Central Nervous System Adverse Effects Research Articles

Once Daily Trospium Chloride is Effective and Well Tolerated for the Treatment of Overactive Bladder: Results From a Multicenter Phase III Trial

An extended release formulation of trospium chloride was recently developed for the once daily treatment of overactive bladder. We investigated the safety, efficacy and tolerability of 60 mg trospium chloride once daily. Subjects with overactive bladder were randomized 1:1 to receive 60 mg trospium chloride once daily or placebo in this 12-week multicenter, parallel, double-blind, placebo controlled trial. Primary end points were calculated changes in diary recorded daily urinary frequency and daily urgency urinary incontinence episodes. Secondary end points were urgency severity, volume voided per void and the number of urgency voids per day. Safety was assessed by clinical examination, adverse event monitoring, clinical laboratory values and resting electrocardiograms. Overall 601 subjects were prescribed trospium once daily (298) or placebo (303). Trospium once daily treatment resulted in significant improvements over placebo in all primary and key secondary efficacy outcomes at weeks 1 through 12. The most common adverse events were dry mouth (trospium 8.7% vs placebo 3%) and constipation (trospium 9.4% vs placebo 1.3%). Central nervous system adverse events were rare (headache with trospium 1.0% vs placebo 2.6%). No clinically meaningful changes in laboratory, physical examination or electrocardiogram parameters were noted. Trospium once daily provided significant improvements in overactive bladder symptoms (frequency, urgency urinary incontinence and urgency). Efficacy was similar to that seen previously with trospium chloride twice daily, while class effect anticholinergic adverse events occurred at comparatively low levels. Dry mouth was elicited at the lowest reported rate in the oral antimuscarinic drug class.

Adverse Effects of Opioids on the Central Nervous Systems of Palliative Care Patients

Opioids, defined as drugs that stimulate opioid receptors, are primarily used in the treatment of moderate to severe pain. They induce central nervous system (CNS) adverse effects which can be divided into three groups. The first group includes effects that lower the level of consciousness-sedation, drowsiness and sleep disturbance. The second group affects the thinking process and the ability to reactcognitive impairment, psychomotor impairment, delirium, hallucinations, dreams and nightmares. The third group is of the direct toxic effects of opioids on neurons and includes myoclonus (perhaps), hyperalgesia and tolerance.This review addresses the incidence, possible mechanisms, and treatment of each of these groups of Opioid-induced adverse effects.

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Assess the Efficacy and Safety of Topiramate Controlled Release in the Treatment of Obese Type 2 Diabetic Patients

This is a randomized, placebo-controlled study of the weight-loss efficacy and safety of a controlled-release (CR) formulation of topiramate in overweight and obese patients with type 2 diabetes treated with diet and exercise alone or in combination with metformin. Patients with type 2 diabetes, BMI > or =27 kg/m2, A1C >6.5 and <11.0%, treated with diet and exercise alone or in combination with metformin monotherapy were enrolled. Patients were randomized to placebo or topiramate CR titrated up to 175 mg/day. Treatment consisted of a 7-week titration phase followed by a 9-week maintenance phase. A total of 111 subjects were randomized and analyzed. By the end of week 16, patients in the placebo and topiramate groups lost 2.5 and 6.0 kg, which represented 2.3 and 5.8%, respectively, of their baseline body weight (P < 0.001 vs. placebo). A1C improved from a baseline of 7.4% in the placebo and 7.6% in the topiramate groups to 7.1 and 6.7%, respectively, representing a 0.4 and 0.9% reduction from baseline, respectively (P < 0.001 vs. placebo). Topiramate also significantly reduced blood pressure and urinary albumin excretion. Adverse events were predominantly neuropsychiatric or central and peripheral nervous system related. Topiramate CR treatment produced significant weight loss and meaningful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated with diet and exercise or in combination with metformin. However, the central nervous system and psychiatric adverse event profile of topiramate CR makes it unsuitable for the treatment of obesity and diabetes.

