trial. Intervention group participants (n = 74) received daily motivational text messages, additional texted tips in response to keywords, and weekly study questions while control group participants (n = 76) received only weekly study questions. Both groups received individualized counseling. Self-reported non-smoking and exhaled breath CO <10ppm were used to validate smoking abstinence at 3 weeks and 12 weeks., Results: Overall, 30.7% (46/150) of participants were abstinent at the 12 week follow-up and the abstinence rate did not differ between groups (INT 31.1% v. CON 30.3%, p = .91). The only predictor of abstinence at 12 weeks was use of varenicline during a previous quit attempt (p = .01). Intervention group participants were more likely to rate the text messaging program as good or excellent (p < .01), to recommend a similar program to family or friends (p < .01), and to complete positive smoking cessation activities (p = .04), when compared with the control group., Conclusion: Although there were no differences in quit rates between the intervention and control group, intervention group participants rated the text messaging system more favorably, were more likely to recommend the program to others, and were more likely to complete positive smoking cessation activities.

Background: Along with the growth in popularity of electronic cigarette devices (e-cigs), the variety of e-cig liquids (e-liquid) available to users has also grown. Although some studies have published data about the use of flavored e-liquid, there is no standardized way to group flavors, making it difficult to interpret the data and replicate results across studies. The current study describes a method to classify user-reported e-liquid flavors and presents the resulting proportion of users in each flavor group in a large online survey of e-cig users., Methods: Three thousand seven hundred sixteen participants completed an online survey about their e-cig use and responded to the following open-ended question regarding their use of e-liquid, "What is your favorite flavor and what brand of flavored liquid do you prefer?" Researchers used a 3 step method to determine the flavor attributes present in the e-liquids reported using an online search engine. Once all flavor attributes were identified, researchers used the constant comparative method to group the flavor attributes and delineate how to classify flavors with mixed components (eg, cinnamon Red Hots as a candy not a spice)., Results: The resulting classification scheme and proportions of e-liquids in each category were as follows: Tobacco (23.7%), Menthol/mint (14.8%), Fruit (20.3%), Dessert/sweets (20.7%), Alcohol (2.8%), Nuts/spices (2.0%), Candy (2.1%), Coffee/tea (4.3%), Beverage (3.1%), Unflavored (0.4%), and Don't Know/Other (5.8%)., Conclusion: To better understand the use of flavored e-liquids, standardized methods to classify the flavors could facilitate data interpretation and comparison across studies. This study proposes a method for classifying the characterizing flavors in e-liquids used most commonly by experienced e-cig users., Implications: Current studies on the use of flavored e-liquid have used unclear methods to collect and report information on the use of flavors. This study adds a proposed method for classifying the flavors in the e-liquids used most commonly by experienced e-cig users. With a clear and explicit method for classifying self-reported flavors, future study results may be more easily compared., (© The Author 2017. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: Exhaled breath carbon monoxide (eBCO) reading is a useful tool for nurse practitioners to evaluate smoking status and other exposures to carbon monoxide (CO) to identify risk for cancer and chronic disease. This study aimed to measure one community's eBCO and identify potential environmental factors that may affect eBCO among nonsmokers., Methods: Data collected by convenience sampling at community health events included self-reported tobacco use and potential CO exposure. Means and frequency calculations describe the sample, two-sided t-tests determine differences in continuous variables, and chi-square tests determine differences in frequencies of CO levels between nontobacco users exposed to additional CO from their environment and nontobacco users who were not., Conclusion: As expected, smokers have significantly higher mean eBCO than nonsmokers (20.1 ppm vs. 4.4 ppm, p < .001). The self-reported nonsmokers (16.2%) had an elevated eBCO (>6 ppm), although there were no environmental factors that explained a higher eBCO., Implications for Practice: Measuring eBCO provides an opportunity for the nurse practitioner to engage in a conversation about the impact of smoking and other environmental factors that contribute to eBCO and health. Keeping record of patients' smoking status and eBCO in their medical record is a valuable measure of the nurse practitioner's delivery of this care., (©2017 American Association of Nurse Practitioners.)

