Evidence Of Rhabdomyolysis Research Articles

A Phase 1/2 Dose Escalation Study of the Myeloid Kinase Inhibitor HM43239 in Patients with Relapsed or Refractory Acute Myeloid Leukemia

INTRODUCTION: HM43239 is an oral kinase inhibitor that potently inhibits myeloid kinases including diverse forms of the FLT3, SYK, JAK1/2, and mutant KIT kinases. These kinases and their mutant forms drive aberrant activation of downstream proliferation pathways and are associated with a high risk of relapse in AML. In a preclinical xenograft and orthotopic model of AML, HM43239 exhibited greater antitumor potency than FLT3 inhibitor gilteritinib, SYK inhibitor entospletinib, BCL-2 inhibitor venetoclax, and demethylation agent azacitidine. HM43239 is being evaluated in an international Phase 1/2 trial in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). AIMS: The primary objectives are to assess the safety and tolerability of HM43239 and determine the recommended phase 2 dose in R/R AML patients. A key secondary objective is to elucidate the pharmacokinetic (PK) profile in dose escalation and expansion cohorts. METHODS: The study is enrolling R/R AML eligible patients into dose escalation and dose exploration cohorts. HM43239 is administered continuously as oral tablets once daily in 28-day cycles. Treatment emergent adverse events (TEAEs) and tumor responses are evaluated using CTCAE and Revised Recommendation International Working Group criteria, respectively. RESULTS: As of July 14, 2022, a total of 50 patients, 26 male and 23 female, median age 59.5 (range 18-84) years, 28 FLT3-WT (56%) and 22 FLT3 mutated (44%) (15 FLT3-ITD (30%), 4 FLT3-TKD (8%) and 3 (6%) FLT3-ITD and / TKD), with a median of 2 prior treatments (range 1-6), have been treated with HM43239 at dose levels of 20 mg (n=2), 40 mg (n=1), 80 mg (n=20), 120 mg (n=13), 160 mg (n=10), and 200 mg (n=4). Nine patients (18%) were previously treated with 1 to 2 FLT3 inhibitors. Six patients (12%) had drug related TEAEs of Grade ≥ 3 which include decreased neutrophil count and muscular weakness (n=2; 4% each), and decreased white blood cell count, leukopenia, and nausea (n=1; 2% each). One patient experienced a DLT (grade 3 muscle weakness upper and lower limb) at the 200 mg dose level, without evidence of rhabdomyolysis. No DLTs were reported up through 160 mg. No drug-related adverse events (AEs) of QT prolongation or CK elevation were noted, and no drug-related serious AEs or deaths were reported. Eight of 50 patients achieved clinical response at multiple dose levels including 80 mg, 120 mg, and 160 mg. These include 7 patients with a reported best response of composite complete remission (CRc, including complete remission [CR], complete remission with incomplete platelet recovery [CRp] and complete remission with incomplete hematological recovery [CRi]) and 1 with partial remission (PR). All responses were achieved 1 or 2 cycles after HM43239 was initiated. Among 7 CRc patients, 5 proceeded to hematopoietic stem cell transplantation (HSCT). Of 22 FLT3 mutated patients, 5 (18%) achieved clinical response (4 CRc and 1 PR). Importantly, 3 of 7 (43%) FLT3-mutated patients who received prior FLT3 inhibitor treatment including gilteritinib and/or midostaurin achieved a response (2 CRc and 1 PR). Of 28 WT-FLT3 patients, 3 (11%) achieved a CRc. Notably, patients with clinical responses had a variety of additional adverse resistance mutations of NPM1, MLL-PTD, IDH2, NRAS, KRAS, DNMT3A, RUNX1, PTPN11, TP53 and others, with or without FLT3 mutation. Markedly, a WT-FLT3 patient with a TP53 mutation achieved CR and continued treatment for 14 cycles. The steady-state PK exposure of HM43239 rose from 20 mg to 120 mg, but no further increase was observed at 160 mg. Considering this and the safety profile, 120 mg was chosen as the expansion single agent starting dose with potential adjustments from 80 to 160 mg upon further evaluation of safety, tolerability, and efficacy. CONCLUSIONS: As of July 14, 2022, HM43239 has delivered CRc at 80 mg, 120mg and 160 mg, and was well tolerated at these dose levels over multiple cycles with no DLTs or drug-related SAEs. Pharmacokinetic data illustrate increasing drug exposures through 120 mg and observed objective responses through 160 mg in both FLT3-WT and FLT3-mutated R/R AML patients even after gilteritinib and midostaurin treatment. An update of this study, including a planned single agent and venetoclax combination expansion, will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clothes dryer–induced heat stroke in three cats

