Idiosyncratic Side Effects Research Articles

Unintentional unblinding in rheumatic disease trials.

The practice of blinding treatment assignment in randomised controlled trials mitigates important biases in observational studies. Unblinding, whereby study participants or investigators become aware of treatment assignments, is an important threat to the validity of trial results. Rheumatology studies might be particularly susceptible to unblinding because rheumatic disease therapies often cause high rates of idiosyncratic side-effects and frequently rely on subjective endpoints. Despite this susceptibility, the degree to which unblinding occurs in randomised controlled trials in rheumatic diseases has rarely been assessed during trials or acknowledged as a limitation. Rheumatologists should be aware of this important threat to the validity of trial results, assessments of unblinding should be undertaken, and strategies to prevent unblinding should be deployed when feasible.

P595 Finding predictors of azathioprine-induced pancreatitis in patients with inflammatory bowel disease

Abstract Background Azathioprine (AZA)-induced pancreatitis (AIP) is a common, idiosyncratic side effect, whose incidence, clinical course and risk factors data in inflammatory bowel disease (IBD) patients are scarce. We aimed to establish the incidence, describe the clinical course and identify risk factors for AIP. Methods Retrospective study including all IBD patients on AZA between January 2013 and July 2020. Patients with AIP were considered. Demographic, clinical, biochemical and imaging data were collected. Results AIP occurred in 33 patients (7.5%; 442 patients on AZA): 81.8% had Crohn’s disease, 54.5% were male, and the mean age was 35±13 years. The mean time under AZA till AIP was 25±11 days, with a mean dosage of 88±44mg. Eighteen patients (54.4%) were hospitalized, with a mean hospital stay of 4±2days. All patients had a mild course of disease which resolved with suspension of AZA, and with no complications or need of invasive interventions or complications. Smoking (p=0.02), single daily dose of AZA (p<0.001) and concomitant treatment with budesonide (p=0.001) were risk factors for AIP. In multivariate analysis, concomitant treatment with budesonide (OR: 5.3; p=0.002) and single daily dose of AZA (OR: 4.8; p=0.002) were the only predictors of AIP. Conclusion Although AIP was a relatively common side effect, it presented a mild course in all patients. Smoking, concomitant treatment with budesonide and single daily dose of AZA were risk factors for AIP. This study suggests that smoking, concomitant use of budesonide and single dose regimen of AZA should be avoided in IBD patients treated with AZA.

POS-014 DOXAZOCINE-INDUCED LUPUS NEPHROPATHY

Drug-induced lupus (DIL) refers to an idiosyncratic side effect of numerous, apparently unrelated medications, in which symptoms overlap with those of systemic lupus erythematosus. Over 100 drugs have been linked to DIL to date and the list is growing. Like idiopathic lupus erythematosus, DIL has systemic, subacute cutaneous, and chronic cutaneous forms. We report the first case of lupus nephrothy related to Doxazocine treatment.

73 - A Rare Case of Methimazole-Induced Concomitant Cholestasis and Severe Agranulocytosis That Recovered Rapidly With High Dose Filgrastim

Agranulocytosis and hepatotoxicity are rare, independent and idiosyncratic side effects of thionamide use with an estimated frequency of 0.2-0.5% and 0.1-0.2%, respectively. Only 4 cases (all females) of their simultaneous occurance in the same patient have been reported so far. Evidence suggests that use of granulocyte colony-stimulating factor (G-CSF) may shorten the duration of thionamide-induced neutropenia.

Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database

ObjectiveDrug-induced lupus (DIL) is an idiosyncratic side effect of treatments in which symptoms overlap with those of systemic lupus erythematosus (SLE). The spectrum of DIL constantly evolves with that of...

Comparative Evaluation of Efficacy and Safety of Monotherapy with Carbamazepine and Phenytoin In Epilepsy : A Meta-Analysis

Aims and Objectives
 
 To review and analyse statistically the evidence from existing randomised controlled trials.
 To compare the efficacy and safety of carbamazepine and phenytoin when used as monotherapy treatments.
 To assess the effectiveness of the drug at controlling seizures and to evaluate tolerability with regard to side effects of these drugs.
 