Background: Some jurisdictions have passed legislation that bans electronic cigarette (e-cig) use (vaping) in public places similarly to smoking. Many other jurisdictions have not yet determined how to regulate vaping in public places. This study examined the proportion of current e-cig users who find their vaping restricted in public places and further evaluated factors associated with the differences between restricted and unrestricted vapers., Methods: 3960 experienced exclusive e-cig users completed an online survey from December 2012 to May 2014 about their e-cig use. Restricted vapers were defined as those who reported not being able to vape in places where smoking is typically banned. Unrestricted vapers were defined as those who reported being able vape in places where smoking is typically banned. χ 2 and two-sided t-tests were used as appropriate to determine differences between variables of interest., Results: Participants were a mean age of 40.3 years, 72.0% male, 91.8% white and 85.1% were from the USA. 26.1% (n=1034) of users reported restricted vaping, while 73.9% (n=2926) reported unrestricted vaping. Restricted vapers used less frequently (p<0.001) and were less dependent compared with unrestricted vapers (p=0.001). Of the restricted vapers, only 12% (n=124) reported finding it difficult to refrain from vaping in places where they were not supposed to. These users were more dependent (p<0.001) and more likely to experience strong cravings (p<0.001), compared with users who did not find it difficult to refrain from vaping., Conclusions: This study found that most vapers report unrestricted use of their e-cig. Of the restricted vapers, the majority (88%) do not find it difficult to refrain from vaping in places where they are not supposed to vape., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Competing Interests: Declaration of Interest All other authors declare that they have no conflicts of interest.

Background: The U.S. Food and Drug Administration can set standards for cigarettes that could include reducing their nicotine content. Such a standard should improve public health without causing unintended serious consequences for sub-populations. This study evaluates the effect of progressive nicotine reduction in cigarettes on smoking behavior, toxicant exposure, and psychiatric symptoms in smokers with comorbid mood and/or anxiety disorders using a two-site, two-arm, double-blind, parallel group, randomized controlled trial (RCT) in four phases over 34 weeks., Methods: Adult smokers (N = 200) of 5 or more cigarettes per day will be randomized across two sites (Penn State and Massachusetts General). Participants must have not had a quit attempt in the prior month, nor be planning to quit in the next 6 months, meet criteria for a current or lifetime unipolar mood and/or anxiety disorder based on the structured Mini-International Neuropsychiatric Interview, and must not have an unstable medical or psychiatric condition. After a week of smoking their own cigarettes, participants receive two weeks of Spectrum research cigarettes with usual nicotine content (11.6 mg). After this baseline period, participants will be randomly assigned to continue smoking Spectrum research cigarettes that contain either (a) Usual Nicotine Content (11.6 mg); or (b) Reduced Nicotine Content: the nicotine content per cigarette is progressively reduced from approximately 11.6 mg to 0.2 mg in five steps over 18 weeks. At the end of the randomization phase, participants will be offered the choice to either (a) quit smoking with assistance, (b) continue smoking free research cigarettes, or (c) return to purchasing their own cigarettes, for the final 12 weeks of the study. The primary outcome measure is blood cotinine; key secondary outcomes are: exhaled carbon monoxide, urinary total NNAL- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and 1-hydroxypyrene, oxidative stress biomarkers including 8-isoprostanes, measures of psychiatric symptoms (e.g., depression, anxiety), smoking behavior and dependence (e.g., cigarette consumption, quit attempts), and health effects (e.g., blood pressure, respiratory symptoms)., Discussion: Results from this study will inform FDA on the potential effects of regulating the nicotine content of cigarettes and help determine whether smokers with mood and/or anxiety disorders can safely transition to significantly reduced nicotine content cigarettes., Trial Registration: TRN: NCT01928758 , registered August 21, 2013.

