Impact of Parkinson's disease and its pharmacologic treatment on quality of life and economic outcomes.

The impact of Parkinson's disease (PD) and its pharmacologic treatment on health-related quality of life (HRQL) and economic outcomes is reviewed. PD is a chronic and progressive neurologic disorder characterized by specific motor deficits resulting from the degeneration of dopaminergic neurons in the substantia nigra. The cardinal symptoms are tremor, rigidity, bradykinesia, and loss of postural reflexes. PD markedly reduces HRQL and places an economic burden on society of up to $25 billion per year. Patients' inability to move freely and to perform everyday tasks restricts their independence and leads to increased reliance on caregivers and assistive devices. Emotional and psychosocial well-being is also negatively affected. As the disease progresses, the response to levodopa typically decreases and various motor complications develop; these are difficult to treat and result in further declines in HRQL. The economic costs of PD include both direct health care costs (for drugs, physician services, and hospitalization) and indirect costs (for lost worker productivity). Economic analyses of PD and its treatments can help guide effective allocation of health care resources. Various antiparkinsonian agents and formulations, such as extended-release levodopa-carbidopa and pramipexole, have been found to be cost-effective relative to other agents. The newest antiparkinsonian drugs, cathechol-O-methyltransferase inhibitors, also have the potential to improve HRQL and economic outcomes, although more study is needed to confirm this. The total impact of PD and its treatment can be fully appreciated only when HRQL and economic outcomes, in addition to clinical outcomes, are examined.

Interventions to achieve tonic exposure to levodopa: delaying or preventing the onset of motor complications.

Variations in levodopa delivery and subsequent dopamine exposure may lead to motor fluctuations and dyskinesias in patients with Parkinson's disease, as the therapeutic window for levodopa narrows with disease progression. Long-term exposure to the oscillations in levodopa-derived dopamine also is suggested to cause postsynaptic changes within the dopaminergic system, leading to further reductions in the drug's efficacy. The need to extend the actions of levodopa led to the development of the catechol-O-methyltransferase (COMT) inhibitors, which are the newest agents introduced to manage the symptoms of Parkinson's disease. Entacapone and tolcapone are two potent, selective, and reversible COMT inhibitors that effectively augment levodopa's pharmacokinetics by increasing area under the plasma concentration versus time curve and plasma elimination half-life without significantly affecting peak levodopa concentrations. This enhanced pharmacokinetic effect results in marked improvements in patients' clinical response. In patients experiencing end-of-dose wearing-off, the addition of either entacapone or tolcapone led to improvements in "on" time, "off" time, and the Unified Parkinson's Disease Rating Scale scoring system, even though many patients already were receiving optimum dosages of various other antiparkinsonian drugs. In patients with stable responses to long-term levodopa, addition of tolcapone significantly reduced the onset of motor fluctuations. These data, combined with the potential for delaying the onset of motor fluctuations, suggest that COMT inhibition may enhance levodopa's short- and long-term efficacy.

Saturable transport of gabapentin at the blood-brain barrier.

Gabapentin readily crosses the blood-brain barrier and concentrates in brain tissue via an active transport process believed to be system-L. Blood-brain barrier system-L has a low K(m), making it particularly susceptible to substrate saturation. The purpose of this study was to determine whether the fraction of gabapentin crossing the blood-brain barrier remains constant over a broad range of doses. Using a rat model, microdialysis techniques were employed to determine if fluctuations in gabapentin concentrations in the brain extracellular fluid (ECF) coincided with proportional changes in plasma concentrations. Area under the concentration-time curve was calculated for plasma (AUCplasma) and brain extracellular fluid (AUCECF). The ratios of AUFECF to AUCplasma (AUCratio) and brain extracellular fluid to midpoint plasma gabapentin concentration for each collection interval (Cratio) were determined to provide indicators of the relative (i.e. fractional) amount of gabapentin crossing the blood-brain barrier. Analysis of the association between AUCECF and AUCplasma using linear regression analysis revealed a small, but significant relationship (r = 0.62; p < 0.01). Although higher AUCECF values were obtained with higher AUCplasma values, changes in AUCECF were less than proportional to observed changes in AUCplasma. Blood-brain barrier saturation of gabapentin transport was evident as the AUCratio decreased with increased AUCplasma. Collectively, these results support a trend towards saturation at higher plasma concentrations of the carrier-mediated transport mechanism of gabapentin through the blood-brain barrier.

