Mildred D. Gottwald

Therapies for dopaminergic-induced dyskinesias in Parkinson disease.

Existing and emerging strategies for managing L‐dopa–induced dyskinesias (LIDs) in patients with Parkinson disease have involved either delaying the introduction of L‐dopa therapy, treatment with an antidyskinetic agent, using a therapy or delivery system that can provide continuous dopaminergic stimulation, or using novel agents that target receptors implicated in the mechanisms underlying LIDs. Treatment with dopamine agonists such as pramipexole or ropinirole allows levodopa to be delayed, but once levodopa is added to the drug regimen the usual course of onset of dyskinesias is observed. Amantadine, an N‐methyl‐D‐aspartate antagonist, is so far the only approved compound with evidence of providing a sustained antidyskinetic benefit in the absence of unacceptable side effects. These findings support the hypothesis of glutamate overactivity in the development of dyskinesias. More continuous delivery of dopaminergic medication, such as through intraintestinal or subcutaneous routes, is promising but invasive and associated with injection site reactions. As a result of molecular research and elucidation of the role of a variety of neurotransmitters in the mechanism of LIDs, new compounds have been identified, including those that modulate the direct and indirect striatal output pathways; some of these new agents are in the early stages of development or undergoing proof‐of‐concept evaluation as antidyskinetic agents. Ann Neurol 2011;69:919–927

The prehospital treatment of status epilepticus (PHTSE) study: design and methodology.

Status epilepticus is a neurological emergency that is typically first encountered and managed in the prehospital environment. Although aggressive pharmacological treatment of status epilepticus is well established in the emergency department and hospital settings, the relative risks and benefits of active therapy for status epilepticus in the prehospital setting are not known. The Prehospital Treatment of Status Epilepticus (PHTSE) study is a prospective, randomized, double-blind, placebo-controlled study designed to address the following aims: (1) to determine whether administration of benzodiazepines by paramedics is an effective and safe means of treating status epilepticus in the prehospital setting and whether this therapy influences longer-term patient outcome, (2) to determine whether lorazepam is superior to diazepam for the treatment of status epilepticus in the prehospital setting, and (3) to determine whether control of status epilepticus prior to arrival to the emergency department influences patient disposition. The initial phase of the PHTSE study began in January 1994 and was completed in February 1999 after the successful enrollment of 205 patients into the three treatment arms. In this paper, we describe the rationale for the conceptualization of the study and details of the study design and methodology, and emphasize some aspects of study implementation that are unique to research involving the emergency medical system.

Prehospital stability of diazepam and lorazepam.

Injectable benzodiazepines are commonly stocked on ambulances for use by paramedics. We evaluated the stability of lorazepam and diazepam as a function of storage temperature. Diazepam (5 mg/mL) and lorazepam (2 mg/mL) injectable solutions were stored for up to 210 days in clear glass syringes at three conditions: 4 degrees C to 10 degrees C (refrigerated); 15 degrees C to 30 degrees C (on-ambulance ambient temperature); and 37 degrees C (oven-heated). High-performance liquid chromatography (HPLC) analyses of syringe contents were performed at 30-day intervals. After 210 days, the reduction in diazepam concentration was 7% refrigerated, 15% at ambient temperature, and 25% at 37 degrees C. The reduction in lorazepam concentration was 0% refrigerated, 10% at ambient temperature, and 75% at 37 degrees C. Whereas diazepam retained 90% of its original concentration for 30 days of on-ambulance storage, lorazepam retained 90% of its original concentration for 150 days. The decrease in lorazepam concentration correlated with an increase in the maximum ambient temperature in San Francisco. These results suggest that diazepam and lorazepam can be stored on ambulances. When ambient storage temperatures are 30 degrees C or less, ambulances carrying lorazepam and diazepam should be restocked every 30 to 60 days. When drug storage temperatures exceed 30 degrees C, more frequent stocking or refrigeration is required.

Pharmacokinetics of Fosphenytoin in Patients with Hepatic or Renal Disease

Summary: Purpose: The pharmacokinetic behavior of fosphenytoin (FOS), the water‐soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT.

CHAPTER 5:Pharmacologic Management of Dopaminergic‐Induced Dyskinesias in Parkinson’s Disease

Despite the introduction of other classes of dopaminergic therapies, levodopa remains the most effective treatment for managing the motor symptoms of Parkinson’s disease. However, with chronic levodopa exposure, troublesome dyskinesias frequently emerge and limit the potential for maximizing therapy. Although dopamine agonists such as pramipexole or ropinirole may delay the need for levodopa, dyskinesias emerge once levodopa is added to manage motor symptoms. Provision of dopaminergic therapy using parenteral methods for more continuous delivery (e.g., subcutaneous or direct intraintestinal administration) has minimized motor fluctuations and the severity and duration of dyskinesias. Amantadine and, to some extent, clozapine have demonstrated anti‐dyskinetic effects in controlled studies and support the notion that other pharmacologic pathways may be involved. These pathways may provide an opportunity for pharmacologic intervention. Oral therapies such as preladenant, pardoprunox, and levitiracetam are among compounds that may delay or prevent the onset of dyskinesias, and compounds targeting other biochemical pathways are in the early stages of development.