Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia

Central nervous system (CNS) prophylaxis has led to a significant improvement in the outcome of patients with acute lymphocytic leukemia (ALL). Liposomal cytarabine (Enzon Pharmaceuticals, Piscataway, NJ; Skye Pharma, San Diego, CA), an intrathecal (IT) preparation of cytarabine with a prolonged half-life, has been shown to be safe and effective in the treatment of neoplastic meningitis. Liposomal cytarabine was given for CNS prophylaxis to 31 patients with newly diagnosed ALL. All patients were treated concurrently with hyper-CVAD chemotherapy (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) including high-dose methotrexate (MTX) and cytarabine on alternating courses. Liposomal cytarabine 50 mg was given intrathecally on days 2 and 15 of hyper-CVAD and day 10 of high-dose MTX and cytarabine courses until completion of either 3, 6, or 10 IT treatments, depending on risk for CNS disease. Five patients (16%) experienced serious unexpected neurotoxicity, including seizures, papilledema, cauda equina syndrome (n = 2), and encephalitis after a median of 4 IT administrations of liposomal cytarabine. Toxicities usually manifested after the MTX and cytarabine courses. One patient died with progressive encephalitis. After a median follow-up of 7 months, no isolated CNS relapses have been observed. Liposomal cytarabine given via intrathecal route concomitantly with systemic chemotherapy that crosses the blood-brain barrier such as high-dose MTX and cytarabine can result in significant neurotoxicity.     

Rhabdomyolysis associated with hyperthyroidism

BACKGROUND: Nontraumatic rhabdomyolysis has been associated with alcohol and drug abuse, seizures, strenuous exercise, muscle hypoperfusion, hyperthermia, electrolyte disturbances, diabetic coma, and hypothyroidism. Hyperthyroidism can be associated with several neuromuscular manifestations, such as thyrotoxic myopathy and thyrotoxic periodic paralysis, both associated with weakness and normal creatine phosphokinase levels. There have been only three reported cases of rhabdomyolysis as a result of thyrotoxicosis. We are reporting the fourth case of such association. CASE REPORT: The patient is a 26-year-old black woman with history of hypertension. She presented to the clinic with blurred vision, headaches, palpitations, weight loss, weakness, and persistent high blood pressure. She was found to have exophthalmus, lid lag, and a symmetric, smooth, and diffuse goiter. Ptosis and diplopia were absent; neurologic examination findings was normal. The patient had positive TPO antibodies, elevated free T4 level, and low thyroid-stimulating hormone (TSH) level. Graves disease was diagnosed and propylthiouracil was prescribed. The patient then returned to the clinic 2 weeks later with weakness and myalgias. Her physical examination findings were unchanged except for mild muscle weakness. Laboratory evaluation showed normal electrolytes, normal renal function, and negative urine drug screening. Creatine phosphokinase was 1276 U/L. Her free T4 and T3 levels were elevated and TSH level was low. The patient was treated with aggressive oral fluid resuscitation. Propylthiouracil was continued and free T4 and T3 normalized along with creatine phosphokinase with resolution of symptoms. CONCLUSIONS: Hyperthyroidism may, theoretically, cause rhabdomyolysis by means of increasing energy consumption associated with depletion of muscle energy stores and substrates. Our patient constitutes the fourth reported case of rhabdomyolysis associated with hyperthyroidism.     

Pericarditis induced by high-dose cytarabine therapy

Pericarditis with tamponade developed in a patient treated with high-dose cytarabine for acute lymphocytic leukemia. Evidence suggests that this was a direct complication of his treatment.     

Treatment of acute leukemia with amsacrine and high-dose cytarabine

We varied the number of doses of high-dose cytarabine (3 g/m2) given to patients with acute leukemia in relapse who were receiving therapeutic doses of amsacrine (600 mg/m2/course). Twelve patients received 13 courses of therapy. Two of six patients with acute nonlymphocytic leukemia and one of three with acute lymphoblastic leukemia achieved remission. Dose-limiting toxicity (diarrhea) was seen in patients receiving more than five daily doses of high-dose cytarabine. We conclude that therapeutic doses of amsacrine can be combined safely with five daily doses of high-dose cytarabine and that a formal study is now required to assess the efficacy of this regimen.     

Rhabdomyolysis associated with near-drowning.

A variety of conditions can lead to rhabdomyolysis. Only a few cases of rhabdomyolysis resulting from near-drowning exist in the literature. We describe a victim of near-drowning who developed rhabdomyolysis and acute renal failure requiring dialysis. We review the existing literature on near-drowning-induced rhabdomyolysis and discuss the possible pathogenesis.     

Rhabdomyolysis associated with pomegranate juice consumption

This 48-year-old man with possible underlying myopathy was successfully treated with ezetimibe 10 mg/day and rosuvastatin 5 mg every other day for 17 months. Three weeks before presentation, he began drinking pomegranate juice (200 ml twice weekly). He presented urgently with thigh pain and an elevated serum creatine kinase level (138,030 U/L, normal < 200 U/L). In conclusion, because both grapefruit and pomegranate juice are known to inhibit intestinal cytochrome P450 3A4, this report suggests that pomegranate juice may increase the risk of rhabdomyolysis during rosuvastatin treatment, despite the fact that rosuvastatin is not known to be metabolized by hepatic P450 3A4.     

