3 Toxicity and drug safety

Safety concerns at the FDA

Strategy support for the Post‐Market Monitoring (PMM) of GM plants: Review of existing PMM strategies developed for the safety assessment of human and animal health

Chapter 29 - Drug safety in Yemen

Drug tolerability and drug safety are sometimes used interchangeably, but they represent somewhat different concepts. This editorial examines the differences between drug tolerability and safety. A literature search was conducted on MEDLINE (PubMed) to assess the differences between drug tolerability and safety. Drug tolerability is predominantly dependent on patients’ subjective experiences, whereas drug safety is determined by a carefully regulated process based on objective measures. For a drug to be useful, it must be tolerable and safe.

Safe drugs to fight mutant protein overload and alpha-1-antitrypsin deficiency

The American College of Medical Toxicology (ACMT) recently published an updated Code of Ethics for Medical Toxicologists [1]. The guidelines laid out in this document are said to supplement the Code of Medical Ethics of the American Medical Association, rather than to replace them [2]. This begs the question, BWhy do medical toxicologists need their own code of ethics?^ Perhaps one reason is because ethical standards are a crucial element that can distinguish medical toxicologists from some other practitioners who offer services related to poisoning. Medical toxicologists continue to suffer an identity crisis. For example, the distinction between medical toxicologists, forensic toxicologists, environmental toxicologists, and laboratory toxicologists is often unclear to the public. While it may be easy to explain that a medical toxicologist treats patients while a laboratory toxicologist analyzes specimens, it becomes a bit more complicated to explain the difference between a medical toxicologist and another health practitioner who identifies as a ‘toxicologist’ and claims expertise in poisoning treatment. While the most obvious factors that differentiate medical toxicologists are specialized training in an ACGMEaccredited fellowship and confirmation of expert-level knowledge through subspecialty board certification by the Medical Toxicology Sub-board of the American Board of Emergency Medicine, a less recognized but incredibly important distinction is the high ethical standard expected of a medical toxicologist. The ACMT Code of Ethics addresses topics that are relevant to physicians across many specialties, such as the physician-patient relationship, expert testimony, and involvement in research and medical education. Situations that may be disproportionately encountered by medical toxicologists, such as treating a suicidal patient or establishing a nontreating relationship during an independent medical examination, can present challenges that the ACMT Code of Ethics may help guide. While all of these topics are important to the ethical practice of medical toxicology, it is the unassuming, short section toward the end of the document on BUse of NonAccepted Therapies^ that especially speaks to the differences between the fellowship-trained, board-certified medical toxicologist and a practitioner who promotes poisoning diagnoses and provides services that are not medically justifiable. Regarding the BUse of Non-Accepted Therapies,^ the code of ethics states that the medical toxicologist must never use personal gain as a motivating factor in choosing a therapy. Most obviously, personal gain may be financial. In fact, there is great financial opportunity in diagnosing and treating poisoning, regardless of whether poisoning is present. When scientific evidence does not support a test, diagnosis, or treatment, the medical toxicologist must discuss this with the patient honestly and respectfully. This honest discussion can be much more difficult than supporting a belief or previous diagnosis of toxicity and agreeing to initiate or continue an unproven therapy. And it leaves the medical toxicologist without the security of future patient visits and payments. ACMT’s participation in the ABIM Foundation’s BChoosing Wisely^ campaign reflects this position with many of its choices of BThings Providers and Patients Should Question^ [3]. ACMT asks providers not to recommend use of dietary supplements, which currently constitute a multi-billion dollar industry in the US. Other ACMT BChoosing Wisely^ action items recommend against the use of provoked urine tests to diagnosemetal poisoning, the use of unproven detoxification therapies such * Anne-Michelle Ruha michelle.ruha@bannerhealth.com

“Black box” 101: How the Food and Drug Administration evaluates, communicates, and manages drug benefit/risk

