Current Drug Safety - Volume 14, Issue 3, 2019

Background: Antipsychotic medication is currently the treatment of choice for psychosis, but few studies directly survey the first-hand experience of recipients. Objective: To ascertain the experiences and opinions of an international sample of users of antipsychotic drugs, regarding positive and negative effects. Methods: An online direct-to-consumer questionnaire was completed by 832 users of antipsychotics, from 30 countries – predominantly USA, UK and Australia. This is the largest such sample to date. Results: Over half (56%) thought, the drugs reduced the problems they were prescribed for, but 27% thought they made them worse. Slightly less people found the drugs generally ‘helpful’ (41%) than found them ‘unhelpful’ (43%). While 35% reported that their ‘quality of life’ was ‘improved’, 54% reported that it was made ‘worse’. The average number of adverse effects reported was 11, with an average of five at the ‘severe’ level. Fourteen effects were reported by 57% or more participants, most commonly: ‘Drowsiness, feeling tired, sedation’ (92%), ‘Loss of motivation’ (86%), ‘Slowed thoughts’ (86%), and ‘Emotional numbing’ (85%). Suicidality was reported to be a side effect by 58%. Older people reported particularly poor outcomes and high levels of adverse effects. Duration of treatment was unrelated to positive outcomes but significantly related to negative outcomes. Most respondents (70%) had tried to stop taking the drugs. The most common reasons people wanted to stop were the side effects (64%) and worries about long-term physical health (52%). Most (70%) did not recall being told anything at all about side effects. Conclusion: Clinical implications are discussed, with a particular focus on the principles of informed consent, and involving patients in decision making about their own lives.

Background: Cisplatin is a commonly used chemotherapy agent known to induce serious adverse reactions that may require hospital readmission. We aimed to analyze the extent and factors associated with unplanned hospital admissions due to cisplatin-based chemotherapy regimen-induced adverse reactions. Methods: Retrospective review of medical records of those patients who received at least one cycle of chemotherapy with cisplatin-based regimen during a six-month period from March to August 2017. Results: Of the 458 patients who received cisplatin during the study period, 142 patients did not meet inclusion criteria. The remaining 316 patients had a total of 770 episodes of primary admissions for chemotherapy administration. Overall, 187 episodes (24%) of intercycle unplanned hospital admission were recorded of which a major proportion (n=178; 23%) was due to chemotherapy-induced adverse reactions. Underweight patients had higher odds of unplanned admission (OR 1.77, 95% confidence interval [CI] 1.11 to 1.77). Significantly, more number of patients with cancers of head and neck and cancers of musculoskeletal were readmitted (p<0.001). Compared to high-dose cisplatin, low- and intermediate-dose cisplatin had lesser odds of unplanned admission (OR 0.52 and 0.77; 95% CI, 0.31 to 0.88 and 0.41 to 1.45, respectively). Patients without concomitant radiotherapy, drug-drug interaction and initial chemotherapy cycles had lesser odds of unplanned admission (OR 0.38, 0.50 and 0.52; 95% CI, 0.26 to 0.55, 0.25 to 0.99 and 0.32 to 0.84 respectively). Unplanned admissions were mainly due to blood-related (31%) and gastrointestinal (19%) adverse reactions. Among chemotherapy regimens, cisplatin monotherapy (34%) and cisplatin with doxorubicin (20%) regimens resulted in a major proportion of unplanned admissions. Conclusion: These findings highlight risk factors that help identify high-risk patients and suggest that therapy modifications may reduce hospital readmissions due to cisplatin-based chemotherapy-induced adverse reactions.