Pre-emptive administration of corticosteroids prevents the development of ARDS associated withStreptococcus mitis bacteremia following chemotherapy with high-dose cytarabine

Summary Adult respiratory distress syndrome (ARDS) complicatingStreptococcus mitis bacteremia is a major cause of mortality in patients undergoing therapy for leukemia. In order to try to prevent the development of ARDS in 11 patients withS. mitis bacteremia following chemotherapy including cytarabine, high doses of corticosteroids were administered pre-emptively. None of these patients developed ARDS. In a historical control group of 21 comparable patients who had not been given corticosteroids, the incidence of ARDS was high (38%), with a death rate of 14%. Preemptive administration of high-dose corticosteroids appeared to be highly effective in suppressing the mechanisms that induce ARDS in patients withS. mitis bacteremia after cytarabine treatment. The results suggest that ARDS complicatingS. mitis bacteremia is not merely a microbiological problem but may, at least in part, represent an immunologically mediated phenomenon.     

Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors

Background

The recent withdrawal of cerivastatin by the manufacturer has led to an interest in hydroxymethylglutaryl-coenzyme A (HMG-CoA) inhibitors and the incidence of myopathy. We review the epidemiology, pharmacology, and presumed mechanisms of statin-induced myopathy, with a particular focus on cerivastatin.

Methods

A MEDLINE search of English-language articles published between 1985 and 2003 was performed. Key words included HMG-CoA inhibitors, statins, myopathy, myotoxicity, rhabdomyolysis, adverse events, drug interactions, and cerivastatin.

Results

The initial trials, which assessed the efficacy of first-generation HMG-CoA inhibitors, did not show a clinically significant increase in the incidence of myopathy. However, on the basis of Food and Drug Administration post-marketing surveys, the rate of cerivastatin-induced rhabdomyolysis appeared to be 10-fold greater than that of the other statins, despite safe pre-clinical profiles. However, no clinical trials have been performed directly comparing the rates of myotoxicity of all commercially available statins. The mechanism of statin-induced myopathy remains unclear. The prevailing theory is that lipophilic statins lead to depletion of intermediates normally formed after cholesterol synthesis within myocytes. Risk factors for the development of myopathy include drug interactions (especially with fibrates) and the coexistence of conditions known to predispose patients to rhabdomyolysis.

Conclusion

The cerivastatin experience emphasizes the need for large safety trials before drug approval and for vigilant post-marketing surveillance. Further research and sound clinical judgment may lead to the identification of high-risk individuals in whom statins should be avoided.     

Rhabdomyolysis associated with influenza A virus infection

Rhabdomyolysis is characterized by local or generalized skeletal muscle neclosis. It is caused by many clinical conditions and drug or alcohol abuse. Clinical symptoms are muscle pain and muscle weakness. Laboratory investigations show a rise in serum creatine phosphokinase and electrolyte disturbances. The most serious complication is acute renal failure. We present a patient with rhabdomyolysis and renal failure associated with a recent Influenza A virus infection.     

大剂量阿糖胞苷治疗难治性急性髓性白血病

目的探讨难洽性急性髓性白血病的有效治疗方法。方法对难洽性急性髓性白血病采用大剂量阿糖胞苷治疗。结果12例难治性急性髓性白血病采用大剂量阿糖胞苷治疗，完全缓解（CR）41％，部分缓解（PR）25％，总有效率66％。结论大剂量阿糖胞苷方案是治疗难治性急性髓性白血病的有效方案。     

Phase I study of high-dose cytarabine and cisplatin in patients with advanced malignancy

Nineteen patients with advanced malignancy participated in a phase I trial of high-dose cytarabine (ara-C) and cisplatin in combination. Dose and schedule were based on laboratory data indicating synergy for concurrent use of these drugs. Cisplatin (100 mg/m2) was administered during the 2nd and 3rd hours of a 3-hour ara-C infusion. The ara-C dose was escalated in subsequent patients following a starting dose of 1 g/m2. Two brief responses were noted. The study was terminated prematurely due to protracted (several weeks) nausea, occasional vomiting, and severe lassitude.     

Brachial plexus neuropathy following high-dose cytarabine in acute monoblastic leukemia

We describe brachial plexus neuropathy with high-dose cytarabine (Ara-C) therapy in a man who had acute monoblastic leukemia. Signs and symptoms of brachial plexus neuropathy appeared on two occasions within hours of exposure to high-dose Ara-C. Central nervous system complications have been described following systemic and intrathecal Ara-C. High-dose Ara-C has not been implicated previously as a cause of brachial plexus neuropathy.     

Rhabdomyolysis associated with cytomegalovirus infection in kidney transplant recipients

Rhabdomyolysis is a pathological syndrome caused by skeletal muscle cell damage that affects the integrity of the cellular membrane and leads to the release of toxic intracellular constituents into the bloodstream. Although cytomegalovirus (CMV) has rarely been reported as a cause of rhabdomyolysis, CMV infection could be considered as a possible cause because of its clinical significance in kidney transplant recipients (KTRs). We report 2 cases of rhabdomyolysis associated with CMV infection in KTRs. A 64‐year‐old woman (Case 1) and a 65‐year‐old man (Case 2), who had each received a kidney from a living unrelated donor, were admitted with complaints of weakness in both legs and myalgia. Laboratory findings revealed highly increased creatine phosphokinase and myoglobinuria. In both cases, no recent alterations of medications had occurred, and other causes of rhabdomyolysis—such as trauma, alcohol, drugs, and electrolyte abnormalities – were excluded. CMV pp65 antigen was positive, and patients were diagnosed with rhabdomyolysis associated with CMV infection. Both patients recovered without complications after ganciclovir treatment. In conclusion, CMV infection should be considered as a possible cause of rhabdomyolysis in KTRs.