To describe the clinical course of 3 cats successfully treated following clothes dryer-induced heat stroke. Three cats were treated after accidental clothes dryer-induced heat stroke. All cats fulfilled canine heat stroke criteria and showed evidence of heat injury, including neurological dysfunction, corneal and mucosal ulceration, and evidence of rhabdomyolysis. Coagulopathy, acute liver injury, acute kidney injury, cardiac dysfunction, and gastrointestinal signs were seen in cats with a longer duration of dryer exposure. Describes the management of cats after inadvertent clothes dryer-induced heat stroke.

Case Study: Acute Lumbar Paraspinal Compartment Syndrome in an Austere Military Environment.

The incidence of compartment syndrome of the lumbar paraspinal muscles is exceedingly rare. Approximately 24 hours following a high-intensity kettlebell swing workout, a 33-year-old Sailor presented to the medical department on board a forward deployed Wasp-class amphibious assault ship with increasing discomfort in his middle and lower back, and evidence of rhabdomyolysis. Discomfort quickly turned to unrelenting pain coupled with dorsal paresthesias and rigidity in the paraspinal muscles. He was taken emergently to the operating room, where his paraspinal muscles were released via fasciotomy. As a result of limited resources aboard the deployed ship, a negative pressure wound dressing was fashioned using the supplies available aboard the ship. Following 3 days of the negative pressure wound therapy, muscle bulging decreased substantially, and the skin was closed. After 4 weeks of physical therapy, he returned to full duty.

Severe falciparum malaria with hypophosphataemia and presumed hypophosphatemia induced rhabdomyolysis: a case report

Malaria is eliminated from Sri Lanka, yet cases contracted overseas are still encountered in the country. It is therefore important to be vigilant of possible complications of severe malaria. We report a 31-year-old sailor (Sri Lankan national) with a recent travel history to West Africa who presented with an acute febrile illness of seven days duration. He had high fever, myalgia, drowsiness as well as profuse watery diarrhea. Clinical examination revealed a febrile patient with GCS 15 with no features of meningism. He was icteric with right hypochondrial tenderness. Investigations showed hemolysis. Microscopy and rapid diagnostic assays revealed Plasmodium falciparum infection. He was started on IV artesunate followed by artemisinin based combination therapy orally to which he responded. On day 4 he developed evidence of rhabdomyolysis with low serum phosphate and normal urine phosphate levels. Hypophosphatemia was considered to be the driving factor for rhabdomyolysis, and phosphate replacement was done for which the patient responded and was discharged on day 10 fully recovered.

Young man with severe metabolic acidosis after transformer oil ingestion: a case report

BackgroundTransformer oil is used in oil-filled transformers for its insulating as well as coolant properties. Transformer oil ingestion for attempted suicide is seldom heard of. Our patient’s case presented us with a major diagnostic as well as treatment challenge because we encountered such a case for the first time and were totally unaware of the fact that methanol might make up the main component of an aged transformer oil.Case presentationA 19-year-old Pakistani/Asian man was brought to our hospital with altered sensorium. He was found to have elevated anion gap acidosis, increased osmolal gap, and acute kidney injury. He had no evidence of rhabdomyolysis or hemolysis. Computed tomography of his head showed cerebral edema. He was resuscitated with intravenous fluids and bicarbonate. Three days later, he confessed taking transformer oil with suicidal intention. His clinical picture mimicked acute methanol intoxication. With an initial improvement in his neurological status, he started complaining of constant headache with episodes of agitation and delirium. His renal function continued worsening despite an adequate urine output. He showed a remarkable improvement in his neurological state after just one session of hemodialysis.ConclusionsThere is evidence that aged transformer oil contains methanol, and a patient who consumes it can present with features mimicking acute methanol intoxication.