Tiagabine: a novel antiepileptic drug.

OBJECTIVE: To provide a comprehensive review of tiagabine, including its pharmacology, toxicology, pharmacokinetics, drug interactions, efficacy, adverse effects, and dosing recommendations. DATA SOURCES: A computerized search of the MEDLINE database from 1966 to December 1997 was used to identify publications related to tiagabine and nipecotic acid derivatives. Included in this review was information gathered from scientific meetings. Manufacturer's information was used when there was no primary literature. DATA SYNTHESIS: Tiagabine amplifies gamma-aminobutyric acid (GABA) neurotransmission, the predominant inhibitory neurotransmitter in the brain. Its mechanism of action is selective and has shown promise as an antiepileptic drug (AED) in patients with seizures refractory to other pharmaceutical products. Tiagabine exhibits dose-independent absorption, 90-95% bioavailability, high protein binding (96%), metabolism via hepatic cytochrome P450 enzymes (CYP3A subfamily), and displays first-order elimination pharmacokinetics. The mean plasma half-life is 5-8 hours. Concomitant medications that induce hepatic metabolism enhance tiagabine elimination; metabolism is reduced in patients with hepatic dysfunction. Adverse events of tiagabine typically involve the central nervous system, have been mild to moderate in intensity, and also have been transient in nature. CONCLUSIONS: Tiagabine has demonstrated a good safety profile and, while it has not been demonstrated to be superior to other second-line AEDs for partial seizures, its safety and select mechanism of action warrant its further evaluation in the clinical setting. Tiagabine should be a good alternative add-on agent for patients with unsatisfactory seizure control or intolerable adverse effects of traditional therapies; thus, this agent should be made available to these patients.

Fosphenytoin.

Fosphenytoin is a phenytoin prodrug that has been introduced to overcome some of the problems and limitations associated with parenteral phenytoin sodium administration. Fosphenytoin is a phosphate ester prodrug that is converted to phenytoin in vivo by peripheral esterases. Fosphenytoin has several advantages and disadvantages that should be considered when selecting its use in place of parenteral phenytoin. Advantages with fosphenytoin include better tolerability, improved safety, better stability, ability for intramuscular administration, and faster infusion rates. Disadvantages with fosphenytoin include rate and dose related paresthesias and pruritus, delayed decreases in blood pressure, the potential for therapeutic drug monitoring errors, and higher drug acquisition costs. In general, given the pros and cons of the new drug, fosphenytoin offers an attractive alternative for parenteral phenytoin in select individuals.

New and investigational treatment options for ischemic stroke.

We conducted a MEDLINE search of new treatment strategies and experimental agents for treating acute ischemic stroke published from 1989-1996. Clinical trials involving thrombolytics, glutamine release inhibition, N-methyl-D-aspartate receptor antagonism, opioid antagonism, calcium channel blockade, free radical scavenging, membrane stabilization, intercellular adhesion molecule-1 antagonism, ganglioside administration, and growth factor administration were included. Basic research articles were selected based on progress of the therapeutic class toward clinical trials. Approval of tissue plasminogen activator indicates progress in new treatments for acute ischemic stroke. Experimental therapies with potential may become available soon. Recognizing signs and symptoms of stroke is crucial to ensure prompt administration of these agents. The time to diagnosis determines the therapeutic approach for acute ischemic stroke.

Intraventricular atrial natriuretic peptide for acute intracranial hypertension.

