Pharmacokinetic simulation of fatal carbamazepine intoxication in 23-month old child following phenytoin discontinuation.

The antiepileptic, carbamazepine, is extensively metabolized via hepatic enzymes in the cytochrome P450 family and is therefore subject to a myriad of drug interactions. Concomitant administration with phenytoin enhances carbamazepine metabolism thus reducing serum concentrations and necessitating the use of a higher maintenance dose. Removal of phenytoin therapy in the absence of anticipatory dose adjustments and careful monitoring of serum concentrations may result in catastrophic outcomes. Reported herein are the events leading to the death of a 23-month old child who suffered a fatal carbamazepine overdose following withdrawal of phenytoin therapy.

Multiple Sclerosis and Use of Medical Cannabis: A Retrospective Review of a Neurology Outpatient Population.

BACKGROUND: Patients diagnosed as having multiple sclerosis (MS) experience a wide range of symptoms requiring pharmacologic management, and many do not achieve adequate symptom control. The purpose of this study was to evaluate the role of medical cannabis (MC) as part of a comprehensive treatment plan for patients with MS. METHODS: A retrospective medical record review of 141 patients with MS receiving MC for symptom management was conducted. Data were collected for up to 4 follow-up appointments after initiation of MC. Outcomes included changes in MS symptoms, medication changes, adverse events, and changes in cognition and mobility. RESULTS: Patients experienced extensive MS symptom improvement after initiation of MC, with alleviation of pain (72% of patients) and spasticity (48% of patients) and improvement in sleep (40% of patients) the most common. There was a significant reduction in concomitant opioid use after initiating MC as evidenced by a significant decrease in daily morphine milligram equivalents among patients prescribed opioid analgesics (P = .01). Decreases in muscle relaxant use and benzodiazepine use did not reach significance (P > .05). The most common adverse reaction to MC was fatigue (11% of patients). CONCLUSIONS: In many patients with MS, MC was well tolerated, eased pain and spasticity, improved sleep and other symptoms, and reduced use of concomitant opioid analgesics. Prospective studies are needed to further investigate the role of MC in the treatment of patients with MS.

Medical Cannabis in the Treatment of Parkinson's Disease.

OBJECTIVES: Medical cannabis (MC) has recently garnered interest as a potential treatment for neurologic diseases, including Parkinson's disease (PD). A retrospective chart review was conducted to explore the impact of MC on the symptomatic treatment of patients with PD. METHODS: Patients with PD treated with MC in the normal course of clinical practice were included (n = 69). Data collected from patient charts included MC ratio/formulation changes, PD symptom changes after initiation of MC, and adverse events (AEs) from MC use. Information regarding changes in concomitant medications after MC initiation, including opioids, benzodiazepines, muscle relaxants, and PD medications, was also collected. RESULTS: Most patients were initially certified for a 1:1 (∆ 9 -tetrahydrocannabinol:cannabidiol) tincture. Eight-seven percent of patients (n = 60) were noted to exhibit an improvement in any PD symptom after starting MC. Symptoms with the highest incidence of improvement included cramping/dystonia, pain, spasticity, lack of appetite, dyskinesia, and tremor. After starting MC, 56% of opioid users (n = 14) were able to decrease or discontinue opioid use with an average daily morphine milligram equivalent change from 31 at baseline to 22 at the last follow-up visit. The MC was well-tolerated with no severe AEs reported and low rate of MC discontinuation due to AEs (n = 4). CONCLUSIONS: The MC may improve motor and nonmotor symptoms in patients with PD and may allow for reduction of concomitant opioid medication use. Large, placebo-controlled, randomized studies of MC use in patients with PD are required.

Population pharmacodynamic modelling of aspirin- and Ibuprofen-induced inhibition of platelet aggregation in healthy subjects.

