Drug Withdrawn Research Articles

Gemtuzumab ozogamicin for relapsed or primary refractory acute myeloid leukemia in children-the Polish Pediatric Leukemia and Lymphoma Study Group experience.

Gemtuzumab ozogamicin (GO), one of the first targeted drugs used in oncology, consists of an anti-cluster of differentiation 33 (CD33) monoclonal antibody bound to a derivative of cytotoxic calicheamicin. After the drug withdrawn in 2010 due to a significantly higher rate of early deaths, GO regained approval in 2017 for the treatment of newly diagnosed, refractory, or relapsed acute myeloid leukemia (AML) in adults and children over 15 years of age. The objective of the study was a retrospective analysis of clinical characteristics, treatment outcomes, and GO toxicity profile in children with primary refractory or relapsed (R/R) AML treated in Poland from 2008 to 2022. Data were collected through the Polish Registry of Acute Myeloid Leukemia. From January 2008 to December 2022, 35 children with R/R AML were treated with GO in seven centers of the Polish Pediatric Leukemia and Lymphoma Study Group. Most of the children (30 of 35) received only one GO cycle in combination with various chemotherapy cycles (IDA-FLA, DOXO-FLA, FLA, FLAG, and others). Eighteen children (51%) achieved complete remission (CR), 14 did not respond to treatment, and three progressed. GO therapy was followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 18 children in CR. The 5-year overall survival (OS) after GO therapy was 37.1% ± 8.7% for the total cohort. There was a trend toward a superior outcome in patients with strong expression of CD33 expression (over 50% positive cells) compared with that in patients with lower expression of CD33 (OS, 41.2% ± 11.9% versus 27.8% ± 13.2%; p = 0.5; 5-year event-free survival, 35.4% ± 11.6% versus 25.7% ± 12.3%; p = 0.5, respectively). Children under 15 years have better outcome (OS, 34.9% ± 10.4% versus 30% ± 14.5%, p = 0.3). The most common adverse events were bone marrow aplasia, fever of unknown origin, infections, and elevated liver enzyme elevation. Sinusoidal obstruction syndrome occurred in two children. The use of GO in severely pretreated children, including those under 15 years of age, with previous failure of AML treatment is a feasible and effective bridging therapy to allo-HSCT with an acceptable toxicity profile.

Analysis of Mitochondrial Function in Cell Membranes as Indicator of Tissue Vulnerability to Drugs in Humans.

Drug side effects are one of the main reasons for treatment withdrawal during clinical trials. Reactive oxygen species formation is involved in many of the drug side effects, mainly by interacting with the components of the cellular respiration. Thus, the early detection of these effects in the drug discovery process is a key aspect for the optimization of pharmacological research. To this end, the superoxide formation of a series of drugs and compounds with antidepressant, antipsychotic, anticholinergic, narcotic, and analgesic properties was evaluated in isolated bovine heart membranes and on cell membrane microarrays from a collection of human tissues, together with specific inhibitors of the mitochondrial electron transport chain. Fluphenazine and PB28 promoted similar effects to those of rotenone, but with lower potency, indicating a direct action on mitochondrial complex I. Moreover, nefazodone, a drug withdrawn from the market due to its mitochondrial hepatotoxic effects, evoked the highest superoxide formation in human liver cell membranes, suggesting the potential of this technology to anticipate adverse effects in preclinical phases.

Impact of the SARS-CoV-2 Delta Variant on the Psychological States and Health-Related Quality of Life in Patients With Crohn's Disease.