 Methodology: A systemic review with the comparative evaluation of efficacy and safety of monotherapy with Carbamazepine and Phenytoin in epilepsy was carried out. Seven studies with Randomised Controlled Trials of carbamazepine and phenytoin as monotherapy were taken up for Meta Analysis based on the inclusion and exclusion criteria. Time to withdrawal of allocated treatment (retention time) was chosen as the primary outcome. Secondary outcomes included Time to achieve 12-month remission (seizure-free period), Time to achieve six-month remission (seizure-free period), Time to first seizure post-randomisation, Adverse events (including adverse events relating to treatment withdrawal. The data was entered in the MedCalc Statistical Software version 17.5.5 and analysed. The principal summary measure were the Odd’s Ratio And Hazard Ratio (HR) (at 95% Confidence Interval). Funnel Plot and Forest Plot were plotted.
 Results: The overall pooled odd‘s ratio for the primary outcome (for 862 participants) was 0.882(fixed effect model) and 0.877(random effect model) (95% confidence interval (CI)0.63 to 1.22, P = 0.3643). The P value was 0.3643 which proved the statistically insignificant difference in the efficacy of the two drugs(0.05 is considered as significant p value). As for the adverse effects ; rash, dysmorphic and idiosyncratic side effects include gum hypertrophy , hirsutism , acne etc. are more frequently associated with phenytoin. Drowsiness, Tiredness, Fatigue and sedation are more associated with carbamazepine as compared to phenytoin. The overall pooled odd’s ratio for “Time to achieve 6 month remission” (for 232 participants) was 1.232(fixed) and 1.272(random) (95% confidence interval (CI) 0.732 to 2.073(fixed), P = 0.0910), indicating an advantage for phenytoin for the 6 month remission outcome.
 Conclusion: The study concluded that there was no statistically significant difference achieved between the two treatment arms. Hence the neurophysician is compelled to rely on the individual patient characteristics for dispensing the drug. Hence the study provides a robust evidence that the two treatments are equally efficacious.

Recapturing Disease Response: A Phase II Study of High Dose Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma Who Have Progressed on Standard Dose Carfilzomib