Burn injuries in the United States account for over one million hospital admissions per year, with treatment estimated at four billion dollars. Of severe burn patients, 30-90% will develop hypertrophic scars (HSc). In this study, we evaluate the impact of an elastomeric, randomly-oriented biostable polyurethane (PU) scaffold on HSc-related outcomes. In vitro, fibroblast-seeded PU scaffolds contracted significantly less and demonstrated fewer αSMA(+) myofibroblasts compared to fibroblast-seeded collagen lattices. In a murine HSc model, collagen coated PU (ccPU) scaffolds significantly reduced HSc contraction as compared to untreated control wounds and wounds treated with the clinical standard of care. Our data suggest that electrospun ccPU scaffolds meet the requirements to reduce HSc contraction including reduction of in vitro HSc related outcomes, diminished scar stiffness, and reduced scar contraction. While clinical dogma suggests treating severe burn patients with rapidly biodegrading skin equivalents, our data suggest that a more long-term scaffold may possess merit in reducing HSc., Statement of Significance: In severe burns treated with skin grafting, between 30% and 90% of patients develop hypertrophic scars (HSc). There are no therapies to prevent HSc, and treatments are marginally effective. This work is the first example we are aware of which studies the impact of a permanent electrospun elastomer on HSc contraction in a murine model that mimics the human condition. Collagen coated polyurethane scaffolds decrease αSMA+ myofibroblast formation in vitro, prevent stiffening of scar tissue, and mitigate HSc contraction. Unlike current standards of care, electrospun, polyurethane scaffolds do not lose architecture over time. We propose that the future bioengineering strategy of mitigating HSc contraction should consider a long-term elastomeric matrix which persists within the wound bed throughout the remodeling phase of repair., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Hypertrophic scar (HSc) occurs in 40-70% of patients treated for third degree burn injuries. Current burn therapies rely upon the use of bioengineered skin equivalents (BSEs), which assist in wound healing but do not prevent HSc contraction. HSc contraction leads to formation of a fixed, inelastic skin deformity. We propose that BSEs should maintain their architecture in the wound bed throughout the remodeling phase of repair to prevent HSc contraction. In this work we study a degradable, elastomeric, randomly oriented, electrospun micro-fibrous scaffold fabricated from the copolymer poly(l-lactide-co-ε-caprolactone) (PLCL). PLCL scaffolds displayed appropriate elastomeric and tensile characteristics for implantation beneath a human skin graft. In vitro analysis using human dermal fibroblasts demonstrated that PLCL scaffolds decreased myofibroblast formation as compared to an in vitro HSc contraction model. Using a validated immune-competent murine HSc contraction model, we found that HSc contraction was significantly greater in animals treated with standard of care, Integra, as compared to those treated with collagen coated-PLCL (ccPLCL) scaffolds. Finally, wounds treated with ccPLCL were significantly less stiff than control wounds at d30 in vivo. Together, these data suggest that scaffolds which persist throughout the remodeling phase of repair may represent a clinically translatable method to prevent HSc contraction., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cellular reprogramming holds tremendous potential for cell therapy and regenerative medicine. Recently, fibroblasts have been directly converted into induced neurons (iNs) by overexpression of the neuronal transcription factors Ascl1, Brn2 and Myt1L. Hypothesizing that cell-topography interactions could influence the fibroblast-to-neuron reprogramming process, we investigated the effects of various topographies on iNs produced by direct reprogramming. Final iN purity and conversion efficiency were increased on micrograting substrates. Neurite branching was increased on microposts and decreased on microgratings, with a simplified dendritic arbor characterized by the reduction of MAP2(+) neurites. Neurite outgrowth increased significantly on various topographies. DNA microarray analysis detected 20 differentially expressed genes in iNs reprogrammed on smooth versus microgratings, and quantitative PCR (qPCR) confirmed the upregulation of Vip and downregulation of Thy1 and Bmp5 on microgratings. Electrophysiology and calcium imaging verified the functionality of these iNs. This study demonstrates the potential of applying topographical cues to optimize cellular reprogramming., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To estimate the maximum-tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with irinotecan at 40 mg/m(2) daily for 3 days in the treatment of relapsed or refractory acute leukemia or lymphoma., Patients and Methods: Patients with leukemia or lymphoma were escalated in separate strata. Stratum I consisted of 11 patients, median age of 47 years (range, 18 to 68 years), with relapsed or refractory leukemia. Stratum II contained nine patients, median age of 48 years (range, 39 to 68 years), who had refractory non-Hodgkin's lymphoma. Patients received irinotecan at 40 mg/m(2) daily for 3 days, beginning just before the first dose of gemcitabine. Gemcitabine was given at 10 mg/m(2)/min, with the total duration adjusted following a modified continuous reassessment model., Results: Severe myelosuppression and stomatitis/esophagitis were the most serious hematologic and nonhematologic toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours delivered at 10 mg/m(2)/min (7,200 mg/m(2)). The overall response rate for one cycle of this therapy in this phase I trial for patients with leukemia was 18% (95% confidence interval, 8% to 45%), and for those with lymphoma, 33% (95% confidence interval, 17% to 66%)., Conclusion: A prolonged infusion of gemcitabine at 10 mg/m(2)/min for 12 hours with 3 days of irinotecan at 40 mg/m(2)/d is a tolerable induction regimen for patients with acute leukemia or lymphoma. Stomatitis/esophagitis should be anticipated; however, this regimen may induce responses in patients with difficult-to-treat hematologic malignancies.

