Insights on food safety evaluation: A synopsis

The Life Sciences Research Office's Select Committee on GRAS Substances has completed a report entitled, “Insights on Food Safety Evaluation.” The report, in conjunction with an earlier report of the Select Committee, reflects the opinions and experiences garnered from a decade of evaluating the health aspects of generally recognized as safe (GRAS) substances. This second report identifies and discusses the principal components of the evaluation process and offers a perception of the issues that are critical for effectively evaluating the safety of foods and other ingested substances. Specific suggestions stemming directly from the Select Committee's experience in the GRAS review are made for improvements in the safety evaluation of food ingredients. Suggestions include phaseout of the GRAS list, modification of the Delaney Clause, utilization of appropriate human testing in protocols for evaluating candidate food additives, development of improved animal tests for behavioral effects of food ingredients, and improvement in procedures for detection of hypersensitivity to food ingredients. General priorities for study of the contribution of food and food ingredients to major causes of mortality and morbidity are also discussed.     

Cardiac safety of citalopram: prospective trials and retrospective analyses.

The selective serotonin reuptake inhibitors (SSRIs) are believed to have a more benign cardiovascular safety profile than do the tricyclic antidepressants. The effects of the SSRI citalopram on cardiac conduction and repolarization have been extensively evaluated, both in prospective studies in volunteers and patients and in retrospective evaluations of all electrocardiographic (ECG) data from all clinical trials conducted from 1978 through 1996 (a total of 40 studies). A randomized, double-blind, placebo-controlled study was conducted in healthy volunteers (N = 23) to assess intraindividual variability of the QTc interval, as well as possible changes during treatment with placebo or citalopram, and its correlation to plasma drug levels. To document any dose-related changes, ECGs were performed at baseline and at the end of study in three randomized, double-blind, placebo- or active-controlled, fixed-dose trials in adult and elderly patients (N = 1,460) with major depression and/or dementia. Finally, more than 6,000 ECGs (N = 1,789 citalopram-treated patients) collected from all clinical trials conducted from 1978 through 1996 were reassessed in a standardized manner to identify any effects of citalopram on ECG parameters. Results of both prospective and retrospective analyses showed that the only effect of citalopram on ECG findings is a small reduction in heart rate (< or = 8 beats per minute). There were no significant effects on PQ, QRS, or QTc intervals, indicating that citalopram has no effect on cardiac conduction and repolarization during short- or long-term treatment.     

Regulatory perspectives on data safety monitoring boards: protecting the integrity of data.

The use of interim analyses and data safety monitoring boards (DSMBs) can assist greatly in the timely determination of whether or not a medicine has an acceptable benefit-risk profile. Regulatory authorities regard the appropriate use of interim analyses favourably, but will consider the extent to which the conduct of interim analyses and the involvement of DSMBs may have compromised the evidence of efficacy and safety from a clinical trial. Issues of particular concern, which may potentially introduce bias, include the dissemination of interim data and the rules by which a trial might be terminated early. If data from trials which employ a DSMB are to be considered reliable and scientifically valid, it is the responsibility of the trial sponsor to demonstrate that the DSMB is set up and run appropriately and to verify that any bias introduced has had no important effect on the conclusions.     

甲磺酸倍他司汀联合盐酸氟桂利嗪治疗耳鸣的效果及安全性分析

目的 探讨甲磺酸倍他司汀联合盐酸氟桂利嗪治疗耳鸣的效果及安全性。方法 选取2016年1月-2017年12月西宁市第一人民医院收治的耳鸣患者178例,按照治疗方法的不同分为对照组、观察组,每组89例。对照组给予盐酸氟桂利嗪进行治疗,5 mg/次,1次/d,疗程2周。观察组在对照组基础上联合甲磺酸倍他司汀进行治疗,12 mg/次,3次/d,疗程2周。比较两组的临床疗效、治疗前后耳鸣程度、听力水平及治疗期间不良反应的发生情况。结果 观察组临床疗效的总有效率（87.64%）显著高于对照组（42.70%）,差异有统计学意义（P<0.05）。治疗前两组患者的耳鸣评分差异不显著,治疗后两组患者的耳鸣评分均显著降低,同组治疗前后比较差异有统计学意义（P<0.05）;且观察组显著低于对照组,差异有统计学意义（P<0.05）。治疗前两组患者的听力水平差异不显著;治疗后两组患者的听力均显著降低,同组治疗前后比较差异有统计学意义（P<0.05）;且观察组显著低于对照组,差异有统计学意义（P<0.05）。两组不良反应发生率差异不显著。结论 甲磺酸倍他司汀联合盐酸氟桂利嗪治疗耳鸣的效果优于单纯使用盐酸氟桂利嗪,安全可靠,值得临床应用与推广。     