Background:Carfilzomib (CFZ) is FDA approved at 27 mg/m2 D1,2,8,9,15,16 (except 20 mg/m2 D1,2, of cycle 1) to be given over 10 minutes with an overall response rate (ORR) of 23.7% (Siegel 2012). When CFZ is given as a 30 minute infusion, the dose can be safely escalated to 56 mg/m2, presumably due to a lower Cmax, on a twice weekly schedule with a higher ORR of 55% (Papadopoulos 2014). Our hypothesis was that the disease response of patients who progressed on CFZ 27 mg/m2 could recaptured by dose escalation to 56 mg/m2.Methods:Inclusion criteria were progressive disease (PD) at time of study entry, refractory to CFZ 27 mg/m2 without any Grade 3/4 toxicities, > 2 lines of therapy (including bortezomib and an IMID), measurable disease, adequate heme parameters (ANC > 1.0, plt > 50k), and organ function (Cr Cl > 15, cardiac ejection fraction (EF) > 40%).CFZ was given at 56 mg/m2 Day 1,2,8,9,15,16 over 30 minutes with dexamethasone (dex) 8 mg and ondansetron 8mg premedication. EF was monitored every 2 cycles.Results:13 patients received study treatment. The median age was 64.5 (50% greater than age 65 yo) with 4.5 median lines of treatment over 4 years from MM diagnosis. 5 (38%) were high molecular with risk gain of 1q21 by FISH and 3 with concurrent deletion of p53. Also 67, 58, 67, and 100% were refractory to each of the following respectively: lenalidomide, pomalidomide (pom), bortezomib, & CFZ.Prior to study entry, the median duration of time on CFZ 27 mg/m2 before PD was 136 days. All but 1 patient had been receiving dex 40 mg weekly and 3 had been receiving triplet therapy - 2 with concomitant pom and 1 with ibrutiinib (on a clinical trial).Of the 12 patients evaluable for efficacy, responses include 1 VGPR, 4 PRs, & 6 SDs, for an ORR of 42% and a median DOR of 6.5 mos. The median PFS was 3.5 mos. Interestingly, 2 of the 3 patients who progressed on CFZ based triplet regimens prior to study entry achieved a PR with CFZ dose escalation.Grade 3/4 toxicities (regardless of drug attribution) were primarily heme, with neutropenia (36%), thrombocytopenia (8%) and anemia (22%) respectively. Grade 3/4 nonheme AEs included 4 hypertension (HTN), 1 acute dyspnea, 1 ggt elevation, 1 back pain and 1 leg pain. When ggt was added on to screening labs for the patient with grade 4 ggt elevation prompting study discontinuation, it was noted to be elevated to grade 3 even at baseline.Of the 4 patients with Grade 3/4 HTN, 1 required dose CFZ modification but the remaining 3 were classified as grade 3 only due to the addition of an anti-HTN medications and did not require any CFZ dose modifications. HTN in one these 3 patients was also was in the setting of bone pain and PD. In the 4 patients with serial measurements of brain naturetic peptide (BNP), there were no changes. Similarly, EF was monitored on study for all patients and there were no decreases in EF or symptoms of CHF.Conclusions:Consistent with previous data, including from the Endeavor study, CFZ 56 mg/m2 is efficacious and well tolerated with manageable HTN. Even in this heavily pretreated population refractory to CFZ 27 mg/m2 and dex 40 mg weekly refractory and with high molecular risk features, dose escalation of CFZ to 56 mg/m2 with only dex 16 mg weekly was able to recapture disease response at ORR and PFS that have already surpassed the preplanned futility analysis. By avoiding early dose escalation of those that may be at risk for likely idiosyncratic side effects, both safety and lower cost may be maximized. These findings support enrollment to the ongoing SWOG S1304 randomized study comparing CFZ 27 and 56 mg/m2. DisclosuresChari:Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Osman:Millennium / Takeda: Research Funding. Catamero:Onyx: Other: Lecturer; Millennium/Takeda: Other: Lecturer; Celgene: Honoraria, Other: Lecturer. Verina:Celgene: Other: Lecturer. Jagannath:Novartis: Honoraria; Janssen: Honoraria; Merck: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria.

Azathioprine-induced Acute Pancreatitis in Patients with Inflammatory Bowel Diseases--A Prospective Study on Incidence and Severity.

Background and Aims:Azathioprine [AZA] is recommended for maintenance of steroid-free remission in inflammatory bowel disease IBD. The aim of this study has been to establish the incidence and severity of AZA-induced pancreatitis, an idiosyncratic and major side effect, and to identify specific risk factors.Methods:We studied 510 IBD patients [338 Crohn’s disease, 157 ulcerative colitis, 15 indeterminate colitis] with initiation of AZA treatment in a prospective multicentre registry study. Acute pancreatitis was diagnosed in accordance with international guidelines.Results:AZA was continued by 324 [63.5%] and stopped by 186 [36.5%] patients. The most common cause of discontinuation was nausea [12.2%]. AZA-induced pancreatitis occurred in 37 patients [7.3%]. Of these: 43% were hospitalised with a median inpatient time period of 5 days; 10% had peripancreatic fluid collections; 24% had vomiting; and 14% had fever. No patient had to undergo nonsurgical or surgical interventions. Smoking was the strongest risk factor for AZA-induced acute pancreatitis [p < 0.0002] in univariate and multivariate analyses.Conclusions:AZA-induced acute pancreatitis is a common adverse event in IBD patients, but in this study had a mild course in all patients. Smoking is the most important risk factor.

Molecular Docking Study, Green Synthesis and Pharmacological Evaluation of 1,3,4-thiadiazole Derivatives as Potential Antiepileptic Agents

Epilepsy is one of the commonly occurring chronic neurological disorders which involves abnormal electrical impulses in the brain. It is characterized by the sudden loss of consciousness, followed by abnormal shaking of the body. Though there are various types of antiepileptic drugs available clinically, the treatment of epilepsy still remains inadequate because of their toxicity and idiosyncratic side effects. Thus, there is unmet medical need to develop safe drugs for the treatment of epilepsy with lower side effects and improved bioavailability profiles. Considering the structural similarity between phenytoin/lamotrigine, a series of 1,3,4-thiadiazole was designed based on molecular docking study into the active site of the voltage-gated sodium channels. Antiepileptic activity of the synthesized compounds was evaluated in rats by maximal electroshock induced seizures (MES) model at different doses. Among the tested compounds, some exhibited significant anticonvulsant activity as compared to phenytoin in a dose-dependent manner. The neurotoxicity study was carried out using the rotarod test and the results of which suggests that the target compounds are safe and could be further developed as potential lead for antiepileptic drugs.

