Norberto Krivoy

Lamotrigine for intractable sciatica: correlation between dose, plasma concentration and analgesia

An open trial was conducted to study the potential efficacy of the antiepileptic agent lamotrigine in relieving the sciatic pain and the relationship between lamotrigine dosage, plasma concentration and the clinical response. Subsequent to a 1 week washout period from previous analgesics, lamotrigine dose was titrated on a weekly basis from 25 to 400 mg/day and was maintained at that dose for additional 4 weeks. Spontaneous pain, the Short Form McGill Pain Questionnaire (SFMPQ), the Straight Leg Raise (SLR) test, and range of motion of the lumbar spine (leaning foreword, to the affected side) were used to assess lamotrigine efficacy. Lamotrigine plasma concentration was tested at the end of each week during the titration period and at the end of the study. Fourteen patients were enrolled in the study. All outcome measurers improved compared to baseline during the titration period, but reached a statistically significant level of improvement only at the 400 mg dose. A linear correlation was found between mean lamotrigine dose, mean plasma concentration and mean weekly spontaneous pain, mean SLR and mean bending the affected side, but not with the SFMPQ score. Study results suggest lamotrigine is a potentially effective and safe compound for the treatment of painful lumbar radiculopathy, and that it is likely to act in a dose‐ and plasma concentration‐dependent fashion.

Nimesulide-Induced Acute Hepatitis

OBJECTIVE: To report the occurrence of nimesulide-induced acute hepatitis confirmed by biopsy and an in vitro lymphocyte toxicity assay. CASE SUMMARY: A 54-year-old Arabic woman treated with nimesulide for chronic low back pain was admitted to the hospital with acute hepatitis confirmed by biopsy. Her liver function test results returned to normal within one month after nimesulide discontinuation. An in vitro lymphocyte toxicity assay confirmed that the liver injury was due to nimesulide exposure. DISCUSSION: A case of acute hepatitis secondary to nimesulide, confirmed by biopsy and a laboratory in vitro assay, is described. Although the occurrence of clinically significant liver damage due to nonsteroidal antiinflammatory drugs (NSAIDs) is low, the enormous consumption of these drugs has made them an important cause of liver damage. Nimesulide, a relatively new NSAID commonly used in Europe, with a relative selectivity to cyclooxygenase type 2, can cause a wide range of liver injuries, from mild abnormal liver function to severe liver injuries. These effects are usually reversible on discontinuation of the drug, but occasionally can progress to fatal hepatic failure. CONCLUSIONS: Drug-induced acute hepatitis is a well-recognized adverse effect of many drugs, including nimesulide. Identification of a drug as a cause for this life-threatening disease is important because the discontinuation of it may be life saving. This article confirms the occurrence of nimesulide-induced hepatitis. It also highlights the importance of monitoring liver function test results after initiating therapy with such a drug.

A fatal case of enoxaparin induced skin necrosis and thrombophilia

Abstract:  Skin necrosis caused by heparins is a rare complication. We report a case of a 71‐yr‐old white woman who developed painful diffuse skin lesions, most probably related to enoxaparin treatment. Other causes of skin necrosis, including heparin induced thrombocytopenia, disseminated intravascular coagulation, protein C/protein S deficiencies, anti‐phospholipid antibodies, and vitamin K deficiency were less likely in this case. The concomitant combined thrombophilia possibly aggravated the patients clinical presentation.

Effective acute desensitization for immediate- type hypersensitivity to human granulocyte- monocyte colony stimulating factor

BACKGROUND Granulocyte-monocyte colony stimulating factor (GM-CSF) is the treatment of choice for patients with life threatening neutropenias. Hypersensitivity to GM-CSF may lead to cessation of treatment. Acute desensitization is an alternative mode of managing drug hypersensitivity, especially when other common modes like substitution of offending drug or premedication with antihistamines and/or corticosteroids are not available or fail. CASE REPORT A 42-year-old woman with a 17-year history of severe chronic mucocutaneous candidal infections became resistant to all common antifungal drugs. As her disorder was associated with defective functions of monocytes and granulocytes, GM-CSF treatment was started yielding a very good clinical effect. After a short period of treatment, however, the patient developed anaphylactic reactions which could not be abolished by preadministration of antihistamines and/or corticosteroids. Replacement of therapy by G-CSF caused identical hypersensitivity phenomena. METHODS Prick skin tests with 100, 200, or 400 microg/mL of GM-CSF or G-CSF, using also negative and positive controls, were performed on the patient and three healthy control subjects. A positive local reaction was observed only in patient at the prick point of 200 microg/mL GM-CSF or 400 microg/mL G-CSF. Acute desensitization to GM-CSF was initiated adopting a protocol used for parenteral desensitization to penicillin. RESULTS The patient tolerated the desensitization procedure very well and we could resume the administration of GM-CSF. For the past 30 months the patient has been treated uneventfully by subcutaneous administration of GM-CSF, 500 microg twice weekly, and is free of candidal infections. Skin prick tests were repeated 1 month postdesensitization and resulted in a very weak response to GM-CSF compared with the predesensitization response. CONCLUSIONS Acute desensitization can be utilized in patients who develop drug hypersensitivity reactions to GM-CSF. As GM-CSF is a very unique agent and in most cases cannot be replaced by another one, acute desensitization may play a very important role in managing failure of GM-CSF treatment due to hypersensitivity reactions.