Background: ADRs represent a substantial burden on health care resources worldwide and are considered as one of the leading causes of morbidity and mortality which significantly affects hospitalization rates. However, ADR related hospital admissions are not well explored in Saudi Arabia. Objective: The current study aims to evaluate ADR-related admissions at King Saud Hospital, Unaizah, Qassim, Saudi Arabia. Methods: A prospective, observational study was conducted at King Saud Hospital Unaizah. Over a period of 6 months, patients above 12 years of age who visited the Emergency Department (ED) with an ADR were included in this study. The investigators collected patient data by reviewing the patient's medical records and the ED records for admission. The Naranjo algorithm was used to assess the causality of the suspected ADR, and Hartwig’s Severity Assessment Scale was used to assess the severity of the ADR. Results: Out of 4739 admissions to the wards, 38 (0.801%) were related to an ADR. The majority of patients were male (52.6%), with a mean age of ± 49.08 years. The total length of hospital stay was 565 days with a mean of ± 14.87 days. The causality assessment shows that 35 (92.1%) cases were probable ADRs, whereas 3 (7.9%) cases were possible ADRs. Moreover, the severity assessment showed that 6 (15.1%) cases were mild, and 27 (71.1%) and 5 (13.2%) cases were moderate and severe, respectively. In regard to the outcome of patients, most patients recovered after the ADR, and 2 ADRs resulted in the death of the patient. Conclusion: Our study shows that ADRs as a cause of hospitalization in Qassim population is considerably low. However, ADRs may contribute to morbidity and mortality and result in a considerable financial burden.

Introduction: Antibiotic abuse is a common phenomenon in Egypt as medications are prescribed without supervision. It is suggested that the excess use of antibiotics modifies the gut microbiota and plays a role in the development of neurological and psychiatric disorders. Objective: The aim of the present study was to use bulb-c mice as models for curam (amoxicillin /clavulanic acid) abuse compared to the locally acting neomycin model, then restoring the probiotic balance to look at the possible effects on the animal brains. Methods: The results showed early excitable brains demonstrated by S100b immunohistochemistry in both cortexes and hippocampuses of neomycin-treated mice. Staining with PAS stain showed no suggested neurodegenerative changes. Treatment with probiotics improved the S100b immunohistochemistry profile of the curam group partially but failed to overcome the neuroinflammatory reaction detected by hematoxylin and eosin stain. Curam was possibly blamed for the systemic effects. Results: The neurobehavioral tests showed delayed impairment in the open field test for the curam group and impaired new object recognition for the neomycin group. These tests were applied by video recording. The neurobehavioral decline developed 14 days after the end of the 3-week antibiotic course. Unfortunately, curam abuse induced animal fatalities. Conclusion: Antibiotic abuse has a neurotoxic effect that works by both local and more prominent systemic mechanisms. It can be said that antibiotic abuse is a cofactor behind the rise of neuropsychiatric diseases in Egypt.

Background: Cyclophosphamide (CPA) is the most widely prescribed cancer chemotherapeutic agent which shows serious neurotoxic side effect. Generation of reactive oxygen species at the cellular level is the basic mechanism of cyclophosphamide induced neurotoxicity. Edaravone is the synthetic drug used for brain stroke and has potent antioxidant property. Objective: This study aimed to investigate the effect of edaravone on neurobehavioral and neuropathological alteration induced by cyclophosphamide in male rats. Methods: Twenty eight Sprague-Dawley rats were equally divided into four groups of seven rats in each. The control group received saline, and other groups were given CPA intraperitoneally (100 mg/kg), CPA (100 mg/kg) intraperitoneally + Edaravone (10 mg/kg) orally, or Edaravone (10 mg/kg) orally for one month. Results: Our data showed that CPA significantly elevated brain AChE activity in the hippocampal region. A decrease in the total antioxidant capacity and a reduction in the CAT, SOD, and GPX activity occurred in the brains of the rats exposed to CPA. CPA-treated rats showed a significant impairment in long-termmemory and motor coordination. These results were supported by histopathological observations of the brain. Results revealed that administration of edaravone reversed AChE activity alternation and ameliorated behavioral and histopathological changes induced by CPA. Conclusion: This study suggests that co-administration of edaravone with cyclophosphamide may be a useful intriguing therapeutic approach to overcome cyclophosphamide induced neurotoxicity.