Treatment-Emergent CNS Symptoms Following Triptan Therapy are Part of The Attack

If treatment-emergent central nervous system (CNS) symptoms following triptan therapy represent direct pharmacological effects of the drug, they should occur independent of response to active drug. However, if they represent unmasking of neurological symptoms of the migraine attack after pain is relieved, they should be more common in responders both to active drug and to placebo. To explore this issue, we evaluated the relationship between the CNS adverse events and treatment response following triptan or placebo treatment. We used pooled data from seven double-blind, placebo-controlled trials involving eletriptan 20 mg (E20, n = 402), eletriptan 40 mg (E40, n = 1870), eletriptan 80 mg (E80, n = 1393), sumatriptan 100 mg (S100, n = 275) and placebo (Pbo, n = 1024). Somnolence was more prevalent among 2 h headache responders than non-responders for all treatments, including E80 (8.8% vs. 5.0%; P < 0.05), E40 (6.4% vs. 5.0%; NS), E20 (4.0% vs. 2.0%; NS), S100 (4.7% vs. 3.2%; NS) and Pbo (7.6% vs. 3.0%; P < 0.05). Similarly, the incidence of asthenia was higher among patients who responded to treatment compared with those who did not respond to E80 (15.2% vs. 7.8%; P < 0.05), E40 (6.5% vs. 3.6%; P < 0.05), E20 (6.5% vs. 1.0%; P < 0.05), S100 (10.1% vs. 4.7%; NS) and Pbo (4.4% vs. 2.7%; NS). The generally higher rates of somnolence and asthenia in patients who respond to treatment suggests that these treatment-emergent neurological symptoms may represent the unmasking of CNS symptoms associated with the natural resolution of a migraine attack, rather than simply representing drug-related side-effects. The rate of somnolence in placebo responders is comparable to that in responders to E40 and E80, indicating that somnolence is related, at least in some important part, to headache relief and not treatment.

Transitory Severe CNS Adverse Effects after Accidental Efavirenz Overdose During Post-Exposure HIV Prophylaxis

"Transitory Severe CNS Adverse Effects after Accidental Efavirenz Overdose During Post-Exposure HIV Prophylaxis." Journal of Chemotherapy, 19(1), p. 110

Polypharmacy and Central Nervous System Adverse Effects of Anticholinergic Agents in the Men with Benign Prostate Hyperplasia

Polypharmacy and Central Nervous System Adverse Effects of Anticholinergic Agents in the Men with Benign Prostate Hyperplasia

Treatment of Obesity

Treatment of Obesity

Adverse Effects of Opioids on the Central Nervous Systems of Palliative Care Patients

Opioids, defined as drugs that stimulate opioid receptors, are primarily used in the treatment of moderate to severe pain. They induce central nervous system (CNS) adverse effects which can be divided into three groups. The first group includes effects that lower the level of consciousness-sedation, drowsiness and sleep disturbance. The second group affects the thinking process and the ability to reactcognitive impairment, psychomotor impairment, delirium, hallucinations, dreams and nightmares. The third group is of the direct toxic effects of opioids on neurons and includes myoclonus (perhaps), hyperalgesia and tolerance.This review addresses the incidence, possible mechanisms, and treatment of each of these groups of Opioid-induced adverse effects.