Genetic polymorphisms predicting methotrexate blood levels and toxicity in adult non-Hodgkin lymphoma

Abstract Methotrexate (MTX), a folate antagonist employed for treating a wide range of malignancies, has an extensive interpatient variability, resulting in unpredictable toxicity. The present study evaluated the impact of single gene polymorphisms (SNPs: rs1801133 and rs1801131 in the MTHFR gene; rs4149056 and rs11045879 in the SLC01B1 gene; and rs2032582 and rs1045642 in the ABCB1 transporter gene) on MTX blood levels and toxicity in samples from 69 patients with diffuse large-B-cell lymphoma (DLBCL) treated with high dose intravenous (HD IV) MTX, > 2 g/m2. None of the studied genotypes was found to be associated with a statistically significant risk for elevated MTX levels at 24–48 h after completing therapy with MTX. Ancestral alleles (T) for SLC01B1 rs4149056 (T521C) and SLC01B1 rs11045879 (intron C21273886T) were found to be associated with an increased risk for MTX-related toxicity (p < 0.05 and p = 0.07, respectively), emphasizing the potential importance of employing pharmacogenetic assessment for personalized medicine.

Antimicrobial Utilization Pattern in a Hematologic Intensive Care Unit

Background: Recently, a new method for assessing the quality of prescription — The drug utilization 90% index (DU-90%) — Was introduced. The defined daily dose (DDD) concept is an established parameter in pharmacoepidemiologic studies. Objective: To evaluate antibiotic utilization in a specialized hospital unit where the use of antibiotics in immune-compromised patients undergoing intensive chemotherapy or bone marrow transplantation may be one of the main components in the direct cost of therapy of this type of patient. Methods: The antibiotic utilization pattern and accompanying costs were prospectively measured for 48 patients in a hematologic intensive care unit during a 60-day period, accumulating 896 admission days of follow-up. The DU-90% level is arbitrarily chosen as a reasonable cutoff point; it concentrates on the bulk of the prescribed antibiotics. Results: Of 26 antimicrobial agents prescribed, 14 were included in the DU-90%. Amphotericin B was delivered to 100% of the study population, with a total of 57.99 DDD/100 admission days. Ceftriaxone was the antimicrobial least prescribed, with a total of 0.22 DDD/100 admission days. The DU-90% index showed that 53% of the prescribed medications equal 92% of the total antibiotic cost. A discrepancy between the pharmacys report and the calculated costs based on DDDs was observed. Failure to have a real-time inventory and costs unification, the use of mean instead of median acquisition costs, and failure to use electronic prescription systems are the main elements affecting and disrupting drug utilization studies. This possibly explains, in part, the difference between the two cost reports.

Tolerability and feasibility of eptifibatide in acute coronary syndrome in patients at high risk for cardiovascular disease: A retrospective analysis*