Impaired Ribosome Biogenesis and P53 Activation in Haematological Disease: Novel Therapeutic Strategies

Hereditary forms of bone marrow failure and aplastic anaemia (AA) manifest in rare blood syndromes (Dyskeratosis Congenita, Diamond-Blackfan Anaemia and Shwachman-Diamond Syndrome) in which genetic abnormalities directly impair ribosome biogenesis. These conditions are all associated with varying degrees of predisposition to haematological malignancy. Various studies of ribosome proteins have revealed an intimate relationship between ribosome biogenesis and p53 that governs cell fate in human haematopoietic disease. Over 70 years ago, recognition of the bone marrow suppressive properties of nitrogen mustards led to the development of early chemotherapeutics. Since, a multitude of seemingly unrelated drugs have emerged that also provoke AA as an idiosyncratic side effect. Here we hypothesize that at least some of these bone marrow suppressive drugs target ribosome biogenesis thereby mimicking congenital forms of bone marrow failure and inducing AA. If so, these bone marrow suppressive drugs may also share the anti-cancer potential of mustard gas through targeting abnormal ribosome biogenesis in malignant haematopoietic stem cells. Targeted drug development is an arduous and time-consuming process, however, repurposing of bone marrow suppressive drugs could provide a novel, clinically applicable therapeutic strategy in haematological malignancies.

Idiosyncratic Side Effects of Hydroxyurea in Patients with Sickle Cell Anemia

Hydroxyurea was approved by the Food and Drug Administration for the treatment of adults with moderate to severe sickle cell anemia and sickle-β0-thalassemia. Its major side effect is myelotoxicity, which is reversible upon discontinuation of the drug. Other side effects that have been described in animal studies but unconfirmed in humans include its teratogenic and carcinogenic potential. Additionally, hydroxyurea has idiosyncratic side effects that occur in some individuals and this may be a genetic or epigenetic phenomenon. We report three idiosyncratic side effects of hydroxyurea in four patients with sickle cell anemia (SS). Desquamating rash, decreased libido and partial complex seizures have not been previously described in patients who are hydroxyurea responders. Although these reactions are rare, they can be serious in some patients.

Sudden Onset Agranulocytosis and Hepatotoxicity after Taking Methimazole

Agranulocytosis is a rare adverse effect of methimazole. The usual duration of treatment prior to the onset of agranulocytosis is approximately 1 to 4 months, and can be as long as 1 year. Agranulocytosis together with hepatotoxicity is an extremely rare idiosyncratic side effect of methimazole treatment. We present an unprecedented case of a Grave's disease patient who showed a strong reaction to methimazole with obvious agranulocytosis and hepatotoxicity which developed only six days after administration. This case, along with a literature review, is offered with the aim to increase the awareness of physicians of sudden onset agranulocytosis and hepatotoxicity from methimazole.