Smoldering myocarditis following immune checkpoint blockade

BackgroundSevere myocarditis associated with electrical conduction abnormalities and occasionally heart failure has been well documented following treatment with immune checkpoint blockade with an estimated incidence of less than 1%. However, the incidence, early detection, and management of less severe immune-related myocarditis are unknown since most immunotherapy trials have not included routine cardiac monitoring. Herein, we provide the first description of subclinical or smoldering myocarditis with minimal signs and symptoms following immune checkpoint blockade with a single dose of ipilimumab and nivolumab.Case presentationOur patient was diagnosed with immune checkpoint blockade-induced myocarditis based upon an acute rise in serum cardiac troponin I beginning 2 weeks after the initial dose of ipilimumab/nivolumab consistent with the reported median onset of clinical myocarditis at 17 days, as well as a lack of other causes despite extensive cardiac evaluation. The patient initially presented with intractable nausea with no known gastrointestinal etiology. High dose glucocorticoid therapy led to rapid resolution of nausea and a four-fold decrease in troponin I over 4 days. Serum troponin I spiked again following a steroid taper to 13 times the upper limit of normal with endomyocardial biopsy revealing collagen fibrosis and lymphocytic inflammation predominantly comprised of CD8+ T cells consistent with chronic smoldering myocarditis. Serum anti-striated muscle antibodies were also detected with no evidence of rhabdomyolysis. Serum cardiac troponin I levels as an indicator of ongoing myocyte damage gradually improved with chronic prednisone at 10 mg daily. Late addition of intravenous immunoglobulin was associated with rapid normalization of creatine kinase-myocardial band.ConclusionsThis case demonstrates that subclinical, smoldering myocarditis may occur following immune checkpoint blockade, with evidence of both humoral and cell-mediated immunity responsive to corticosteroid therapy. This experience supports early monitoring for myocarditis with serial electrocardiograms and serum troponin I determinations in large, prospective cohorts of patients receiving combination immune checkpoint blockade as early detection and initiation of immunosuppression may forestall fulminant presentation of this disease and limit myocardial damage.

Clinical profile and outcome of pigment-induced nephropathy.

ABSTRACTBackgroundPigment nephropathy represents one of the most severe complications of rhabdomyolysis or hemolysis.MethodsWe performed a retrospective observational study to analyze the etiology, clinical manifestation, laboratory profile and outcome in patients with biopsy-proven pigment-induced nephropathy between January 2011 and December 2016. History, clinical examination findings, laboratory investigations and outcome were recorded.ResultsA total of 46 patients were included with mean follow-up of 14 ± 5.5 months. Mean age was 40.15 ± 12.3 years, 65% were males (male:female, 1.8:1) and ∼37 (80.4%) had oliguria. Mean serum creatinine at presentation and peak creatinine were 7.5 ± 2.2 and 12.1 ± 4.3 mg/dL, respectively. Evidence of rhabdomyolysis was noted in 26 patients (64%) and hemolysis in 20 patients (36%). Etiology of rhabdomyolysis include snake envenomation (10 patients), seizures (7), strenuous exercise (5), wasp sting (2) and rifampicin induced (2). The causes of hemolysis include rifampicin induced (7 patients), sepsis (5), malaria (3), mismatched blood transfusion/transfusion reaction (3) and paroxysmal nocturnal hemoglobinuria (2). On renal biopsy, two patients had acute interstitial nephritis and two had immunoglobulin A deposits in addition to pigment nephropathy. All except one (97.8%) required hemodialysis (HD) during hospital stay and mean number of HD sessions was 9 ± 2. A total of three patients with sepsis/disseminated intravascular coagulation died, all had associated hemolysis. On statistical analysis, there was no difference between AKI due to rhabdomyolysis and hemolysis except for high creatine phosphokinase in patients with rhabdomyolysis and Lactate dehydrogenase level in patients with hemolysis. At mean follow-up, five patients (12%) progressed to chronic kidney disease (CKD).ConclusionsPigment nephropathy due to rhabdomyolysis and hemolysis is an important cause of renal failure requiring HD. The prognosis was relatively good and depends on the etiology; however, long-term studies and follow-up are needed to assess the true incidence of CKD due to pigment nephropathy.