Objective: This study evaluated the relation between baseline clinical phenomena and response to amitriptyline in patients with posttraumatic stress disorder (PTSD)., Method: Data were obtained from an 8-week placebo-controlled, double-blind study of combat veterans. Bivariate and multivariate statistics were used to evaluate the relations between the following variables and outcome: age, depression, anxiety, severity of PTSD symptoms, personality, psychiatric comorbidity, level of exposure to trauma, and individual symptoms of depression, anxiety, and traumatic stress. Outcome measures were scores on the Clinical Global Impression scale, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, and Impact of Event Scale., Results: Drug response was related to lower baseline levels of depression, neuroticism, combat intensity, anxious mood, impaired concentration, somatic symptoms, feelings of guilt, and one intrusion and four avoidance symptoms of PTSD., Conclusions: The results demonstrate that response to amitriptyline is related to measures of depression, anxiety, PTSD, personality, and intensity of combat trauma. Similar relationships were not observed in the placebo group, suggesting a specific relationship to the drug.

Amitriptyline hydrochloride was compared with placebo in 46 veterans with chronic posttraumatic stress disorder. Treatment continued up to 8 weeks, and efficacy was measured by five observer and two self-rated scales. Percent recovery rates were higher for amitriptyline than placebo on two measures. In patients who completed 4 weeks (n = 40), better outcome with amitriptyline was noted on the Hamilton depression scale only. In the group completing 8 weeks of treatment (n = 33), the drug was superior to placebo on Hamilton depression, Hamilton anxiety, Clinical Global Impression severity, and Impact of Event scales. There was no evidence for drug effects on the structured interview for posttraumatic stress disorder. Drug-placebo differences were greater in the presence of comorbidity in general, although recovery rates were uniformly low in the presence of major depression, panic disorder, and alcoholism. At the end of treatment, 64% of the amitriptyline and 72% of the placebo samples still met diagnostic criteria for posttraumatic stress disorder.

The authors present a case of intermittent delirious mania in a hypomanic man. Studies revealed no other cause for the delirium, and it remitted with lithium carbonate therapy.

Fifty-six inpatients with unipolar depression completed treatment with isocarboxazid. In comparing the differences between responders and nonresponders, it was found that psychomotor retardation, pathological guilt, daily persistence of unremitting symptoms, phobic anxiety, dexamethasone suppression test nonsuppression, and neuroticism were significantly more common among nonresponders. Reactivity of mood, blaming others, and extraversion were more common in responders. Total endogenous depression scores on the Newcastle 1, Newcastle 2, and Michigan scales were also significantly higher in nonresponders. Attained platelet monoamine oxidase inhibition was similar in both groups.

We have previously reported 10 patient histories involving various intractable pain syndromes where the administration of Haloperidol either eliminated the need for narcotic analgesics or resulted in a significant reduction in narcotic dosage. We are presently undertaking a controlled double-blind evaluation of Haloperidol as an adjunctive treatment for intractable cancer pain. Based upon the reported clinical observations, these findings are discussed from the following aspects: 1. The isomeric similarity of Haloperidol to Meperidine. 2. Dose response between Haloperidol and analgesic effect. 3. The clinical literature regarding the use of Haloperidol for the effective withdrawal or maintenance of narcotic addicts. 4. The analgesic property as it relates to the opiate receptor.

Platelet monoamine oxidase (MAO) activity was assessed in 23 patients with posttraumatic stress disorder and 19 age-matched male control subjects. An overall significantly lower MAO activity was observed in the posttraumatic stress disorder group. When the group was divided into those with and those without a history of alcohol abuse, only the former group differed significantly from control subjects. The heuristic importance of these findings is discussed.

There are now several studies in the literature which document low blood platelet monoamine oxidase (MAO) activity in alcoholics. However, these reports are in disagreement as to the stability of reduced enzyme activity over time. The present study provides evidence that reduced platelet MAO activity in alcoholics is a relatively stable phenomenon, independent of ethanol consumption and proximate factors of the illness which are associated with excessive ethanol consumption.

A family history study of 36 patients with chronic posttraumatic stress disorder revealed a positive history of familial psychopathology in 66% of the patients. Alcoholism, depression, and anxiety disorders were the disorders most commonly found. The patients also had a higher prevalence of alcoholic siblings than did a retrospectively derived control group of depressed and anxious male patients. With respect to the proportion of familial anxiety to familial depression, the probands with posttraumatic stress disorder more closely resembled probands with generalized anxiety than probands with depression. Every patient had experienced at least one significant psychiatric illness during his lifetime, most commonly alcohol abuse or depression.