Background : Benign prostatic enlargement (BPE) is the most frequent cause of lower urinary tract symptoms (LUTS) in men. The objective of this study was to evaluate the efficacy and safety of Prostasan, the plant extract of saw palmetto in men with LUTS/BPE. Methods : The study was approved by the Ethical Committee of the Republic of Slovenia. In a prospective, open clinical study, men between 45 and 80 years of age with at least moderate LUTS/BPE, normal serum PSA, in a good physical condition were included after having given their written informed consent . At the beginning of this study, the digito-rectal examination of the prostate was performed together with the evaluation of IPSS and quality of life, total PSA in serum, uroflow and transabdominal US measurement of prostate volume. They were also asked about their erectile dysfunction and libido. All patients received Prostasan 320 mg per day for 12 months. The same parameters as at the beginning of the study were assessed after 6 and 12 months. The subjective assessments of the efficacy and safety of the drug were also recorded byinvestigators and by patients. The side effects of the treatment were recorded at both follow-ups. For statistical analyses, t-test and chi-square tests were used. Results : 72 men out of 76 (94.7 %) with LUTS/BPE completed the trial. They were 62.7 ± 8.54 years old. IPSS score and quality of life were reduced from 14.46 ± 5.36 to 11.08 ± 3.92 (p = 0.0000) and from 2.72 ± 0,96 to 2.25 ± 1.05 (p = 0.0001) respectively after 12 months of treatment. The uroflow increased from 13.94 ± 5.00 to 15.34 ± 4.07 ml/s (p = 0.0005). Total PSA did not change significantly. After 12 months, prostate volume decreased by 3 % (p = 0.0392). Prostasan had no important influence on erectile function or libido. The majority of patients and doctors rated the efficacy of drug as good (69.7 % and 72.4 % ) and safe (86.8 % and 88.2 %), respectively. Seven patients (9.2 %) reported drug-related side effects. Conclusions : According to our 12-month clinical trial, we could conclude that Prostasan is a safe and efficient natural drug for the treatment of men with mild to moderate LUTS/BPE.

Introduction: Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder with a high prevalence. Besides efficacy, the safety of each drugs used to treat GI disorders is an important issue in the drug development process.Areas covered: This article reviews all Phase I to IV clinical trials or case reports with results related to the safety of novel GI drugs. The drugs are currently approved or under evaluation for approval.Expert opinion: Most of the reported adverse events were related to the GI tract with mild-to-moderate severity. Diarrhea was significantly higher versus placebo following use of linaclotide and renzapride, similar to that of constipation with ramosetron. Lubiprostone, linaclotide and rifaximin with low systemic bioavailability have less adverse events and exert more advantageous results. Asimadoline acts peripherally on κ-opioid receptors and is not associated with CNS side effects. As lubiprostone and linaclotide cause dose-dependent adverse events, starting the treatment with the lowest effective doses is advised. Ramosetron is under evaluation for diarrhea-predominant IBS due to its acceptable safety and tolerability, besides its efficacy. Rifaximin, asimadoline and renzapride are still in need of more long-term studies regarding their safety.