More pieces to the iron chelation puzzle

More pieces to the iron chelation puzzle

A prospective audit of adjunctive zonisamide in an everyday clinical setting

This audit examined outcomes for 203 patients prescribed zonisamide (ZNS) for various uncontrolled seizure types at a specialist outpatient service. Forty-two (20.7%) patients achieved 6months of seizure freedom, and an additional 37 (18.2%) had a ⩾50% seizure reduction for 6months on a stable ZNS dose. Seizure freedom was more likely in patients with primary generalized (24/61, 39%) than in those with partial-onset (18/141, 12.7%) seizures (P<0.001). Eight patients (5 seizure free) were maintained on ZNS monotherapy. More patients became seizure free with ZNS as monotherapy or first add-on, compared with those in whom ZNS was the second, third, or fourth adjunctive drug (P=0.001). Seizure freedom was less likely in patients treated with hepatic enzyme-inducing agents (13/113, 11.5%) than in those receiving noninducing AEDs (24/82, 29.3%) (P=0.002). ZNS was discontinued in 72 (35.5%) patients largely because of side effects (n=58, 28.6%). Commonest complaints leading to withdrawal were sedation (n=14), nausea and vomiting (n=13), neuropsychiatric symptoms (n=12), rash (n=6), and weight loss (n=6). Around 80% of patients who became seizure free on ZNS or had the drug withdrawn did so on a dose ⩽200mg. ZNS is an effective broad-spectrum AED that can also produce a range of dose-dependent and idiosyncratic side effects.

Acute cholestatic hepatitis along with agranulocytosis: A rare side effect of carbimazole

Antithyroid drugs have been used for more than 50 years for the management of hyperthyroidism. Most patients tolerate treatment well but some may develop life-threatening side effects such as agranulocytosis, aplastic anemia and cholestatic hepatitis. A 45-year-old female was diagnosed with severe hyperthyroidism. Treatment with Carbimazole 30 mg/day was initiated. Within six weeks following the start of therapy, patient developed potentially life-threatening acute cholestatic hepatitis and agranulocytosis as adverse effects to carbimazole. The patient's symptoms and laboratory abnormalities resolved following withdrawal of offending drug. Agranulocytosis and cholestatic hepatitis together is an extremely rare idiosyncratic side effect of Carbimazole treatment and considered to be dose and age-related. Antithyroid drugs are deceptively easy to use, but because of the variability in the response of patients and the potentially serious side effects, all practitioners who prescribe the drugs need to have a working knowledge of their complex pharmacology.

The use of etanercept as a non‐surgical treatment for temporomandibular joint psoriatric arthritis: a case report

Psoriatic arthritis (PsA) is a chronic inflammatory disease of the skin and joints characterized by extensive intra-articular bone resorption and silver-red scaly plaques most commonly found on extensor surfaces of the skin. When this arthritis affects the temporomandibular joint (TMJ) and does not successfully halt in its early degenerative process, patients may undergo invasive joint reconstruction that irreversibly changes the TMJ physiologic joint dynamics. This study presents a case of TMJ PsA: anterior open bite, limited range of motion, and erythematous desquamative plaques of the upper limb extensors surfaces. The patient previously received non-steroidal anti-inflammatory drugs, immunosuppressors, and corticosteroids over a four-year period while suffering the idiosyncratic drug side effects from long-term therapy without improvement in joint function or rash resolution. The treatment team then chose etanercept, a synthetic fusion protein therapy that binds with tumor necrosis factor (TNF)-alpha, to interrupt reactive inflammatory arthritis. The patient received the TNF-alpha inhibitor monthly for two years. This last treatment led to full remission of both joint symptomatology and skin lesions. Our results should encourage general dental practitioners' involvement in curing patients with psoriatic arthritis when it affects the TMJ.

Farmacogenética e antiepilépticos (farmacologia das drogas antiepilépticas: da teoria à prática)

A otimização do uso de antiepilépticos para o tratamento da epilepsia freqüentemente é comprometido pela falta de resposta terapêutica, efeitos colaterais inesperado ou variações inexplicadas dos níveis séricos dos antiepilépticos. A presença de polimorfismo do DNA destes indivíduos está implicada em alterações no transporte de drogas, receptores cerebrais, metabolização de drogas e efeitos colaterais idiossincrásicos graves, que podem explicar partes dos problemas. A maioria dos antiepilépticos são metabolizados pela via do Citocromo P450 ou da UDP-glucoronil-transferase. As enzimas do Citocromo P450 com maior significado clínico são CYP1A2, CYP2D6, CYP2C9, CYP2C19 e CYP3A4. A fenitoina é metabolizados pelo CYP2C9 e CYP2C19, cujos polimorfismos reduzem a atividade metabólica em até 27-54%, ocorrendo em 20-30% da população, variando conforme a origem étnica do indivíduo. A utilização da farmacogenética no tratamento de pessoas com epilepsia é bastante promissora, porém mais estudos são necessários.