BackgroundSince the outbreak of the coronavirus disease 2019 (COVID-19) pandemic first reported in Wuhan, China, several research on the psychological impact of the pandemic on patients with Crohn’s disease (CD) have been conducted. However, with the progression of the global pandemic and the emergence of the SARS-CoV-2 B.1.617.2 (Delta) variant, follow-up studies need to be performed to monitor the alterations of psychological status and health-related quality of life (HRQoL) among CD patients.AimsWe aimed to evaluate the impact of the SARS-CoV-2 Delta variant on the mental health and life quality among the CD population and tried to explore potent risk factors.MethodsThis observational study included 153 CD patients who responded to our pre-designed self-reported questionnaire. Demographic, clinical, and psychological information were collected and analyzed.ResultsQuite a number of CD patients were confronted with different levels of anxiety and depression, with incidence of 28.10 and 31.37% for anxiety and depression, respectively. Compared with non-pandemic circumstances, the life quality of CD patients due to the present situation was more often compromised. Isolation [odds ratio (OR): 4.71, P = 0.007] was verified as a risk factor for anxiety while use of telemedicine could help relieve anxiety (OR: 0.22, P < 0.001). Worsening of symptoms (OR: 4.92, P = 0.006), isolation (OR: 5.75, P = 0.005), and drug withdrawn (OR: 2.66, P = 0.026) were identified to be independent factors for developing depression. Likewise, use of telemedicine (OR: 0.13, P < 0.001) was negatively related to depression. Considering life quality, vaccination (OR: 3.07, P = 0.021) together with no medication (OR: 7.73, P = 0.010) was relevant to better life quality while worsening of symptoms (OR: 0.09, P = 0.034) were an independent risk factor for impaired life quality.ConclusionMany CD patients suffered from symptoms of anxiety and depression and impaired life quality during the COVID-19 pandemic. Those in isolation or with worsening of symptoms and drug withdrawn were more prone to experience psychological stress. Individualized management such as drug delivery and telemedicine should be promoted to maintain control of mental health and life quality during the pandemic.

Association between clinically relevant toxicities of pazopanib and sunitinib and the use of weak CYP3A4 and P-gp inhibitors.

Sunitinib and pazopanib, two tyrosine kinase inhibitors (TKI), may be targets of potential pharmacokinetic drug-drug interactions (P-PK-DDIs). While strong cytochrome P4503A (CYP3A4) inhibitors or inducers should cause a clinically relevant modification in plasma TKI concentrations, the effect of weak inhibitors is unknown. The objective of this study was to evaluate the association between weak P-PK-DDI and clinically relevant toxicity in real life. This was a single-center retrospective study including patients treated with sunitinib or pazopanib for any malignancies, for whom a PK-DDI analysis was performed before starting TKI. The primary endpoint was the correlation between P-PK-DDIs and a dose decrease after 1month of treatment. The secondary endpoint was the correlation between PK-DDIs and drug withdrawal due to toxicity. Seventy-six patients were assessed. A P-PK-DDI with weak CYP3A4 or P-gp inhibition was found in 14 patients. In patients with P-PK-DDI or without, the dose was reduced during the first month in 57.1% and 17.7% (p = 0.003) and the drug withdrawn in 42.8% and 11.3% (p = 0.011), respectively. In multivariate analysis, a significant correlation was found between P-PK-DDI (CYP3A4 and P-gp inhibitors) and dose reduction, and between drug withdrawal and PK-DDI (CYP3A4 inhibitors). P-PK-DDI was correlated with dose reduction and drug withdrawal due to toxicity. The causality of this relationship warrants to be assessed; therefore, therapeutic drug monitoring is necessary in patients treated with TKI.

RPS warns of 'huge extra cost' to NHS after bipolar drug withdrawn

RPS warns of 'huge extra cost' to NHS after bipolar drug withdrawn

Transcriptomic analysis associated with reversal of cisplatin sensitivity in drug resistant osteosarcoma cells after a drug holiday