The effect of intraventricular atrial natriuretic peptide (ANP) on elevated intracranial pressure (ICP) was evaluated in a rodent model of global ischemia and reperfusion. ANP administration into the lateral ventricle 30 minutes after reperfusion statistically significantly reduced ICP compared with both vehicle treated animals (p < 0.001) and pretreatment pressures (p < 0.001). The ICP effects of ANP did not coincide with specific changes in regional perfusion parameters measured by laser-Doppler flowmetry. Two different vehicles for ANP were used to verify that the changes in ICP observed were independent of the sodium content administered in the vehicle. Based on the reductions observed in ICP, ANP deserves further evaluation as a treatment modality for the acute elevations in ICP associated with ischemic brain injury.

Microdialysis in the human brain: review of its applications.

The analysis of brain extracellular fluid can provide essential information about both the physiology and the pathology of the human nervous system. The introduction of microdialysis into the clinical sciences has provided a new opportunity to study this environment. Using microdialysis, endogenous substances can be obtained and drugs can be delivered in very close proximity to the receptors and ion channels on neuronal membranes. In this sense, microdialysis can be regarded as a novel technique since it can continuously measure interstitial brain activity in living tissue while causing minimal adverse effects. Although it has been well established as an experimental technique for neurochemistry, the true utility of microdialysis as a clinical tool is still being defined. The potential clinical applications of microdialysis to characterize the human brain extracellular environment in patients with pathologic conditions has grown rapidly. The number of publications in which microdialysis has been performed in clinical studies has been increasing during recent years and this article gives a summary of those reports where microdialysis was applied in the study of human brain disorders.

Stability of fosphenytoin sodium with intravenous solutions in glass bottles, polyvinyl chloride bags, and polypropylene syringes.

OBJECTIVE: To determine the stability of fosphenytoin sodium admixtures with NaCl 0.9% injection and dextrose 5% (D5W) injection when stored in glass or polyvinyl chloride (PVC) containers, to evaluate the compatibility of fosphenytoin with 11 other intravenous solutions, and to determine the stability of fosphenytoin repackaged in polypropylene syringes. METHODS: Dilutions of fosphenytoin sodium 1, 8, and 20 mg phenytoin sodium equivalents (PE)/mL were prepared in NaCl 0.9%, D5W, and 11 other intravenous fluids. Aliquots of each solution in NaCL 0.9% or D5W were transferred to three glass bottles for storage at 25 degrees C and 21 PVC bags for storage at 25, 4, or -20 degrees C. Aliquots of each admixture with the other intravenous fluids were transferred to three PVC bags and stored at 25 degrees C for 7 days. In addition, 63 syringes were filled with fosphenytoin sodium 50 mg PE/mL (undiluted) and stored at 25, 4, or -20 degrees C. Samples of each solution from the three containers were analyzed for visual compatibility, pH, and fosphenytoin concentration initially and at 0.5, 1, 2, 3, 7, 14, and 30 days during storage at 25 and 4 degrees C and at 1, 7, 14, and 30 days during storage at -20 degrees C. Following removal of containers from the freezer, additional samples were obtained after 7 days at 4 or 25 degrees C, and 7 days at 25 degrees C, and then 7 days at -20 degrees C. RESULTS: No visible precipitation or change in color or clarity was observed in any of the fosphenytoin solutions during the study. The concentration of fosphenytoin at each sampling time remained within 97-104% of initial concentration, regardless of container, concentration, intravenous admixture, or storage temperature. CONCLUSIONS: Fosphenytoin sodium, either undiluted in polypropylene syringes or diluted with NaCl 0.9% or D5W in PVC bags, remains stable for at least 30 days at room temperature, under refrigeration, or frozen. After removal from the freezer, fosphenytoin can be thawed, kept at 4 or 25 degrees C for 7 days, and then returned to the freezer for another 7 days. Admixtures of fosphenytoin sodium in various other intravenous fluids are stable for at least 7 days at room temperature.

Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: a Phase II safety and efficacy trial.

The purpose of this study was to determine the effect of insulin-like growth factor-I (IGF-I) on the catabolic state and clinical outcome of head-injured patients. Thirty-three patients between the ages of 18 and 59 years with isolated traumatic head injury and Glasgow Coma Scale (GCS) scores of 4 to 10 were randomized to one of two groups. All patients received standard neurosurgical intensive care plus aggressive nutritional support; the patients in the treatment group also received intravenous therapy with continuous IGF-I (0.01 mg/kg/hour). During the 14-day dosing period, the control patients lost weight, whereas treated patients gained weight despite a significantly higher measured energy expenditure and lower caloric intake (p = 0.02). Daily glucose concentrations and nitrogen outputs were greater in control patients (p = 0.03) throughout the study period. During Week 1, only treated patients achieved positive nitrogen balance. Fifteen of 17 treated and 13 of 16 control patients survived the 1st week. No deaths occurred in patients whose serum IGF-I concentrations were higher than 350 ng/ml. Dichotomized Glasgow Outcome Scale scores for patients with baseline GCS scores of 5 to 7 improved from poor to good for eight of 12 treated patients but for only three of 11 control patients (p = 0.06). Eight of 11 treated patients with serum IGF-I concentrations that were at least 350 ng/ml achieved moderate-to-good outcome scores at 6 months, compared to only one of five patients with lower concentrations (p < 0.05). These findings indicate that pharmacological concentrations of IGF-I may improve clinical outcome and nitrogen utilization in patients with moderate-to-severe head injury.

Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: a phase II safety and efficacy trial.

The purpose of this study was to determine the effect of insulin-like growth factor-I (IGF-I) on the catabolic state and clinical outcome of head-injured patients. Thirty-three patients between the ages of 18 and 59 years with isolated traumatic head injury and Glasgow Coma Scale (GCS) scores of 4 to 10 were randomized to one of two groups. All patients received standard neurosurgical intensive care plus aggressive nutritional support; the patients in the treatment group also received intravenous therapy with continuous IGF-I (0.01 mg/kg/hour). During the 14-day dosing period, the control patients lost weight, whereas treated patients gained weight despite a significantly higher measured energy expenditure and lower caloric intake (p = 0.02). Daily glucose concentrations and nitrogen outputs were greater in control patients (p = 0.03) throughout the study period. During Week 1, only treated patients achieved positive nitrogen balance. Fifteen of 17 treated and 13 of 16 control patients survived the 1st week. No deaths occurred in patients whose serum IGF-I concentrations were higher than 350 ng/ml. Dichotomized Glasgow Outcome Scale scores for patients with baseline GCS scores of 5 to 7 improved from poor to good for eight of 12 treated patients but for only three of 11 control patients (p = 0.06). Eight of 11 treated patients with serum IGF-I concentrations that were at least 350 ng/ml achieved moderate-to-good outcome scores at 6 months, compared to only one of five patients with lower concentrations (p < 0.05). These findings indicate that pharmacological concentrations of IGF-I may improve clinical outcome and nitrogen utilization in patients with moderate-to-severe head injury.

New pharmacologic strategies for acute neuronal injury.

The number of new drugs for treating neurotrauma is rapidly expanding. Emerging theories regarding the mechanisms of secondary neuronal injury provide the scientific basis for evaluating these new agents. Some of the most promising mechanisms for intervention are ionotropic channel antagonism, inhibition of lipid peroxidation, and neurotrophic factor augmentation. Many of these new agents are undergoing clinical trials to establish their roles in therapy.

New pharmacologic approaches to acute spinal cord injury.