Impact of a clinical pharmacist on medication safety in mental health Hospital-in-the-Home: a retrospective analysis

Background

Integration of clinical pharmacists into multidisciplinary Mental Health Hospital-in-the-Home teams is increasing but little is known about the medication safety contribution these pharmacists make.

Aim

To evaluate whether clinical pharmacist involvement in a Mental Health Hospital-in-the-Home service improved medication safety key performance indicators.

Method

Medical records were retrospectively reviewed of all patients admitted to 2 Western Australian Mental Health Hospital-in-the-Home services from September to November 2015.

Site 1

was a 16-bed service incorporating a clinical pharmacist as part of its multidisciplinary team.

Site 2

was a similarly structured 18-bed service but without clinical pharmacist involvement. The primary outcome measure was completion of medication safety key performance indicators obtained from the Western Australian Government Pharmaceutical Review Policy and mental health-specific best practice guidelines.

Results

Key performance indicators from Site 1 (n?=?75 records), which incorporated a clinical pharmacist, demonstrated significantly (p?<?0.001) higher rates of completion of medication reconciliation [65 (87%) versus 17 (29%)], accurate adverse drug reaction list [73 (97%) versus 34 (58%)], accurate discharge medication list [51 (74%) versus 18 (45%)], accurate medication profile [74 (99%) versus 40 (68%)] and medication chart review [74 (99%) versus 0 (0%)] than Site 2 (n?=?59).

Conclusion

Integrating a clinical pharmacist into a Mental Health Hospital-in-the-Home program significantly improved achievement of medication safety key performance indicators.

     

Sustained efficacy and safety of infliximab in psoriasis: a retrospective study of 73 patients

BACKGROUND: Infliximab inhibits T-cell activation by binding tumor necrosis factor-alpha (TNF-alpha). This medication is widely used in the US for treatment of psoriasis as an off-label indication. The durability of its effect is largely unknown. OBJECTIVE: To assess the proportion of patients still on infliximab 12 months after initiation of therapy for psoriasis. Methods: Retrospective chart review analysis of 73 patients with psoriasis treated with infliximab for at least 12 months or those who experienced treatment failure in less than 12 months. The point where infusions were deemed to no longer be efficacious was determined by physician's global assessment (PGA). RESULTS: Of 73 patients who started infliximab at least 12 months prior to this chart review, 22 (30.1%) had discontinued treatment secondary to loss of efficacy. Thirty seven patients (50.7%) had no loss of efficacy and continued to receive infusions. Two patients (2.7%) discontinued due to loss of efficacy after greater than 12 months. Of the 22 patients who discontinued treatment due to loss of efficacy, 2 were on concomitant methotrexate (5-7.5 mg/wk) therapy. Of the 37 patients still receiving treatment with no loss of efficacy at 12 months, 3 patients were on concomitant methotrexate therapy. Five patients (6.8%) discontinued secondary to minor adverse events: sinus infection (1), acne (1), fever (1), arthralgia (1), and transient rash (1). Three patients (4.1%) discontinued due to major adverse events: reactivation of tuberculosis (1), breast cancer (1), and gastrointestinal bleeding (1). One patient discontinued infliximab secondary to concerns of possible lymphoma risk (though there were no signs of symptoms of disease on examination), and 3 patients discontinued due to insurance concerns. CONCLUSION: Infliximab treatment resulted in significant improvement in psoriasis, with 37 out of 73 patients (50.7%) experiencing no loss of efficacy. This longitudinal retrospective chart review demonstrates continued benefit of infliximab infusions in about half of patients after 1 year, though a notable percentage (30.1%) experienced loss of efficacy as determined by physician's global assessment (PGA) and a number of others discontinued due to adverse events or insurance difficulty.     

Predictors of placebo response: a retrospective analysis.