Datura poisoning, clinical and laboratory findings. Report of five cases

Introduction. Plants of Datura species contain belladonna alkaloids that can cause central and peripheral anticholinergic effects. Abuse of Datura plants for their hallucinogenic effects is growing among adolescents and young adults. Datura poisoning has caused a diagnostic challenge in medical emergency wards. In this article we report 5 cases of Datura toxicity at Clinical Toxicology Emergency of Baharloo Hospital, Tehran, Iran during Summer-Fall 2015, and discuss their clinical presentations and laboratory findings. Cases Description. All 5 cases with Datura toxicity were young males and had intentionally used the plants. Mean duration of hospitalization was 3.2 days. ree cases were multiple drug abusers. Mydriasis, tachycardia, tachypnea and ushing alongside with psychotic-like signs and symptoms were observed in all cases. Elevation of liver enzymes was present in three of cases but without clinical signi cance. Raised LDH or CPK in four patients were without myoglubinuria and evidence of rhabdomyolysis and these biomarkers returned to normal by supportive care. All patients discharged with complete recovery and there was no need to ICU admission. Discussion. With the absence of routine laboratory screening tests for alkaloids and complex and confusing presentations of Datura intoxication, diagnosis of such cases is difficult. Physicians' clinical suspicion and su cient knowledge plays the mainstay role in appropriate and timely diagnosis and management of cases with Datura toxicity. Since regulatory legislation wouldn't be successful in halting the availability of natural plants, the best strategy to prevent Datura abuse is informing people about the adverse e ects of these plants. Key Words: datura stramonium, poisoning, abuse, anticholinergic, laboratory ndings, liver function tests, rhabdomyolysis. Language: en

Mixed Acid-Base Abnormality in a Patient with Herbicide Poisoning - Possible Insights on the Mechanism of Toxicity

2, 4-Diclorophenoxyacetic acid (2, 4-D), a herbicide, is an uncommon cause of intentional poisoning in humans. We report a patient who survived after ingestion of a fatal dose of 2, 4-D and explore possible mechanisms for the observed metabolic abnormalities. A 48-year-old male was brought following ingestion of a mixture of 2, 4-D and metribuzin (50-gm each). He presented with vomiting and altered sensorium and required intubation and mechanical ventilation. There was evidence of rhabdomyolysis, non-oliguric renal failure and multiple electrolyte abnormalities. The acid-base abnormalities were consistent with mixed respiratory alkalosis with normal anion gap metabolic acidosis. The patient was treated with supportive care and alkaline diuresis and made an uneventful recovery. The metabolic acidosis was attributed to proximal tubular dysfunction while the respiratory alkalosis with altered conscious state and normal oxygenation suggested central hyperventilation as the mechanisms for the observed metabolic abnormalities with 2, 4-D poisoning.

Wasp sting-induced acute kidney injury.

BackgroundWasp stings are a common form of envenomation in tropical countries, especially in farmers. The aim of this study was to document the clinical presentation, treatment and outcomes of patients with acute kidney injury (AKI) due to multiple wasp stings in a tertiary care hospital.MethodsWe conducted a retrospective observational study of patients with multiple wasp stings and AKI at the Department of Nephrology between July 2011 and August 2015. The clinical features, laboratory data, treatment details and outcomes were noted.ResultsA total of 11 patients were included. All were from rural areas. All of them were males with age ranging from 21 to 70 years, mean age 45 ± 23 years. Six had oliguria and two had hypotension. All 11 patients had evidence of rhabdomyolysis and three also had hemolysis. Ten patients required hemodialysis with a mean number of hemodialysis sessions of 8.7 ± 2.8. Renal biopsy carried out on four patients, showed acute interstitial nephritis (AIN) in one patient, acute tubular necrosis (ATN) in two patients, and one patient had both AIN and ATN. The two patients with AIN were given steroids, while all other patients were managed with supportive measures. One patient died within 48 h of presentation due to shock. At a mean follow-up of 24 months, one had progressed to chronic kidney disease and the remaining nine had normal renal function.ConclusionsWasp sting is an occupational hazard. AKI was most commonly due to rhabdomyolysis. Early renal biopsy is indicated in those patients who do not respond to supportive measures. Timely dialysis and steroid in the case of AIN improves renal survival.