BACKGROUND Despite the beneficial effects of glycoprotein (GP) IIb/IIIa antagonists in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI), GP IIb/IIIa antagonists are rarely administered in general internal medicine wards in Israel, where most patients with UA/ NSTEMI are admitted, due to lack of adequate monitoring and safety concerns. OBJECTIVE The aims of this study were to compare the prevalence of bleeding complications in patients with UA/NSTEMI receiving combination treatment with eptifibatide (a GP IIb/IIIa antagonist), the low-molecular-weight heparin enoxaparin, and acetylsalicylic acid (ASA) versus that in patients receiving enoxaparin and ASA in internal medicine wards in Israel, and to identify risk factors for bleeding complications. METHODS This retrospective analysis included information from the database at Rambam Medical Center, Haifa, Israel. The database provided information from 4 of the 5 wards (the ward from which data were unavailable did not routinely use eptifibatide). Data were included from patients aged ≥l.8 years who were admitted to the center with a diagnosis of UA/NSTEMI, were at high risk for death and/or nonfatal ischemic events based on American College of Cardiology/American Heart Association guidelines, were to undergo coronary intervention, and who had a Thrombosis in Myocardial Infarction risk score ≥3 (moderate to high risk). Patients in the eptifibatide group received eptifibatide IV (180-μg/kg bolus followed by a continuous infusion of 2 μg/kg · min up to 72 hours), enoxaparin SC (2 mg/kg · d), and ASA (100 mg/d). Patients in the control group received enoxaparin SC (2 mg/kg - d up to 96 hours) and ASA (100 mg/d). The prevalence of bleeding events was assessed using data up to 24 hours after the end of study drug administration. Major bleeding was defined as life-threatening bleeding at any site, intracranial hemorrhage, or bleeding accompanied by a decrease in plasma hemoglobin concentration of 5 g/dL or more. Otherwise, bleeding was considered minor. The risk for bleeding events was assessed using multivariate regression analysis. RESULTS Data from 105 patients (64 men, 41 women) were included in the analysis. In the eptifibatide and control groups, the mean (SD) ages were 68.7 (11.1) and 74.8 (11.0) years, respectively. These characteristics were statistically similar between the 2 groups. The rates of major bleeding were similar between the eptifibatide and control groups (2 [3.8%] vs 0 patients). The rate of minor bleeding was significantly higher in the eptifibatide group compared with that in controls (11 [21.2%] vs 4 [7.5%] patients; P = 0.03). The incidence of thrombocytopenia was statistically similar between the eptifibatide and control groups (0 vs 2 [3.8%] patients). The risk for bleeding was found to be associated with eptifibatide use (odds ratio, 4.8; 95% CI, 1.29-17.80), whereas an association with treatment was not found in the control group. CONCLUSION The results of this retrospective analysis suggest that the risk for bleeding complications is higher with combination treatment with eptifibatide, enoxaparin, and ASA compared with that with enoxaparin and ASA in high-risk patients with UA/NSTEMI admitted to internal medicine wards in Israel.

Seizures: An Unusual Complication of Intrapleural Povidone–Iodine Irrigation

Objective: To report a case of seizures that probably developed because of the disinfectant and antiseptic agent povidone iodine (PVI). Case Summary: A 67-year-old healthy white man developed pleural empyema that was treated with drainage and intrapleural PVI irrigation. Within 10 minutes, complex partial seizures with secondary generalization lasting several minutes were documented. Several hours later, the patient developed a similar episode. Both events resolved spontaneously and, in 10 months of follow-up, there was no recurrence. Discussion: The adverse effects of iodine are known; however, little has been reported about seizures following the administration of PVI. This complication is thought to be due to either the osmotic and hydrophilic qualities or the presence of ionic changes and lipid solubility of PVI. Conclusions: Intracavitary PVI should be considered in the differential diagnosis of localized and generalized seizures.

Pharmacokinetic analysis of once-daily gentamicin in immune-compromised adults with normal renal function

Objective To analyze and compare the pharmacokinetic parameters of a single daily dose (SDD) of gentamicin 5 mg/kg in adults with normal renal function who developed neutropenic fever during intensive non-nephrotoxic chemotherapy. Methods Ten patients received gentamicin in a 60-minute infusion and blood samples were drawn at 0, 0.5, 1, 2, 8, and 24 hours after the end of the infusion. Gentamicin concentrations were fitted to a noncompartment analysis (NCA) model and a 2-compartment open model for comparison. Results The mean ± SD gentamicin concentrations were: maximum concentration at 0.5 hours, 15.7 ± 3.4 mg/L; at 1 hour, 12.3 ± 2.3 mg/L; at 2 hours, 8.3 ± 2.5 mg/L; and at 8 hours, 1.7 ± 1 mg/L. The minimum concentration at 24 hours was 0.27 ± 0.36 mg/L. No statistical differences were established between the mean AUC (63 ± 8.5 and 54.2 ± 9.9 mg/L · h; p = 0.5) and gentamicin clearance (101.0 ± 13.3 and 160.6 ± 27.3 mL/min; p = 0.065). Statistical differences were demonstrated between the mean elimination rate constant (p < 0.001), half-life (p < 0.001), and volume of distribution (p < 0.001), measured by the NCA and the 2-compartment models. Conclusions Based on our findings, the NCA method for kinetic analysis of gentamicin prescribed in high SDD can be applied only for AUC and gentamicin clearance calculations.