Plasma and Cerebrospinal Fluid Concentrations of Indomethacin in Children After Intravenous Administration

The objective of this study was to evaluate the cerebrospinal fluid (CSF) permeation of indomethacin in healthy children. The participants (n = 31, aged 4-144 months) received indomethacin (0.35 mg/kg) as a 10-minute intravenous infusion prior to surgery under spinal anaesthesia. A single CSF and plasma sample from each individual was collected 14 to 225 minutes after the infusion. Indomethacin concentrations were determined from the CSF, plasma, and protein-free plasma. Total plasma, protein-free plasma, and CSF concentrations of indomethacin ranged between 90 and 2200 ng/mL (median, 780 ng/mL), 0.3 and 0.8 ng/mL (median, 0.5 ng/mL), and 0.2 and 5.0 ng/mL (median, 1.4 ng/mL), respectively. The CSF to plasma concentration ratio remained less than 0.01. There was no correlation between the administration time and CSF concentrations. Eleven children developed 12 nonserious adverse effects, from which 5 were central nervous system (CNS) effects (agitation). In conclusion, indomethacin permeated into the CSF of children, which enables both desired and adverse CNS effects of indomethacin.

Effect of trospium chloride on somnolence and sleepiness in patients with overactive bladder

An objective of a large US phase-3 study was to determine the effects of trospium chloride 20-mg tablets versus placebo, administered twice daily, on central nervous system (CNS) adverse events (eg, somnolence) and on daytime sleepiness using the validated Stanford Sleepiness Scale. The impact of age groups also was assessed. Trospium chloride did not increase daytime sleepiness or appear to produce CNS adverse effects, as measured by the Stanford Sleepiness Scale and the incidence of CNS adverse events. Furthermore, there was no difference in these findings across age groups.

(960): Constipation is a predominant side effect of opioid treatment for persistent pain

Opioids are regularly used for persistent pain, offering superior pain relief versus other available agents. However, opioid use is often complicated by central nervous system (CNS) and gastrointestinal adverse events (GIAEs; constipation, abdominal pain/bloating, reflux, and decreased appetite). While CNS effects are well documented and lessen with continued opioid use, the incidence/impact of GIAEs are less well understood and some persist throughout treatment. Data on AEs associated with opioid use were collected as part of a National Health and Wellness Survey in 2004.

Ziconotide Infusion for Severe Chronic Pain: Case Series of Patients with Neuropathic Pain

Ziconotide intrathecal infusion was recently approved by the United States Food and Drug Administration for the treatment of intractable severe chronic pain. Patients with neuropathic pain make up a significant population among those who experience chronic pain for which there are less than optimal pharmacotherapeutic options. Published clinical trials provide a global view of ziconotide efficacy and safety. A subset of patients in clinical trials obtained complete pain relief, a remarkable finding given the history of drug treatment for neuropathic pain. To provide more information regarding those who respond to ziconotide therapy, we discuss three patients with neuropathic pain who received ziconotide infusion. Two patients with longstanding neuropathic pain, one with complex regional pain syndrome (formerly known as reflex sympathetic dystrophy) of the leg and one with lumbar radiculitis, achieved temporary but complete pain relief from single 5- and 10-microg epidural test doses. In the third case, a patient with longstanding bilateral leg and foot neuropathic pain from acquired immunodeficiency syndrome and antiretroviral drug therapy achieved considerable pain relief from a long-term continuous intrathecal infusion. The patients who received a single dose had mild central nervous system adverse effects such as sedation, somnolence, nausea, headache, and lightheadedness. The patient who received the intrathecal infusion experienced mild-to-severe adverse effects depending on the rate of infusion; these effects included sedation, confusion, memory impairment, slurred speech, and double vision. This patient could sense impending adverse effects and made rate adjustments or suspended infusion to avert untoward symptoms. In all three cases, patients achieved considerable pain relief that was long-lasting and persisted well after dose administration or suspension of infusion.