Simple SummaryGiven the low prevalence and the heterogeneity of childhood cancers, information about the safety of anti-angiogenic drugs in pediatric patients is only partially assessed. We aimed to evaluate the safety of these drugs in children with solid tumors. This systematic review and meta-analysis reported that one out of two pediatric patients using anti-angiogenic drugs in monotherapy experienced a serious adverse event despite proportions varying per single drug.Cancer is a clinical condition that can benefit from anti-angiogenic drugs (AADs). Given the low prevalence and the heterogeneity of childhood cancers, information about the safety of these drugs in pediatric patients is partially assessed. The aim of this study was to evaluate the safety of AADs in pediatric patients with solid tumors. Clinical trials and observational studies were searched in PubMed, ISI Web of Science, and ClinicalTrials database For each included study, adverse events (AEs) were extracted. A meta-analysis was conducted by pooling proportions of AEs using a random intercept logistic regression model. Seventy studies were retrieved. Most part were clinical trials (55 out of 70), and only fifteen observational studies were found. Overall, proportion of serious and non-serious AEs of AADs used as monotherapy was 46% and 89%, respectively. Proportions of serious AEs varied among drugs: sunitinib, 79%; lenvatinib, 64%; sorafenib, 48%; ramucirumab, 41%; pazopanib, 30%; and vandetanib, 27%. A higher proportion of non-serious hematological AEs was found in the patients receiving pazopanib with respect to sunitinib and lenvatinib. The safety profile of AADs has been extensively investigated for mostly drugs in phase I and II trials and is limited to acute toxicities. Overall, one out of two patients using AAD drugs in monotherapy experienced a serious AE despite proportions varied per single drugs. When AADs were combined with standard chemotherapy, the proportion of AEs varied in relation to the single combinations.

Objectives:To assess the efficacy and safety of anti-tuberculosis drugs in HIV-positive patients at a tertiary care teaching hospital.Materials and Methods:As a part of an ongoing study of opportunistic infections (OIs) in HIV-positive patients, drug treatment in patients suffering from tuberculosis was assessed to determine its efficacy and safety. Based on prevalence data for last three years, a purposive sampling of study population was carried out in this observational, prospective, single centre study. Tuberculosis (TB) was the most common OI observed. The selected patients were followed up for a period of one year to evaluate the clinical course and outcome of OIs, and the efficacy and safety of drugs used was checked.Results:Tuberculosis was observed in 89 out of 134 enrolled patients. These included 79 adults and 10 children. Males (66.2%) were commonly affected. Extra pulmonary TB (73%) was the most common manifestation with abdominal TB observed in 55 (61.7%) patients. All patients were treated in accordance with the Revised National Tuberculosis Control Programme (RNTCP) guidelines as recommended by National AIDS Control Organization (NACO), India. Outcome of TB was assessable in 70 patients. Majority (82.8%) of the patients were cured, while 12 patients (17.1%) died during the course of treatment. A total of 149 ADRs were observed in 67 (75.2%) patients. Majority of ADRs (n = 147) were non-serious and did not warrant a change in therapy. Discoloration of urine was the most common ADR observed.Conclusion:TB is the most common opportunistic infection in HIV-positive patients with abdominal TB being the most common manifestation. RNTCP and NACO guidelines are adhered to in these patients. Anti-tuberculosis drugs are well tolerated and effective in majority of the patients.

Modern animal husbandry and poultry farming is developing very rapidly compared to the possibilities of previous years. Obtaining high economic indicators is possible with balanced feeding and strict observance of veterinary and sanitary measures. Failure to comply with the technology of cultivation leads to the activation of opportunistic pathogens. During the industrial rearing of animals, microflora accumulates both indoors and in the environment. Fattening animals with pelleted feed indoors and the lack of contact with donors of typical microorganisms available in nature (soil, insects, plants) lead to the intestine's colonization by enterobacteria. As a result, probiotics have become very popular in animal husbandry and poultry to normalize the intestinal microflora and disinfect humus, treat animal housing, and eliminate odors: probiotics – microbial drugs which are stabilized cultures of microorganisms that have antagonistic activity against pathogenic microflora. Today, the sources of probiotic strains are nine species of microorganisms. However, probiotics' antimicrobial and stimulating potential based on safe and effective strains of B. subtilis and B. amyloliquefaciens bacilli is much higher than probiotics based on Lacto- and bifidobacteria. The study aimed to investigate the safety and cute toxicity of the probiotic drug “Biozapin” based on a mixture of probiotic bacteria Bacillus sybtilis, Bacillus amyloliquefaciens and aluminosilicate with a single injection into animals and to establish the maximum therapeutic, toxic and lethal doses. The article presents information on the study results of acute toxicity and safety of the drug “Biozapin”. At intragastric administration of this drug to white mice at a dose of 5000 mg/kg of body weight, it does not cause their death; therefore, it is possible to draw a conclusion that this drug is nontoxic. Dilution of the drug “Biozapin” in various concentrations are harmless to the simplest tetrachimene piriformis. The increase in live weight of one head of mice with forced administration of the drug “Biozapin” intragastrically in different concentrations was: sample № 1 – 11.5 %, sample № 2 – 10.0 %, sample № 3 – 13.5 %, sample № 4 – 11.7 %, sample № 5 – 11.1 %, in the control group – 13.9 %. At pathological autopsy of animals, no visible pathological changes were found. The results of toxicological studies have shown that the drug “Biozapin” is harmless and non-toxic.