BackgroundResistance to chemotherapy is one of the major hurdles in current cancer therapy. With the increasing occurrence of drug resistance, a paradigm shift in treatment strategy is required. Recently “medication vacation” has emerged as a unique, yet uncomplicated strategy in which withdrawal of drug pressure for certain duration allowed tumor cells to regain sensitivity to the drug. However, little is known about the molecular alterations associated with such an outcome.MethodsIn this study, human osteosarcoma (OS) cells resistant to the extensively used drug cisplatin, were withdrawn from drug pressure, and thereafter cytotoxic response of the cells to the drug was evaluated. We further performed next-generation RNA sequencing and compared transcriptome between parental (OS), resistant (OS-R) and the drug withdrawn (OS-DW) cells. Differentially expressed transcripts were identified, and biological association network (BAN), gene ontology (GO) and pathway enrichment analysis of the differentially regulated transcripts were performed to identify key events associated with withdrawal of drug pressure.ResultsFollowing drug withdrawal, the sensitivity of the cells to the drug was found to be regained. Analysis of the expression profile showed that key genes like, IRAK3, IL6ST, RELA, AKT1, FKBP1A and ADIPOQ went significantly down in OS-DW cells when compared to OS-R. Also, genes involved in Wnt signaling, PI3K-Akt, Notch signaling, and ABC transporters were drastically down-regulated in OS-DW cells compared to OS-R. Although, a very small subset of genes maintained similar expression pattern between OS, OS-R and OS-DW, nonetheless majority of the transcriptomic pattern of OS-DW was distinctively different and unique in comparison to either the drug sensitive OS or drug resistant OS-R cells.ConclusionOur data suggests that though drug withdrawal causes reversal of sensitivity, the transcriptomic pattern does not necessarily show significant match with resistant or parental control cells. We strongly believe that exploration of the molecular basis of drug holiday might facilitate additional potential alternative treatment options for aggressive and resistant cancers.

Effect of early adverse events on response and survival outcomes of advanced melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib: A pooled analysis of clinical trial data.

This study aimed to evaluate the impact of early adverse events on overall survival (OS), progression-free survival (PFS) and objective response within a pooled secondary analysis of participants treated with first-line vemurafenib or vemurafenib plus cobimetinib in the clinical trials BRIM3 and coBRIM. The study included 583 participants who received vemurafenib monotherapy and 247 who received vemurafenib plus cobimetinib. Adverse events requiring vemurafenib/cobimetinib dose adjustment within the first 28days of therapy were significantly associated with OS (hazard ratio (HR) [95% CI]: dose reduced/interrupted=0.79 [0.65-0.96]; drug withdrawn=1.18 [0.71-1.96]; p=0.032), PFS (HR [95% CI]: dose reduced/interrupted=0.82 [0.67-0.99]; drug withdrawn=1.58 [0.97-2.58]; p=0.017) and objective response (odds ratio (OR) [95% CI]: dose reduced/interrupted=1.35 [0.99-1.85]; drug withdrawn=0.17 [0.06-0.43]; p=<0.001). Arthralgia occurring within the first 28days of vemurafenib or vemurafenib plus cobimetinib therapy was also significantly associated with favourable OS (p=0.026), PFS (p=0.042) and objective response (p=0.047).

Analysis of the Cochrane Review: Fibrates for secondary prevention of cardiovascular disease and stroke

The influence of fibrates on cardiovascular risk has been the focus of several clinical trials. This Cochrane Collaboration Systematic Review evaluated the efficacy of fibrates for secondary prevention of cardiovascular events and stroke, analyzing 13 randomized controlled trials, in a total of 16112 participants with a history of cardiovascular disease. Fibrates showed a protective effect for the composite outcome of non-fatal stroke, non-fatal myocardial infarction (MI) and vascular death, mainly due to reduction in the risk of non-fatal or fatal MI. Nonetheless, these results largely relied on studies including clofibrate, a drug withdrawn from the market in 2002. No statistically significant differences regarding adverse events were found between fibrates and placebo. Although insufficient to support the routine prescription of fibrates in this setting, this evidence should be taken into account when deciding on lipid-modifying therapy in dyslipidemic patients with a history of cardiovascular disease.

Análise da Revisão Cochrane: fibratos na prevenção secundária de doença cardiovascular e acidente vascular cerebral

The influence of fibrates on cardiovascular risk has been the focus of several clinical trials. This Cochrane Collaboration Systematic Review evaluated the efficacy of fibrates for secondary prevention of cardiovascular events and stroke, analyzing 13 randomized controlled trials, in a total of 16 112 participants with a history of cardiovascular disease. Fibrates showed a protective effect for the composite outcome of non‐fatal stroke, non‐fatal myocardial infarction (MI) and vascular death, mainly due to reduction in the risk of non‐fatal or fatal MI. Nonetheless, these results largely relied on studies including clofibrate, a drug withdrawn from the market in 2002. No statistically significant differences regarding adverse events were found between fibrates and placebo. Although insufficient to support the routine prescription of fibrates in this setting, this evidence should be taken into account when deciding on lipid‐modifying therapy in dyslipidemic patients with a history of cardiovascular disease.