Background: Adverse drug reactions (ADRs) due to antiepileptic drugs (AEDs) in children contribute to poorer patient outcomes. However, reliable data ragarding such ADRs is not available. Objectives: Thus, the aim of the present study was to determine the incidence and patterns of ADRs of antiepileptic drugs in children aged 2-17 years presenting to a tertiary care teaching hospital. Methods: An observational study was conducted in the Department of Pediatrics, Kalawati Saran Children’s Hospital for a period of one year. Two hundred consecutive eligible patients (aged 2-17 yrs with epilepsy on AED) with consenting parents were enrolled. ADRs were noted using Paediatric Epilepsy Side Effect Questionnaire (PESQ) at clinic visits and any other ADRs reported by parents were also recorded. Causality, severity and avoidability assessments were done. Results: The mean age was 10.5 ± 3.6 years. A total of 139 ADRs occurred in 97 patients. One hundred and nine ADRs were reported by use of PESQ, in addition, 30 ADRs were reported by parents. Poor school result (33.8%) was the commonest ADR. Valproate (61.9%) was the main drug causing ADRs. Valproate, when used in polytherapy, was associated with more number of children experiencing ADRs (72.2%). The most common add on drug was clobazam (42.3%). Children with poorly controlled epilepsy were associated with more ADRs. Causality assessment revealed that 91.3% of the ADRs were probable. Most (94.9%) ADRs were of ‘mild’ category and 95.7% were probably preventable. Treatment was discontinued only in 6 patients of phenytoin toxicity. Conclusion: Cognitive and neurological problems were the most common ADRs seen in children with epilepsy. Polytherapy significantly increases the likelihood of ADRs in children.

Background: Immune checkpoint inhibitors (CPIs) are new promising anti-cancer drugs that block negative costimulation of T-cells leading to an enhanced anti-tumor immune response. Pembrolizumab, an a monoclonal antibody, targeting the programmed cell death protein 1 (PD-1) pathway. CPIs have been associated with a number of immune-related adverse events (AEs), including musculoskeletal and rheumatic disease. Objective: To present a case with lung adenocarcinoma treated with pembrolizumab, which developed inflammatory arthritis and fasciitis. Case Report: A 73-year-old male patient was referred to the rheumatology outpatient clinic with complaints of pain in the pretibial area, pain and swelling in both ankles joints and the right fırst metacarpophalangeal (MCP) joint. Three months ago he had diagnosed with lung adenocarcinoma and pembrolizumab was started. Locomotor system complaints were started after receiving two infusions of pembrolizumab. Physical examination revealed both ankle arthritis, mild edema in the pretibial region, tenderness in the muscles and arthritis in the right fırst MCP joint. Laboratory examinations showed mild acute phase reactants elevation. Lower extremity MRI showed diffuse edema in both gastrocnemius muscle and fascia, compatible with fasciitis. Pembrolizumab-related fasciitis and seronegative arthritis were diagnosed. Low dose corticosteroid was started and a significant regression was observed in the patient's complaints. Conclusion: Inflammatory myositis with fasciitis and inflammatory arthritis in lower extremities appears to be a new adverse effect of pembrolizumab therapy.

Background: Hemocoagulase agkistrodon has been widely used for visceral bleeding, however, its adverse reaction has not been fully recognized. Case Report: A 65-year-old female with upper gastrointestinal hemorrhage occurred severe coagulation disorder during her hospitalization. Transfusion of blood products can not improve coagulation function. Coagulation parameters returned to normal two days after discontinuation of hemocoagulase agkistrodon. Conclusion: So intravenous administration of hemocoagulase should be cautiously used for the treatment of gastrointestinal bleeding.