Prevalence and Characteristics of Adverse Drug Reactions in Neurosurgical Intensive Care Patients

To evaluate the prevalence and characteristics of adverse drug reactions (ADRs) in neurosurgical intensive care patients. Retrospective analysis of ADR data obtained from a spontaneous reporting system in a tertiary care university hospital. Reports of suspected ADRs in adult patients admitted emergently or electively to the neurosurgical service were included. Over the 3 year period, 3496 neurosurgical intensive care unit (ICU) patient admissions accounted for 5% of all hospital admissions. A total of 10% of all neurosurgical patients developed a suspected ADR, with three patients experiencing multiple reactions. Other adult ICU patients developed ADRs at a comparable rate (9%, P > 0.05). Overall, neurosurgery patients accounted for 12% of all spontaneously reported ADRs. Preventable reactions were observed in 43 (13%) cases, and treatment was required for 76%. The majority (96%) of ADRs resolved or improved at the time of the ADR report. Nausea, pruritus, thrombocytopenia, and vomiting were most frequently noted. Therapies most often associated with reported events were analgesics, antipyretics, antibiotics, anticonvulsants, and histamine H2 antagonists. The relationship between central nervous system disease and adverse event occurrence is not clear. Despite the narrow scope of drug regimens in neurosurgical ICU patients, ADRs can complicate therapy in this critically ill population. Neurosurgical ICU patients seem to experience ADRs no more frequently than their adult ICU counterparts.

Multi-drug resistance (MDR1) gene and P-glycoprotein influence on pharmacokinetic and pharmacodymanic of therapeutic drugs

(MDR1) gene expressed in tumor cells and also in several normal tissues, such as intestine, liver, kidney, blood-brain barrier, spinal cord, and placenta. P-gp has been identified in mice, rat, bovine, monkey, rodents, and human beings and has been receiving a particular clinical relevance because this protein expression limits brain access and intestinal absorption of many drugs. This protein plays a role as a protective barrier against a wide variety of substrates, avoiding drug entry into the central nervous system. P-glycoprotein also interferes with drug bioavailability and disposition, including absorption, distribution, metabolization, and excretion, influencing pharmacokinetic and pharmacodynamic of drugs. Modulation of P-gp may help the efficacy of treatment of several diseases and can explain some adverse central nervous system effects induced by drugs after intravenous administration and the poor response of oral administration in patients. Alteration in P-gp expression or function has been associated with several diseases susceptibility in humans and animals. Furthermore, additional studies relating MDR1 and P-gp expression has an important clinical implication also in terms of treatment efficacy.

Pregabalin in neuropathic pain: A more “pharmaceutically elegant” gabapentin?

This article reviews the available information on pregabalin, a new anticonvulsant for peripheral neuropathic pain. Pregabalin was provisionally approved by the US Food and Drug Administration in December 2004 and was granted final approval after controlled substance scheduling (Schedule V) by the US Drug Enforcement Agency in August 2005. A MEDLINE search (1986-August 2005) was conducted to identify pertinent studies in the Englishlanguage. The search terms included pregabalin , PD144723, CI-1008, gabapentin , and neuropathic pain . Additional references were obtained from the bibliographies of identified articles. All studies that evaluated any aspect of pregabalin in vitro or in vivo in animals or humans were included, with a focus on data relevant to older adults. In preclinical studies, pregabalin, a structural congener of gabapentin, exhibited antinociceptive activity in animal models of neuropathic and inflammatory pain. Unlike gabapentin, pregabalin was well absorbed (>90%), and its absorption was dose independent. Like gabapentin, pregabalin was predominantly excreted unchanged in the urine (⩾98%). Dosed at SO to 200 mg TID, pregabalin was superior to placebo in relieving pain and improving sleep and health-related quality of life in patients with diabetic peripheral neuropathy and postherpetic neuralgia ( P < 0.001- P < 0.049). No active-controlled trials were available. The most problematic adverse events associated with pregabalin were dizziness and somnolence (21%26%). In the absence of active-controlled clinical trials and geriatric-specific efficacy/tolerability data, theplace of pregabalin in the analgesic armamentarium for the elderly is unclear. Because pregabalin is a Schedule V controlled substance, its utility is not compromised by substantial limitation of access or the need for extra steps in prescribing. However, abuse potential is a consideration, and utilization should be carefully monitored, particularly in patients with a past or current history of substance abuse. The improved pharmacokinetic profile of pregabalin relative to gabapentin is manifested in linear and dose-independent absorption and a narrow therapeutic dosing range. However, pregabalin still requires multiple administrations per day, and daily doses >150 mg/d require dose titration. The relatively high frequency of central nervous system adverse events, particularly dizziness and somnolence, is a concern in the elderly. Time and further experience should clarify the role of this agent.