A series of cases of rhabdomyolysis after ingestion of Tricholoma equestre.

Tricholoma equestre (hereinafter – T. equestre) is a common edible fungus that is considered to be toxic under certain conditions. Here, we report four cases of acute poisoning caused by T. equestre, including one lethal outcome in Lithuania between 2004 and 2013. In the severe case, fatigue, nausea without vomiting and muscle pain, profuse sweating without fever, and respiratory insufficiency occurred. Laboratory tests showed an elevation of creatine kinase (CK), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Although clinical findings and laboratory tests support evidence of rhabdomyolysis, no renal insufficiency was observed. Significance of T. equestre in cardiac changes is feasible but remains unclear.

Possible association between fluconazole administration and acute hyperkalemia in a critically ill cyanotic infant.

Fluconazole, an azole antifungal agent, inhibits the fungal cytochrome P450 enzyme. Although in vitro data show that fluconazole is not a potent inhibitor of mammalian P450 enzymes, hyperkalemia secondary to adrenal insufficiency associated with fluconazole has been described rarely [1–3]. However, life-threatening severe hyperkalemia related to administration of intravenous fluconazole without adrenal suppression has not been reported before. A 2.5-month-old male infant diagnosed with tetralogy of Fallot with pulmonary atresia and multiple aorto-pulmonary collateral vessels was transferred to a pediatric intensive care unit due to septicemia. On physical examination, he was tachypneic and tachycardic with decreased oxygen saturation (62%) and a temperature of 38.8°C. Laboratory studies included hemoglobin, 12.4 g/dl; white blood count, 23.2 × 109/l; C-reactive protein, 38.3 mg/l (0–3.2); and serum potassium, 3.8 mEq/l (3.5–5.1 mEq/l). Other biochemical parameters and renal function tests were in the normal range. Blood cultures were positive for coagulase negative Staphylococcus. He was started on teicoplanin and meropenem intravenously. As fever persisted after 48 h with new infiltrates on chest radiography, and tracheal colonization with Candida spp., fluconazole 5 mg/kg intravenously once a day was given. After 24 h of treatment with fluconazole, bradycardia developed in the patient. Electrocardiography showed a prolonged PR interval and widening of the QRS complex with bradycardia (Figure 1). His simultaneous laboratory testing demonstrated a serum potassium level of 8 mEq/l. He was treated with repetitive administration of sodium bicarbonate, insulin/glucose, as well as calcium gluconate. Repeat blood results showed potassium 11 mEq/l. The results of renal and liver function tests and the levels of other electrolytes were within normal limits. There were no signs of rhabdomyolysis, hemolysis or severe acidosis. No medication errors could be identified. Infusion of fluconazole was stopped, and he was treated with repetitive administration of bicarbonate, insulin/glucose, and albuterol by nebulizer. In the meantime peritoneal dialysis was administered in the patient. The serum potassium level gradually returned to a normal level (4 mEq/l), and the findings of ECG abnormalities were improved. Figure 1 ECG shows widened QRS and prolonged PR interval Prophylaxis with fluconazole has been shown to reduce the occurrence of candidiasis in intensive care units [4, 5]. Even though fluconazole in standard doses is thought to be safe, there are rare reports of adrenal suppression associated with fluconazole administration [2, 3]. In our patient, severe hyperkalemia was observed after 24 h of treatment with fluconazole. Our patient's renal functions remained normal and evidently did not impair potassium excretion. No evidence of rhabdomyolysis, severe acidosis, hemolysis or adrenal suppression was detected. Although the causative mechanism is unclear, severe hyperkalemia was associated with fluconazole in our patient. All other possible causes of hyperkalemia were excluded. Fluconazole may have unknown life-threatening side-effects, despite having been tested prior to its clinical use. To our knowledge, this is the first report of a life-threatening complication of fluconazole without adrenal insufficiency. We speculate that because of chronic hypoxia of our patient due to his cyanotic heart disease, the drug side effect may have been triggered, and it may be prudent to monitor electrolytes especially in critically ill cyanotic patients.