Background: Panitumumab is an EGFR inhibitor used for the treatment of metastatic colorectal cancer (mCRC), even if its use is related to skin toxicity. Case Presentation: We report the development of forearm panniculitis in two women during the treatment with Panitumumab (6 mg/Kg intravenous every 2 weeks) + FOLFOX-6 (leucovorin, 5- fluorouracil, and oxaliplatin at higher dosage) for the treatment of mCRC. Results: In both patients, clinical, laboratory and radiological evaluation documented the presence of a local panniculitis, probably related to panitumumab (Naranjo score: 6). Panatimumab discontinuation and antimicrobial + corticosteroid treatment induced a remission of skin manifestations. Conclusion: We reported for the first time the development of panniculitis during Panitumumab treatment, and we documented that the treatment with beta-lactams to either fluoroquinolones or oxazolidinone in the presence of corticosteroid improves clinical symptoms in young patients with mCRC, without the development of adverse drug reactions or drug-drug interactions.

Objective: Olmesartan-induced enteropathy consists a syndrome that mimics celiac disease both clinically and histologically. Cases of this entity have sporadically been reported since 2012 and are usually characterized by severe diarrhea and malabsorption, followed by significant weight loss. Case Report: Herein, we report an uncommon case of this syndrome, where weight loss preceded several months the onset of gastrointestinal symptoms. Discussion and Conclusion: Physicians should be aware of unexplained weight loss in patients taking olmesartan, as prompt discontinuation of the drug may prevent the deleterious consequences of malabsorption.

Background: Programmed cell death protein 1 (PD-1) and its ligand, PD-L1, have shown great promise in clinical practice and have been incorporated into standard management of NSCLC. Pneumonitis is a serious autoimmune toxicity associated with the use of anti-PD-1/PD-L1 antibodies, resulting in significant morbidity and mortality. Methods: We described the case of a 73-year-old woman with no history of smoking developing exertional dyspnea four months after taking Pembrolizumab. Results: High resolution contrast CT scan (HRCT) presented a unilateral “crazy paving” pattern, and bronchoalveolar lavage (BAL) an important lymphocytosis (20% of total cell count). The patient reached clinical stability after the administration of systemic steroids (2mg\Kg\die) and was discharged with long term oxygen therapy. Discussion: Pulmonary toxicity is frequent when using PD-1 inhibitors, resulting in significant morbidity and mortality, often leading to the discontinuation of therapy. Clinical presentation is usually protean and HRCT pattern is nonspecific. This is the first case presenting a “crazy paving” pattern associated with BAL lymphocytosis. Conclusion: Oncologists, pulmonologists, radiologists and general practitioners have to consider PD-1 and PD-L1 inhibitor pneumonitis as a potentially disabling and fatal event.

Background: Calciphylaxis is a complex dermatological lesion of micro vascular calcification that is typically presented as panniculitis with gangrenous painful lesions having uremic and non-uremic causes. Case Report: We present a case of a 48-year old male with a history of paroxysmal atrial fibrillation and hypertension taking amlodipine 5 mg and warfarin 5 mg daily for the last 26 months. The patient had a 6- months history of painful swelling followed by necrotic skin ulcer over the right leg. His remarkable examination findings were right leg tender ulcer with surrounding erythema and secondary sepsis. His hemogram, metabolic profile and connective tissue diseases work up were unremarkable except leucocytosis and raised inflammatory markers. His local part radiological and skin biopsy findings were suggestive of calciphylaxis. Results and Conclusion: In our case, warfarin and amlodipine were culprit drugs for the lesion, but Naranjo score (warfarin 7and amlodipine 1) speculate warfarin as a probable adverse reaction of warfarin. The lesion was cured with local wound treatment after discontinuation of warfarin. The physician should be aware of this rare cutaneous disorder of systemic origin for proper management.

Background: Among the first line Anti-Tubercular Drugs (ATDs), ethambutol has been rarely associated to cause drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Case Report: A 34-year-old woman presented in an out-patient department of Dermatology with fever, skin eruptions, eosino- philia, hyperinflated lung fields and deranged liver enzymes after 35 days of the initiation of ATDs. The patient recovered completely after stopping ethambutol and administration of topical and sys- temic corticosteroids. Results and Conclusion: Based on the available evidences of de-challenge and re-challenge of suspected drugs, ethambutol was certainly implicated to cause DRESS syndrome.