The article discusses the results of the study of biological activity and safety of new for the treatment and prevention of diarrhea of calves of various etiologies. The study includes evaluation of protective properties of hyperimmune preparations for treatment and prophylaxis of calf diarrhea in white mice. The safety of the drugs was assessed using standard methods of toxicology and clinical monitoring. According to the results of the study, the preparations demonstrated high effectiveness in prevention of calf diarrhea and acceptable safety characteristics. The methods of evaluation of biological activity of hyperimmune drugs, such as serological tests, tests in rodents and calves,antigen neutralization assay, as well as toxicity and side effects evaluation methods and interactions with other drugs are considered. Information about the application of modern technologies to improve the efficacy and safety of the drugs is also given.The results of the study showed that the new hyperimmune drugs have high biological activity and significantly increase the level of antibodies in animals, which contributes to their protection from infectious diseases. The hyperimmune preparations have shown good safety at the recommended doses, without causing toxic or allergic reactions.The results of the performed studies and possible ways to improve hyperimmune agents in veterinary practice are presented. Examination of biological activity and safety of new hyperimmune drugs in veterinary medicine is necessary to assess their efficacy, safety and applicability in various conditions.

The incidence of schizophrenia in the general population ranges from about 1% to 2%. Schizophrenia affects men and women equally, occurring in all cultures and socioeconomic classes. The peak age of onset in women is 25 to 35 years, which are also the peak childbearing years, and women with psychotic illnesses are likely to have more unplanned pregnancies than women without a psychotic illness. Not only are antipsychotic medications prescribed for schizophrenia, but, especially since the introduction of the second-generation (atypical) antipsychotics, these drugs are also used to treat other psychiatric illnesses such as bipolar disorder. As a result, there is an increase in the number of women requiring antipsychotic drug therapy who are likely to become pregnant. It is important to evaluate the safety of these drugs in pregnancy, as most women with a serious psychiatric illness cannot stop taking their medication, as this would interfere with their activities of daily living, especially taking care of an infant. In this review, we describe available up-to-date, evidence-based information regarding the safety of antipsychotic drugs that are currently used in pregnancy. These include first-generation (conventional) antipsychotics (eg, promethazine, chlorpromazine, prochlorperazine, haloperidol, perphenazine, trifluoperazine, loxapine, thioridazine, flupenthixol, fluphenazine) and second-generation antipsychotics (eg, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone). To date, no definitive association has been found between use of antipsychotics during pregnancy and an increased risk of birth defects or other adverse outcomes. However, there is a paucity of information, with a lack of large, well designed, prospective comparative studies. The information presented here should therefore not be interpreted as conclusive with regard to the safety of these drugs, as more research is needed. Women who require treatment should always discuss the risks and benefits of pharmacotherapy with their physician and, if it is felt that treatment should be continued during pregnancy, the evidenced-based information presented here will be of help in this important decision.

IntroductionLiver cirrhosis can have a major impact on drug pharmacokinetics and pharmacodynamics. Patients with cirrhosis often suffer from potentially preventable adverse drug reactions. Guidelines on safe prescribing for these patients...