Index of Suspicion

The reader is encouraged to write possible diagnoses for each case before turning to the discussion. We invite readers to contribute case presentations and discussions. Please inquire first by contacting Dr. Deepak Kamat at DKamat@med.wayne.edu. An 18-year-old male with a 3-year history of alcohol abuse is referred from a rehabilitation center for fever, nausea, and nonbloody diarrhea for 3 days. Six weeks ago, he enrolled in an alcohol rehabilitation program and stopped drinking alcohol. Three weeks later, he noticed yellowing of his eyes and skin, difficulty sleeping, and dyspnea. On examination, his temperature is 100.6°F (38.1°C), blood pressure is 99/62 mm Hg, pulse is 124 beats per minute, and respiratory rate is 24 breaths per minute. He is slow to answer questions. There is no asterixis. He appears thin and jaundiced with enlarged parotid glands. Decreased breath sounds are noted on the right. A tender, enlarged liver and mild abdominal distension are noted. Trace bilateral lower-extremity edema is present. No stigmata of chronic liver disease are found. Laboratory findings reveal the following: white blood cell count, 25,600/μL (25.6 × 109/L) (87% neutrophils); hemoglobin, 8.2 g/dL (82 g/L); mean corpuscular volume, 106 fL; platelets, 40 × 103/μL (40 × 109/L); sodium, 135 mEq/L (135 mmol/L); potassium, 3.5 mEq/L (3.5 mmol/L); chloride, 106 mEq/L (106 mmol/L); bicarbonate, 15 mEq/L (15 mmol/L); blood urea nitrogen, 24 mg/dL (8.6 mmol/L); creatinine, 1.01 mg/dL (89 μmol/L); glucose, 118 mg/dL (6.6 mmol/L); alkaline phosphatase, 182 U/L; aspartate aminotransferase (AST), 194 U/L; alanine aminotransferase (ALT), 71 U/L; total bilirubin, 11.8 mg/dL (201.8 μmol/L); direct bilirubin, 7.3 mg/dL (124.9 μmol/L); albumin, 2.7 g/dL (27 g/L); prothrombin time, 19.2 seconds; and international normalized ratio, 1.4. Ethanol and acetaminophen were not detected in the serum. A chest radiograph reveals a right pleural effusion …

Rapid Development of Anterotibial Compartment Syndrome and Rhabdomyolysis in a Patient with Primary Hypothyroidism and Adrenal Insufficiency

Anterior compartment syndrome (ACS) and rhabdomyolysis are rare complications of hypothyroid myopathy. We report the case of a young man with rapid onset of ACS who presented with simultaneous primary hypothyroidism and adrenal insufficiency associated with acute renal failure, hyponatremia, and hyperkalemia. A 22-year-old man presenting with a one-month history of tiredness, hyperpigmentation, and cramps in his calves was found to have severe bilateral foot drop. Investigations revealed severe primary hypothyroidism and adrenal insufficiency, renal failure, and evidence of rhabdomyolysis with myoglobinuria. Abnormal biochemical findings included serum sodium of 110 mM, serum potassium of 6.9 mM, and serum creatine kinase (CK) of >25,000 IU/L. Magnetic resonance imaging (MRI) of his legs showed changes of myonecrosis confined to anterior tibial muscles typical of ACS. After treatment with intravenous fluids, potassium-lowering therapies, thyroxine, and hydrocortisone, his renal and metabolic function returned to normal, but irreversible bilateral foot drop persisted. A young man with primary hypothyroidism, adrenal insufficiency, hyponatremia, and hyperkalemia presented with severe myopathy, such that muscle necrosis, apparently confined to the anterior tibial compartment on MRI, led to rhabdomyolysis, acute renal failure, and irreversible bilateral peroneal nerve damage. It is possible that other patients with primary hypothyroidism and marked elevations of CK without widespread myopathy or rhabdomyolysis may demonstrate evidence of differential muscle effects in the anterior compartment when assessed by MRI, but that this patient also had adrenal insufficiency raises the possibility that this was a contributing factor. Severe thyroid myopathy and rhabdomyolysis may be associated with anatomic susceptibility to ACS, particularly in the presence of concomitant adrenal insufficiency. MRI examination reveals a distinctive appearance of myonecrosis confined to the anterior compartment.