Nonoccupational HIV Postexposure Prophylaxis

To the Editor: We agree with the perspective of Drs Merchant and Mayer in their Commentary that the new Centers for Disease Control and Prevention (CDC) guidelines for provision of human immunodeficiency virus (HIV) nonoccupational postexposure prophylaxis (HIV NPEP) represents an important initial step in advising clinicians. However, we note an important caveat with regard to the choice of antiretroviral agents, as discussed in the clinical guidelines developed by the New York State Department of Health AIDS Institute (NYSDOH AI) in 1997 and updated in December 2004. The CDC now endorses 3-drug HIV NPEP regimens rather than 2-drug regimens, as does the NYSDOH AI. Yet, the CDC’s suggestion of efavirenz as an anchor of the simplest 3-drug regimens is concerning. In some resourcelimited countries, efavirenz may be the only viable option to complete a postexposure prophylaxis regimen. However, in the United States, the Food and Drug Administration recently reclassified efavirenz as a category D agent (positive evidence of fetal risk) for pregnant women. Since much of HIV NPEP is likely prescribed for women exposed to HIV through sexual assault, recommendation of 28-day therapy with a category D agent will require more attention to contraception than simply testing for pregnancy and providing emergency postexposure contraception at the time of NPEP initiation. Furthermore, the therapeutic index of efavirenz in this context seems unfavorable, since the incidence of central nervous system adverse effects approaches 25%. The alternative regimen of tenofovir, zidovudine, and lamivudine that is suggested in the NYSDOH AI guidelines for HIV NPEP may offer a potentially less toxic option that maintains a low pill burden (3 pills/d) and also is supported by at least some experimental evidence from animal models. This alternative regimen, in the context of explicit instructions and algorithms for its use (as contained in the NYSDOH AI guidelines), may better serve patients with nonoccupational exposure to HIV, especially those who have been exposed through sexual assault, as well as the practitioners asked to care for them. We also note that clinicians practicing in local jurisdictions in which HIV NPEP guidelines have been created (eg, California, Massachusetts, New York, Rhode Island) should be aware that federal guidelines do not necessarily replace or supplant local medical standards of care.

An open-label, noncomparative study of miglustat in type I Gaucher disease: Efficacy and tolerability over 24 months of treatment