This retrospective evaluation involved 197 patients from independent clinical investigations of four antidepressant medications. Six variables were analyzed for their discriminative utility in predicting placebo response rates: gender; marital status; age; education; duration of illness; and severity of depressive symptomatology, as measured by Hamilton Rating Scale for Depression (HAM-D or HDRS) scores. Men were slightly more responsive to placebo than were women (29.8%, n = 94 vs. 24.3%, n = 103). Married patients demonstrated the highest probability of a positive placebo response (38.15%, n = 76), as compared with widowed/separated/divorced (21.9%, n = 73) or single (16.7%, n = 48) patients. A trend toward an increased probability of placebo response was detected for patients aged 60 and above (35.7%, n = 14). Educational level achieved and duration of illness were not predictive. Severity of illness proved most noteworthy, with the placebo response rate higher in the more mild patients (40.8%, n = 27 vs. 23.4%, n = 77).     

Virus safety of a pasteurized antithrombin III concentrate. Preclinical and clinical data

Blood derived products carry the risk of virus transmission, especially for the hepatitis B virus (HBV), non-A/non-B virus(es) (NANBV) and human immunodeficiency virus (HIV). The precautionary measures for guaranteeing the virus safety of the pasteurized antithrombin III concentrate Kybernin HS/P are described and the efficacy of these measures is demonstrated by in vitro studies and by chimpanzee trials. The inactivation rate is greater than or equal to 10(6.7) for HIV, greater than or equal to 10(6.7) for HBV, and greater than or equal to 10(5.3) for NANBV (Hutchinson Pool). Clinically, virus safety was demonstrated by long-term drug surveillance as well as by both a retrospective and prospective clinical trial. The 13 participants of the prospective study were checked clinically and biochemically according to the standards of the International Committee of Thrombosis and Hemostasis (ICTH). Within an observation period of 12 months, no seroconversion has been detected for HIV or HBV. Neither have any increases in the transaminases occurred which would indicate NANB hepatitis.     

Backtracking booze with Bayes--the retrospective interpretation of blood alcohol data.

1. A Bayesian method is described which allows the explicit estimation of errors produced in estimating drug concentrations at times for which samples are not available for analysis. 2. This method was applied to the problem of 'backtracking' alcohol concentrations for medico-legal purposes. 3. Computer simulation allowed the effect of continuing alcohol absorption on the position and range of estimates of alcohol concentrations to be studied.     

Monopolar radiofrequency facial tightening: a retrospective analysis of efficacy and safety in over 600 treatments

BACKGROUND AND OBJECTIVES: Monopolar radiofrequency skin heating coupled with cryogen cooling of facial skin for skin tightening has been utilized on over 10,000 patients since 2002. In order to establish the actual rate and degree of side effects in our clinical experience, a retrospective chart review was performed. STUDY DESIGN: Charts and clinical images of over 600 consecutive patient treatments between May 2002 and June 2006 using a monopolar radiofrequency device (Thermacool, Thermage, Haywood, CA) for skin tightening at the Maryland Laser, Skin and Vein Institute were retrospectively reviewed. The primary presentation for treatment was skin laxity of the lower face. Treatment was delivered with a 1-cm2 standard tip at fluences of 81 to 124 J/cm2 (level of 12.5 to 15), a 1-cm2 "fast" tip at fluences of 62 to 109 J/cm2 (level of 72.0 to 76.0), a 1.5-cm2 "big fast" tip at fluences of 75 to 130 J/cm2 (level of 61.5 to 65), and a 3-cm2 "bigger" tip at equivalent fluences as each became available. As treatment algorithms evolved over 4 years, the algorithm of multiple passes at lower fluence associated with better clinical outcomes and greater patient acceptance has been adopted. RESULTS: The most common immediate and expected clinical effects were erythema and edema lasting less than 24 hours, although 6 patients reported edema lasting for up to 1 week. There were no permanent side effects. In total, 2.7% of treatments resulted in temporary side effects, the most significant of which was a slight depression on the cheek (n = 1), which completely resolved within 3.5 months. Other side effects included localized areas of acneiform subcutaneous erythematous papules (n = 4) and a linear superficial crust (n = 1) with the original tip, all of which resolved within 1 week. One patient reported small erythematous subcutaneous nodules resolving in 17 days. Tenderness of the neck lasting from 2 weeks (n = 2) to 3 weeks (n = 1) was also reported. CONCLUSIONS: Our data, obtained in an office setting without injectable anesthetic or i.v. sedation, indicate that monopolar RF for skin tightening is a very safe procedure. The treatment algorithm and tips have evolved over several years leading to increased safety and efficacy. Side effects are infrequent, self-limited, and minor, comparing favorably to other nonablative devices utilized for facial rejuvenation.     