Diffusion-weighted MRI of exercise-induced acute renal failure (ALPE)

Acute renal failure with severe loin pain induced by anaerobic exercise (ALPE) is a rare condition that is accompanied by wedge-shaped contrast enhancement on computed tomography (CT) without evidence of rhabdomyolysis. In two pediatric cases with ALPE, we tried to determine the relationship between findings from CT and magnetic resonance imaging (MRI). Case 1 involved a 13-year-old Japanese girl with a diagnosis of ALPE with normo-uricemia. Contrast-enhanced CT after 24 and 48 h showed a wedge-shaped excretion delay for the contrast media. A clear wedge-shaped signal hyperintensity matching the CT images was obtained by diffusion-weighted MRI. Case 2 involved a 16-year-old boy who presented with a second attack of ALPE after diagnosis of ALPE with hypouricemia 1 year earlier. Only diffusion-weighted imaging was performed. Clear wedge-shaped signal hyperintensity was apparent, similar to Case 1. MRI is safer than contrast-enhanced CT for patients with ALPE. Diffusion-weighted MRI is a very useful examination for diagnosing ALPE, providing noninvasive detection of lesions peculiar to ALPE.

Regression of subependymal giant cell astrocytomas with RAD001 (Everolimus) in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in the TSC1 or TSC2 genes and characterized by slow-growing tumors in multiple organs. Of the affected individuals, 10% display subependymal giant cell astrocytomas (SEGAs), which can lead to substantial neurological morbidity. The TSC1/TSC2 protein complex is a negative regulator of the mTOR pathway. Hence, mutations in these genes in preclinical models are associated with increased mTOR pathway activation and heightened sensitivity to mTOR inhibitors. We hereby report our experience with RAD001 (Everolimus) therapy, a novel mTOR inhibitor, in inducing a dramatic regression of SEGAs. A patient with TSC and SEGAs was treated with 10 mg/day oral RAD001. MRIs and neuro-ophthalmological exams were performed before and at regular intervals following the initiation of therapy. The lesions exhibited significant regression in several tumor locations and stabilization in others, accompanied with an improvement of his visual status. Treatment was well tolerated for 11 months but was than discontinued due to hypertension and elevated CPK, without evidence for rhabdomyolysis. Yet, during 9 months following the interruption of therapy, SEGAs remained unchanged. Oral RAD001 demonstrated preliminary encouraging results as treatment of astrocytomas associated with TSC. These preliminary results were recently supported by the Novartis announcement of the phase II study of RAD001 for SEGAs, which was not published yet. According to their statement, 75% of the patients showed reduction of SEGAs' volume following treatment with RAD001. Based on these results, RAD001 may be an alternative to surgery in selected patients with TSC and SEGAs.

Assessment of serum creatine kinase among adolescent patients following jimsonweed (Datura stramonium) and moonflower (Datura inoxia) ingestions: a review of 11 cases

Introduction. Datura stramonium (DS) (jimsonweed) is well known for its abuse potential for hallucinogenic effects and Datura inoxia (DI) (moonflower) has been abused for similar effects. To our knowledge, only one case report describes rhabdomyolysis in association with DS or DI ingestion. Case identification and details. Patient hospital charts were retrospectively screened from January 1, 2002 to December 31, 2007 to identify patients with qualifying ICD-9 codes for toxic plant ingestions. We report on 11 patient cases of DS/DI ingestions in which serum creatine kinase (CK) concentrations were monitored. These admissions occurred at our hospital over a 6-year period. Serum CK concentrations ranged from 72 to 70,230 U/L. Only three patients had serum CK concentrations greater than 1,000 U/L. One patient with a peak concentration of 70,230 U/L and a positive myoglobinuria was diagnosed with rhabdomyolysis. Discussion. Based on our review of the literature and these cases, it is possible that serum CK concentrations may be elevated more frequently than previously realized. The clinical significance of this abnormal laboratory value is uncertain with the majority of patients remaining asymptomatic without any clinical evidence of rhabdomyolysis.