Detection of glutathione conjugates of amiodarone and its reactive diquinone metabolites in rat bile using mass spectrometry tools.

Amiodarone is reported to cause hepato and pulmonary toxicity in humans, which has been envisaged to be due to formation of its reactive metabolites, essentially based on its structural similarity to benzbromarone, a drug withdrawn from the market due to reasons of similar hepatotoxicity. Therefore, the purpose of this study was to detect glutathione conjugates of amiodarone and its reactive diquinone metabolites in rat bile using mass spectrometry tools. Wistar rats were dosed orally with an amiodarone suspension and bile was collected via bile duct cannulation followed by solid-phase extraction, protein precipitation and centrifugation. Samples were analysed by liquid chromatography coupled with linear ion trap mass spectrometry using tandem mass and constant neutral loss scan in positive electrospray ionization mode. Glutathione adducts of amiodarone and its reactive diquinone metabolites were identified and characterized with the characteristic neutral loss of 129 Da. Glucuronide conjugates of previously reported stable phase-1 metabolites were also observed. This study confirmed generation of reactive metabolites of amiodarone for the first time, as was hypothesised earlier by various research groups. Also, the responsible toxicophore was identified to be a benzofuran moiety liable to form reactive diquinone species. However, the results need to be further confirmed in human subjects. Copyright © 2016 John Wiley & Sons, Ltd.

Ponatinib In Heavily Pretreated Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML): Management Of Adverse Events (AEs)

Ponatinib In Heavily Pretreated Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML): Management Of Adverse Events (AEs)

PTH-198 Pooled Analysis of the most Frequent Adverse Events Associated with the use of Lubiprostone

IntroductionLubiprostone, a novel ClC-2 activator, has been shown to be efficacious and well-tolerated by patients with chronic constipation in short- and long-term clinical trials. To better characterise the most frequent...

Understanding hepatotoxicity – from patients to mice to computer

Drug Induced Liver Injury (DILI) remains the major adverse drug event that leads to termination of clinical development programs and regulatory actions including failure to approve for marketing, restricted indications, and withdrawal from the marketplace. The type of DILI that is most problematic is “idiosyncratic” meaning that only a very small fraction of treated patients are susceptible to the DILI. Current preclinical models, even “humanized” ones, do not reliably identify molecules that have this liability and, conversely predict liabilities in molecule that are in fact quite safe for the liver. For example, current preclinical testing does not detect the DILI potential of xymelagatran, a drug withdrawn from worldwide markets due to idiosyncratic hepatotoxicity but would predict a high liver risk for acetaminophen (paracetamol) even when taken as directed. Reliable preclinical testing will probably not be developed until there is greater understanding of the mechanisms underlying DILI. Reasoning that the best models to study DILI are the people who have actually experienced it, we are capitalizing on the resources of the US Drug-Induced Liver Injury Network (DILIN-supported by the National Institutes of Health) that is collecting genomic DNA and other biospecimens from patients who have experienced DILI. In addition to genetic studies, we are partnering with Cellular Dynamics International to reprogram induced pleuripotent stem cells from DILIN subjects in whom we have complete exomic DNA sequence with the goal of producing patient-specific liver cultures, and ultimately, humanized mice. We are also partnering with the Shanghai Centers for Disease Control to prospectively collect a variety of biospecimens, including whole blood for transcriptome analysis, from patients treated for active tuberculosis as part of a larger biomarker discovery initiative. We are using panels of inbred mice to mimic patient population genetic diversity and to identify genes and pathways that may underlie DILI susceptibility in patients. Finally, we have established the DILIsim Initiative which is a public-private partnership that is building a computer model to synthesize the rapidly accumulating data with the goal of predicting DILI liability in drug candidates. DILIsim involves 10 pharmaceutical companies and the Food and Drug Administration.

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.