Jud Coon: 35 years of p450 research, a synopsis of p450 history.

The year 2004 marks the 50th anniversary of the discovery of cytochrome P450. Minor J. (Jud) Coon has been a leader in this field for the last 35 years. This review summarizes his contributions to P450 research by discussing six of his most significant publications; not surprisingly, these papers serve as landmarks for the major directions followed in P450 research.     

Anticoagulation therapy in patients with chronic atrial fibrillation: a retrospective claims data analysis

OBJECTIVES: This study assessed the risk of thrombo embolic events and bleeding complications among atrial fibrillation patients. METHODS: A cohort of patients with chronic non-valvular atrial fibrillation were identified from medical claims (diagnosis codes 427.31 and 427.32). Subjects were identified from 1 January 1998-31 December 2000 and were continuously enrolled for 6 months prior to the first occurring atrial fibrillation medical claim. Cox proportional hazards analysis with time varying covariates was used for the event analysis. RESULTS: Of 6764 subjects retained for analysis, 3541 (52.4%) were exposed to warfarin. Adjusting for baseline characteristics, warfarin exposure was associated with lower likelihood of an arterial thromboembolic event compared to no exposure (HR: 0.710, CI: 0.540-0.934). No benefit was found in the use of warfarin in the prevention of intracranial events (HR: 1.119, CI: 0.929-1.349). Use of warfarin increased the risk of minor bleeding events (HR: 3.600, CI: 2.537-5.109), and all bleeding events (HR: 1.502, CI: 1.289-1.749). CONCLUSIONS: The risk of arterial thromboembolic events was associated with warfarin exposure as expected. An increase in the risk of minor and total bleeding events among patients treated with warfarin was observed. The results of this study suggest that there may be a gap between the clinical trial and coagulation clinic performance of warfarin in reducing the risk of thromboembolic events versus what is achievable in general practice.     

Zanamivir: a review of clinical safety.

Preclinical and clinical studies have clearly demonstrated that zanamivir, a potent and highly selective inhibitor of the influenza A and B virus neuraminidase, has an impressive safety profile. This report describes the safety and tolerability findings from the clinical studies completed up to the 17 July 1998 involving over 6000 adult and adolescent patients from North America, Europe and the Southern Hemisphere. Serious adverse events from an ongoing Japanese clinical programme are also reported. Zanamivir was administered in various dose forms and frequencies and was found to have a comparable safety profile with placebo when given for both the treatment and prophylaxis of influenza-like illness. These findings were independent of age and underlying medical condition. 4152 patients received zanamivir and the most commonly reported adverse events were consistent with the signs and symptoms of influenza-like illness. Most of the adverse events were mild and did not result in patient withdrawal from the studies. Less than 1% of zanamivir and placebo recipients reported a serious adverse event. In addition, 490 healthy volunteers received zanamivir in clinical pharmacology studies. It was well tolerated and the incidence of adverse events was similar in zanamivir and placebo recipients. In addition, no clinically significant laboratory abnormalities were detected. Results from in vitro and in vivo animal studies suggest that zanamivir has low acute toxicity and no significant systemic toxicity or respiratory tract irritancy at plasma exposures more than 100-fold higher than those anticipated following clinical use. Neither genotoxic nor reproductive types of toxicity have been observed in toxicology studies at doses equal to 17 to 197 times the current therapeutic dose (20 mg/day). The characteristics of the molecule and the low systemic exposure indicate a very low potential for drug interactions with the inhaled route. Furthermore, repeated 600mg intravenous doses were well tolerated in healthy volunteers. The observed safety profile of zanamivir compares favourably with currently available agents with anti-influenza virus activity, such as rimantadine and amantadine, as well as GS4104, a neuraminidase inhibitor currently in phase III development. This may be attributed to the low systemic bioavailability of zanamivir, which is given by oral inhalation, direct to the primary site of viral replication. The potential advantages of this include a reduced risk of drug-drug interactions, other nontarget organ toxicities (e.g. brain) and drug clearance issues from both kidney and liver. Therefore, the safety profile of zanamivir supports its use in the management of influenza.