Biochemical and morphological studies of skeletal muscle in experimental chronic alcoholic myopathy

Experimental alcoholic myopathy was induced in rats by a combination of prolonged alcohol intake (mean 15.3 g ethanol/kg/day for up to 10 weeks) and a short fast. In view of literature evidence for impairment of both glycolytic and oxidative metabolism in alcoholic myopathy, we combined histological and histochemical observations with biochemical studies comprising assay of all glycolytic enzymes and measurement of respiration rates and cytochrome content in isolated intact mitochondria. The predominant histological finding was Type IIb fibre atrophy, while levels of the glycolytic enzymes aldolase, pyruvate kinase and lactate dehydrogenase were significantly depressed. Evidence of rhabdomyolysis was seen in a minority of animals. Mean mitochondrial respiratory rates were significantly lower with the Site I substrate glutamate in alcohol-treated animals. It is postulated that chronic alcoholic myopathy is associated with glycolytic deficiency and that acute rhabdomyolysis may arise from a superimposed mitochondrial failure, resulting in a severe energy crisis in muscle.

Excellent outcome using “impaired” standard criteria donors with elevated serum creatinine

To maximize organ utilization, the United Network for Organ Sharing (UNOS) encourages use of Expanded Criteria Donors (ECD). However, Standard Criteria Donors (SCD) may also be under-utilized, some centers discarding kidneys with serum creatinine (S.Cr) >2.0 at nephrectomy. Our experience with the use of such "impaired'' kidneys was reviewed retrospectively. From January 1, 2003 to October 1, 2006, of 130 DD kidneys transplanted at our center, 26 were ECD. Also, 22 kidneys were from Impaired SCD (ISCD), with mean S.Cr 3.2 (2.1-4.4) at nephrectomy; eight of these had S.Cr >4.0. For these 22 ISCD, mean age was 22 yrs (11-42), sex: 16 Males; race:12 Caucasians/10 African-Americans; All had evidence of rhabdomyolysis (Mean peak CPK 11,924 u/l). Thirty-seven percent came from outside OPOs. Recipient demographics: age 45 years; sex 50% male, 45% African-American. Mean HLA match was 1; dialysis was required in 28% within the first week. Mean length of stay was 10.7 days. Average discharge S.Cr was 4.2. All kidneys are currently functioning (S.Cr at 3 months, 6 months and 1 year 1.6, 1.7 and 1.7 respectively). An elevated creatinine should not be the only cause for discarding deceased donor kidneys.

Clopidogrel-Precipitated Rhabdomyolysis in a Stable Heart Transplant Patient

To report the case of an orthotopic heart transplant recipient who developed rhabdomyolysis precipitated by the addition of clopidogrel to the existing regimen of cyclosporine and atorvastatin, which had been tolerated for more than 3 years without adverse effects or laboratory evidence of myositis. Fourteen years after cardiac transplantation, a 58-year-old woman began a planned 4 week course of clopidogrel 75 mg/day following coronary angioplasty and placement of a stent in the left circumflex coronary artery. Almost 4 weeks later, she presented with severe muscle pain and weakness and laboratory evidence of rhabdomyolysis, with marked elevations of plasma creatine kinase (96,000 U/L) and urine myoglobin (332,872 microg/L) as well as early acute renal failure (serum creatinine 2.9 mg/dL). Symptoms and laboratory abnormalities resolved with cessation of cyclosporine, atorvastatin, and clopidogrel. Clopidogrel was not restarted, while atorvastatin and cyclosporine were; the patient had no recurrence of symptoms up to 15 months later. Both atorvastatin and cyclosporine, as well as clopidogrel's active thiol derivative, are metabolized by the cytochrome P450 3A4 isoenzyme. Cyclosporine is also a moderate inhibitor of this isoenzyme. We postulate that competition between atorvastatin and clopidogrel for CYP3A4 receptors, already partially inhibited by cyclosporine, led to increased atorvastatin concentrations, resulting in the acute onset of rhabdomyolysis. This theory is further supported by the patient's continued ability to tolerate the combination of atorvastatin and cyclosporine, without clopidogrel, on rechallenge. Use of the Naranjo probability scale revealed that rhabdomyolysis was probably precipitated by the addition of clopidogrel to the stable baseline regimen of cyclosporine and atorvastatin. Practitioners must be conscious of the potential for adverse effects when prescribing clopidogrel to heart transplant patients who are concomitantly receiving cyclosporine and a statin. If concomitant administration is required, careful clinical and laboratory monitoring of the patient is necessary.