Effects of preslaughter withdrawal period on response of feedlot heifers to zilpaterol hydrochloride supplementation: Growth performance and carcass characteristics1

Sixty-four crossbred heifers (451 +/- 23 kg) were used in a 42-d feeding trial (4 pens per treatment in a randomized complete block design) to evaluate the influence of preslaughter zilpaterol hydrochloride withdrawal period on growth performance and carcass characteristics. Heifers were fed a diet based on steam-flaked corn (2.13 Mcal of NE(m)/kg). Treatments were 1) control, no zilpaterol supplementation; 2) zilpaterol supplementation for 30 d, drug withdrawn from the diet 3 d preslaughter (ZIL-3); 3) zilpaterol supplementation for 30 d, drug withdrawn 6 d preslaughter (ZIL-6), and 4) zilpaterol supplementation for 30 d, drug withdrawn 12 d preslaughter (ZIL-12). Zilpaterol was supplemented at the rate of 0.15 mg/kg of BW daily. Intake of DM averaged 9.2 +/- 0.26 kg/d and was not affected (P > or = 0.36) by treatment. Compared with control heifers, ZIL-3 increased (P < 0.01) carcass-adjusted ADG (59%), G:F (57%), apparent dietary NE(m) (31%), and decreased observed/expected DMI (25%). Treatment with ZIL-3 did not affect marbling score (P = 0.49) or backfat thickness (P = 0.17), but compared with the control group, increased HCW (3.6%, P = 0.03), carcass dressing percentage (3.2%, P = 0.02), LM area (6.3%, P = 0.05), and reduced trimmed fat (31%, P = 0.03). Prolonging the period of zilpaterol withdrawal preslaughter tended to decrease carcass-adjusted ADG (linear, P = 0.11), G:F (linear, P = 0.08), apparent dietary NE(m) (linear, P = 0.11), and carcass dressing percentage (linear, P = 0.11). We conclude that growth performance and carcass yield responses to zilpaterol supplementation are negatively affected by prolonging the period of zilpaterol withdrawal beyond 3 d (the required minimum withdrawal period according to label). Drug withdrawal period may be a relevant factor in explaining variation in performance response to zilpaterol supplementation in commercial feedlots.

Toxicity in Doberman Pinchers with Ventricular Arrhythmias Treated with Amiodarone (1996–2005)

Asymptomatic Doberman Pinschers with dilated cardiomyopathy (DCM) often die suddenly owing to ventricular tachycardia that degenerates into ventricular fibrillation. A safe and effective antiarrhythmic drug treatment is needed. This will require a large, well-controlled, prospective study. Amiodarone toxicity is common in Dobermans with occult DCM and ventricular tachyarrhythmias refractory to antiarrhythmia therapy. Infrequent monitoring of hepatic function is inadequate. Frequent monitoring may be useful to determine dogs in which the dosage should be decreased or the drug withdrawn. Medical records from the University of Georgia and Cornell University were searched for Doberman Pinschers diagnosed with preclinical DCM that received amiodarone for severe ventricular arrhythmias refractory to other antiarrhythmic agents. Echocardiographic data, Holter recording data, hepatic enzyme serum activity, and serum amiodarone concentrations were recorded. The presence of clinical signs of toxicity was recorded. Serum amiodarone concentrations were obtained in some dogs. Reversible toxicity was identified in 10 of 22 (45%) dogs. Adverse effects from amiodarone were common and were, in part, dosage related. Patients should be monitored for signs of toxicity and liver enzyme activity should be measured at least monthly.

Safety assessment of new antithrombotic agents: Lessons from the EXTEND study on ximelagatran

Background Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. Objectives and Methods The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. Results Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to > 2× upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. Conclusions Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.

Osteoarthritis drug withdrawn from the UK market following hepatotoxicity fears

Osteoarthritis drug withdrawn from the UK market following hepatotoxicity fears

Discussion on 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis

GASTROENTEROLOGY 2002;123:1747

Examining Product Risk in Context: The Case of Zomepirac

To the Editor. —Dr Ross-Degnan and colleagues 1 are to be commended for bringing to the attention of physicians the unfortunate results of drug company marketing on the prescribing practices of US physicians. However, the logic of Ross-Degnan et al weakens when they state that the risks of drugs substituted for a drug withdrawn because of unanticipated bad effects should be considered before withdrawing the drug. The drug would not have been released if the bad effects had been known beforehand. Therefore, patients who needed to be treated for conditions for which the drug was putatively indicated would have been given the substituted drugs as first choice. Ergo, no net effect.