pyrimidinones and Rhabdomyolysis

A BRAF V600E mutation is found as driver oncogene in patients with non-small cell lung cancer. Although combined treatment with dabrafenib and trametinib is highly effective, the efficacy of reduced doses of the drugs in combination therapy has not yet been reported.. A Japanese man in his mid-sixties was diagnosed with unresectable lung adenocarcinoma and was unresponsive to cytotoxic chemotherapy and immune checkpoint inhibitors. The BRAF V600E mutation was detected by next generation sequencing, and the patient was subjected to treatment with dabrafenib and trametinib in combination. Although the treatment reduced the tumor size, he experienced myalgia and muscle weakness with elevated serum creatine kinase and was diagnosed with rhabdomyolysis induced by dabrafenib and trametinib. After the patient recovered from rhabdomyolysis, the treatment doses of dabrafenib and trametinib were reduced, which prevented further rhabdomyolysis and maintained tumor shrinkage.. The reduction of the doses of dabrafenib and trametinib was effective in the treatment of BRAF V600E-mutant NSCLC, and also prevented the incidence of rhabdomyolysis.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Off-Label Use; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Rhabdomyolysis; Treatment Outcome

MEK- and BRAF-inhibitors trametinib and dabrafenib are successfully used for BRAF-mutated, metastasizing melanoma, but these compounds may induce side effects. We report a 50 years old female with BRAF-mutated metastasizing melanoma who received trametinib (2 mg/d) and dabrafenib (200 mg/d) after using interferon without benefit. Shortly after starting trametinib/dabrafenib, she experienced an inability to abduct the left eye. Eight days after starting this therapy the patient experienced loss of appetite, vomiting, diarrhea, vertigo, and fever of 40°C. Two days later she experienced visual loss, requiring permanent support for her daily activities. Two further days later myoglobinuria appeared in the absence of myalgias or muscle weakness but accompanied by marked tiredness and inactivity. She could not eat or drink during four days prior to admission. The patient suspected an adverse effect of trametinib/dabrafenib and discontinued it 2 days prior to admission. Thereafter, she experienced an almost complete remission of the deficits except for ocular muscle weakness and visual impairment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Renal Insufficiency; Rhabdomyolysis; Skin Neoplasms; Vision Disorders

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemokine CXCL5; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Prognosis; Pyridones; Pyrimidinones; Rhabdomyolysis; Severity of Illness Index; Skin Neoplasms

The mitogen-activated protein kinase pathway regulates cell growth and differentiation and is activated by BRAF mutations. BRAF mutations are present in about 40-50% of cutaneous melanomas. More than 90% of BRAF mutations are the V600E type. BRAF inhibitor (dabrafenib or vemurafenib) and MEK inhibitor (trametinib or cobimetinib) combination therapies are effective for BRAF-mutant advanced melanomas. A variety of side effects have been observed with combination therapy including pyrexia, fatigue, nausea, and vomiting. Rhabdomyolysis is one of the most severe adverse events, but it is very rare. Only two cases of rhabdomyolysis have been reported in clinical trials. A 41-year-old Japanese woman with cutaneous melanoma was started on a combination of dabrafenib and trametinib therapy after failure of immune checkpoint therapy. One month later, she complained of myalgia and fatigue and was shifted to our hospital. She was diagnosed with trametinib-induced rhabdomyolysis and showed improvement only with a high volume of fluid infusion. We stopped combination therapy, but there were no useful treatment options for her. After resuming dabrafenib, followed by trametinib, she did not have any problems. This is the first case of a patient with metastatic cutaneous melanoma who could recommence combination therapy after trametinib-associated rhabdomyolysis. We assume that not all patients experience recurrence of rhabdomyolysis in trametinib-induced rhabdomyolysis. As few cases have been reported, more information is needed. We have to evaluate safety carefully if rechallenging combination therapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Rhabdomyolysis; Skin Neoplasms

The authors describe an HIV-infected patient with moderate renal failure receiving combination antiretroviral therapy. Because of dyslipidaemia he was initially treated with pravastatin but developed rhabdomyolysis after a switch to rosuvastatin. With this case we illustrate that statins as well as antiretroviral therapy are susceptible to clinical relevant drug-drug or drug-disease interactions. Knowledge of these interactions is important to provide patients with the best possible care.

Topics: Anti-HIV Agents; Drug Therapy, Combination; Dyslipidemias; Fluorobenzenes; HIV Infections; HIV-1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lopinavir; Male; Middle Aged; Pyrimidines; Pyrimidinones; Renal Insufficiency; Rhabdomyolysis; Ritonavir; Rosuvastatin Calcium; Sulfonamides; Treatment Outcome

Telbivudine (beta-l-2'-deoxythymidine) is an orally administered nucleoside analog drug approved for the treatment of patients with chronic hepatitis B since 2006. Initially, it was regarded as being generally well tolerated, with low adverse reaction profiles and no dose-limiting toxicity. Recently, with the result of the telbivudine worldwide phase III GLOBE trial and other clinical experiments, cases of myopathy and neuropathy have been reported undergoing long-term telbivudine treatments. Telbivudine-induced myopathy has been characterized by muscle pain, weakness and moderately elevated creatine kinase levels during treatments, although no severe adverse events have been observed. Rhabdomyolysis has not reported in any patient.

Topics: Acute Kidney Injury; Antiviral Agents; Fatal Outcome; Fibrosis; Hepatitis B; Humans; Male; Middle Aged; Muscular Diseases; Nucleosides; Pyrimidinones; Rhabdomyolysis; Telbivudine; Thymidine; Treatment Outcome

Topics: Antiviral Agents; Hepatitis B, Chronic; Humans; Nucleosides; Peripheral Nervous System Diseases; Pyrimidinones; Rhabdomyolysis; Telbivudine; Thymidine

A case report of drug-induced rhabdomyolysis in a 34-year-old HIV-infected male with a history of liver disease and concomitant use of clarithromycin, atorvastatin, and lopinavir/ritonavir is presented.

Topics: Adult; Anti-Bacterial Agents; Atorvastatin; Clarithromycin; Drug Interactions; Drug Therapy, Combination; Heptanoic Acids; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lopinavir; Male; Pyrimidinones; Pyrroles; Rhabdomyolysis; Ritonavir