The incidence of spinal cord injury (SCI) in the United States is approximately 10,000 new cases per year. Strategies to prevent injury or salvage a few dermatomal levels may have significant effects on outcome. Several pharmacologic agents have been evaluated for their efficacy in patients with acute SCI. Methylprednisolone, when administered early, was the first drug to show significant improvement in outcome and is a standard of comparison for future agents. Several new drugs show promising results in animal models of SCI, with more extensive human trials currently under way. Results of more well-controlled clinical trials are necessary to determine which agents have significant neurologic benefits.

Use of transcranial cerebral oximetry to monitor regional cerebral oxygen saturation during neuroendovascular procedures.

Using transcranial cerebral oximetry, we monitored 30 patients who underwent cerebral angiography by the femoral route. Transcranial cerebral oximetry is a noninvasive technique of regional cerebral oxygen saturation measurement that uses near-infrared spectroscopy to differentiate oxyhemoglobin from reduced hemoglobin. Needle puncture, catheterization, and contrast media injection produced no significant peak changes in saturation from baseline. Acute and persistent decreases in oxygen saturation were associated with vascular complications and were detected before development of clinical symptoms. Greater changes in saturation were observed during several neuroendovascular procedures, indicating the development of complications, signaling a need to stop further endovascular manipulation.

Modified solution for filling MRI coordinate indicators for the ZD stereotactic frame.

Increased use of magnetic resonance imaging and magnetic resonance angiography in stereotactic planning highlight some technical problems in imaging. Visualization of markers during imaging are vital in stereotactic planning. In magnetic resonance imaging-guided stereotaxy, specially designed plates are used that contain water-based copper sulfate solutions as a marker. Replacement of copper sulfate solution is usually required after some time due to precipitation and leaking. The refilling procedure is quite cumbersome and can cause technical problems in imaging. In this study, we describe copper sulfate solution mixed with a water-soluble gel as a simple but useful alternative to water-based copper sulfate resolution to ease the refilling procedure and to overcome the air bubbles.

Regional cerebral oxygen saturation during intra-arterial papaverine therapy for vasospasm: case report.

Cerebral arterial vasospasm continues to be a major secondary medical complication of aneurysmal subarachnoid hemorrhage. Despite hypervolemic hemodilution, arterial hypertension, and pharmacological therapy, morbidity and mortality due to vasospasm remain high. The authors discuss a patient with vasospasm who did not respond to traditional medical therapy and who underwent intra-arterial papaverine infusions while being monitored with transcranial cerebral oximetry. Oximetry during the procedure revealed significant improvements in brain regional saturation of oxygen, with the relief of vasospasm that correlated with clinical improvements in the patient's neurological status. Transcranial cerebral oximetry was used to monitor regional oxygen saturation throughout the angiographic and interventional procedures, providing continuous, real-time, clinically relevant information about the effects of vasospasm and its treatment.

Transcranial cerebral oximetry and carotid cavernous fistula occlusion. Technical note.

Different methods have been used in the evaluation and monitoring of the cerebral oxygen supply during neuro-interventional therapies. Attenuation of near-infrared light by the chromophores oxyhemoglobin and deoxyhemoglobin have shown to be useful in the study of the cellular oxygen metabolism and oxygen delivery to the brain. Transcranial cerebral oximetry (TCCO) has the advantage of providing real-time information regarding regional brain oxygen saturation (rSO2) by using wavelengths in the near-infrared range. We present a patient with a carotid cavernous fistula who underwent balloon occlusion and concurrent continuous TCCO monitoring. TCCO was found to be a useful tool providing immediate rSO2 values during the angiographic and interventional procedures. Initial balloon occlusion of a carotid cavernous fistula resulted in partial occlusion of the internal carotid artery lumen causing an immediate decrease in rSO2 which correlated with angiographic findings. Subsequent reocclusion of the fistula produced a slower and smaller degree of decrease in rSO2 with clinical improvement in the patient. Changes in rSO2 were detected before any adverse clinical event was observed. TCCO was reliable, safe, sensitive, and provided a real-time assessment tool for the monitoring of brain oxygen supply in a patient undergoing a neuroendovascular procedure.