OBJECTIVE: The objective of this study was to develop a mechanism-based pharmacodynamic model that characterizes the antiplatelet effects of aspirin (acetylsalicylic acid) and ibuprofen alone and in combination. METHODS: Ten healthy volunteers were enrolled in a single-blinded, randomized, three-way crossover study. Treatments consisted of single doses of oral aspirin (325 mg) and ibuprofen (400 mg) and concomitant administration of aspirin (325 mg) and ibuprofen (400 mg). Ex vivo whole blood platelet aggregation induced by collagen (1 microg/mL) or arachidonic acid (0.5 mmol/L) was measured by impedance aggregometry. Model development and population parameter estimation were performed using nonlinear mixed-effects modelling implemented in NONMEM. RESULTS: Relatively complete inhibition of platelet aggregation was achieved following aspirin treatment (approximately 77% inhibition within 2 hours), and return to baseline values occurred within 72-96 hours after dosing. In contrast, treatment with ibuprofen alone or in combination with aspirin produced transient inhibition of platelet aggregation, with complete recovery observed in 6-8 hours. The final pharmacodynamic model was based on the turnover of cyclo-oxygenase-1 (COX-1) enzyme, and incorporated irreversible inhibition by aspirin and reversible binding and antiplatelet effects of ibuprofen. The temporal response profiles from all three study arms were well described by the final model, and the parameters were estimated with good precision. The apparent turnover rate constant for COX-1 (kout) and the irreversible inhibition rate constant for aspirin (K) were estimated to be 0.0209 h(-1) and 0.152 (mg/L)(-1).h(-1), with interindividual variability of 30.6% and 26.2%, respectively. Simulations were used to evaluate the influence of clinically relevant ibuprofen regimens on the antiplatelet effect of aspirin, confirming clinical reports that the antiplatelet effect of aspirin would be blocked when multiple daily doses of ibuprofen are given, even if taken after aspirin administration. CONCLUSIONS: A mechanism-based pharmacodynamic model has been developed that characterizes the antiplatelet effects of aspirin and ibuprofen, alone and concomitantly, and predicts a significant inhibition of aspirin antiplatelet effects in the presence of a typical ibuprofen dosing regimen.

Platelet response to increased aspirin dose in patients with persistent platelet aggregation while treated with aspirin 81 mg.

This study demonstrates that patients who are taking 81 mg of aspirin and are nonresponsive benefit from a dose of 162 mg or greater vs a different antiplatelet therapy. We identified 100 patients who were nonresponsive to aspirin 81 mg via whole blood aggregometry and observed how many patients became responsive at a dose of 162 mg or greater. Platelet nonresponsiveness was defined as >10 Ω of resistance to collagen 1 µg/mL and/or an ohms ratio of collagen 1 µg/mL to collagen 5 µg/mL >0.5 and/or >6 Ω to arachidonate. Borderline response was defined as an improvement in 1 but not both of the above criteria. Of the initial 100 patients who were nonresponsive to an aspirin dose of 81 mg, 79% became responsive at a dose of 162 mg or >162 mg. Only 6% did not respond to any increase in dose. We believe that patients treated with low-dose aspirin who have significant risk for secondary vascular events should be individually assessed to determine their antiplatelet response. Those found to have persistent platelet aggregation despite treatment with 81 mg of aspirin have a higher likelihood of obtaining an adequate antiplatelet response at a higher aspirin dose.

Treatment options for multiple sclerosis: current and emerging therapies.

Multiple sclerosis is a chronic autoimmune disease affecting the central nervous system, more specifically, the myelin sheath covering of nerve fibers in the brain and spinal cord. This disease requires lifelong disease-modifying therapy, and all of the currently available first-line disease-modifying agents are parenteral formulations only. To date, eight drugs have entered or completed phases II and III clinical trials, four of which are oral drugs. These include five immunomodulators--cladribine, fingolimod, laquinimod, teriflunomide, and dimethyl fumarate--and three monoclonal antibodies--alemtuzumab, daclizumab, and rituximab. Although comparing these new drugs with available therapies is difficult, they do show promise as potential first-line agents for the treatment of multiple sclerosis. This marks a new frontier in the treatment of this disease, as the advent of new oral drugs will lead to increased patient compliance and contribute to longer sustained symptom-free periods and less marked disability.