Encefalopatía hiperamoniémica por ácido valproico

One of the less frequent idiosyncratic side effects of valproic acid (VPA) is encephalopathy. Here we report one case. An 83-year-old female with no relevant past history, who received treatment with VPA following a post-traumatic subarachnoid haemorrhage and two convulsive seizures. A few days later, she was admitted to the Emergency Department because of a progressive clinical picture of mental slowness, nauseas and apathy. The systemic examination was normal. Neurologically, the most striking features were inattention and disorientation, despite her having a good level of consciousness, and mental confusion. Levels of VPA were within the below-therapeutic range and the basic lab findings (including hepatic profile) were normal, except for hyperammonaemia. Neuroimaging studies and cerebrospinal fluid analysis were also normal. An electroencephalogram (EEG) showed signs of severe diffuse encephalopathy with slow, triphasic waves and a non-convulsive epileptic status was therefore ruled out. After withdrawing the VPA, the patient's condition improved until her basal situation was reached in 48 hours and the EEG became normal, as did her ammonium levels. When faced with a patient who has recently been taking VPA and who presents a clinical picture of mental confusion, the possibility of encephalopathy due to said drug must be taken into consideration.

Levetiracetam

Levetiracetam (LEV) is a broad-spectrum antiepileptic drug that is effective against a variety of seizure types. It is a pyrridoline derivative with a very favourable pharmacokinetic profile: excellent bioavailability, linear kinetics, minimal plasma protein binding and quick achievement of steady state concentrations. It is not metabolized through the P450 hepatic cytochrome system, does not induce its own metabolism and has no clinically relevant drug-drug interactions. It is available as film-coated tablets, liquid formulation for oral ingestion and intravenous concentrated solution. Controlled and open-label studies have shown its efficacy and safety as initial monotherapy and add-on treatment for partial-onset seizures in children and adults, and also as add-on therapy in refractory partial and primary generalized seizures. Its rapid onset of action, lack of drug-drug interactions and availability as an intravenous solution make it an optimal drug to treat epilepsy associated with other medical conditions. Preliminary reports also suggest potential efficacy in refractory status epilepticus, although this is not a registered indication. Levetiracetam is generally well tolerated, and no serious idiosyncratic side effects have been reported so far. Behavioral side effects (hostility up to aggressive behaviour) are not uncommon. Small, uncontrolled studies have suggested potential therapeutic potential in difficult-to-treat dyskinesias in Parkinson's disease, tremors of different etiologies, migraine prophylaxis and mood disorders. This needs to be confirmed in larger, controlled studies.

Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer

BackgroundA phase III study was started to compare oxaliplatin/5FU/LV in the first-line with bolus FU/LV in metastatic colorectal cancer. Patients and methods302 patients were randomised and received bolus 5-FU 425 mg/m2 day 1–5, FA 20 mg/m2 day 1–5, q 4 wk or oxaliplatin 85 mg/m2, 2 h-infusion, FA 200 mg/m2, 1-h infusion. 5-FU 2600 mg/m2, 24-h infusion day 1, q 2 wk. The primary endpoint was response rate (RR). ResultsThe median follow-up is 31.8 months, 90.4% of the patients have died. Confirmed RR, progression free survival (PFS; months) and median overall survival (OS; months) in 5FU/LV versus 5FU/LV/oxaliplatin were respectively 18.5% versus (vs) 33.8% (P = 0.004), 5.6 vs 6.7 (P = 0.016) and 13.3 vs 13.8 (P = 0.619). In the 5FU/LV/oxaliplatin arm less grade ¾ toxicity was measured for diarrhoea, stomatitis, an increase in idiosyncratic side effects and neurosensory events compared with 5FU/LV. The quality of life (QOL) was equal in both arms. Second line treatment was given in 62% of the patients, crossover of 5FU/LV to 5FU/LV/oxaliplatin occurred in 14%. ConclusionsOxaliplatin in the first-line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhoea compared with 5FU/LV alone. Idiosyncratic side effects deserve attention with oxaliplatin. Despite a low treatment cross over rate, OS in both groups was comparable.