The substrate synthesis inhibitor miglustat (N-butyldeoxynojirimycin) is the first oral agent to receive regulatory approval for the treatment of type I Gaucher disease (GD). The aims of this study were to further assess previous observations of the effects of miglustat in adult patients with mild to moderate type I GD and to evaluate the tolerability and safety profile of this drug. This was a noncomparative, open-label study in adult patients with type I GD (confirmed by genotyping and glucocerebrosidase assay) who were unwilling or unable to receive enzyme replacement therapy (ERT) or who had discontinued ERT for at least 3 months. Patients received miglustat 100 mg TID for 12 months, with the option of continuing treatment for a further 12 months. The primary end point was the percentage change in liver volume. Secondary end points included the percentage change in spleen volume and changes in hematologic parameters (hemoglobin, platelets), chitotriosidase activity (a surrogate marker of disease burden), and bone assessments (dual-energy X-ray absorptiometry, magnetic resonance imaging, and radiography). Clinical safety was monitored, including assessment of neurologic status at baseline and throughout the study using a comprehensive battery of standardized neurologic tests (eg, Purdue Pegboard Test, Mini-Mental State Examination, nerve conduction studies) and neuropsychological tests. Of the 10 patients (7 men, 3 women) who received at least 1 dose of miglustat, 7 completed 24 months of treatment. Patients were aged between 32 and 62 years (mean, 46.3 years) and weighed between 55 and 88 kg (mean, 72.4 kg). All patients had at least 1 manifestation of GD, including 10 with splenomegaly (mean size, 8.1 times normal; range, 3.9-15.9 times normal), 9 with thrombocytopenia, and 8 with hepatomegaly (mean size, 1.5 times normal; range, 1.0-2.0 times normal). At baseline, hemoglobin concentrations ranged from 11.5 to 15.1 g/dL (mean, 13.2 g/dL), platelet counts from 55 to 161 x 10(9)/L (mean, 83.8 x 10(9)/L), and chitotriosidase activity from 526 to 29636 nmol/mL . h (mean, 8143.7 nmol/mL . h). In the 8 patients comprising the efficacy set, significant mean percentage changes from baseline in liver volume were seen at 6 months (-8.4%; P = 0.036; 95% CI, -16.1 to -0.7) and 18 months (-15.1%; P = 0.022; 95% CI, -27.1 to -3.0). Although not statistically significant, the 95% CIs for the percentage changes in liver volume at 12 months (-9.4%; 95% CI, -19.5 to 0.6) and 24 months (-5.6%; 95% CI, -12.1 to 1.0) were similar to those at 6 and 18 months, supporting a consistent clinical effect. Significant mean percentage reductions in spleen volume were observed at 6 months (-19.0%; P = 0.006; 95% CI, -30.4 to -7.6) and 18 months (-24.3%; P = 0.001; 95% CI, -33.6 to -15.1). Mean hemoglobin concentrations, which were normal at baseline, remained stable over the course of the study. There were no significant changes in bone status. There was a significant mean increase in absolute platelet count at 12 months (by 13.9 x 10(9)/L; P = 0.030; 95% CI, 1.8 to 26.0); at 24 months, the mean percentage increase from baseline (23.0%) was not statistically significant. The mean percentage reduction from baseline in chitotriosidase activity at 24 months was 25.3%. Treatment was well tolerated, and the incidence of most adverse events decreased with time. Gastrointestinal and central nervous system adverse events reported during 3-month periods at the beginning (0-3 months) and end (>21-24 months) of the study were flatulence (10 and 2 patients, respectively), diarrhea (9 and 0), abdominal pain (7 and 1), tremor (4 and 1), paresthesia (3 and 0), headache (2 and 3), and abdominal distention (2 and 0). No evidence of clinically significant adverse effects on neurologic or neuropsychological function was found during the study. In this small study in symptomatic adult patients with type I GD, miglustat treatment resulted in a significant decrease in liver and spleen volume at 6 and 18 months, with clinical improvement noted over 24 months. Bone involvement and platelet and hemoglobin values remained stable, with no significant changes noted during the observation period. The effects of treatment were consistent with those of earlier studies of miglustat in type I GD.

Ziconotide, an Intrathecally Administered N-Type Calcium Channel Antagonist for the Treatment of Chronic Pain

Ziconotide is a novel peptide that blocks the entry of calcium into neuronal N-type voltage-sensitive calcium channels, preventing the conduction of nerve signals. N-type calcium channels are present in the superficial laminae of the dorsal horn of the spinal cord. In various animal models of pain, intrathecal administration of ziconotide blocked nerve transmission and nociception. The United States Food and Drug Administration recently approved ziconotide intrathecal infusion for the management of severe chronic pain in patients who require intrathecal therapy and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. The drug has a narrow therapeutic window and a lag time for the onset and offset of analgesia and adverse events. In early clinical trials, frequent and severe psychiatric and central nervous system adverse effects were associated with rapid intrathecal infusion (0.4 microg/hr) and frequent up-titration (every 12 hrs). Therefore, patients with psychiatric symptoms are not candidates for this drug. Drug trials of external intrathecal catheters and microinfusion devices demonstrated a 3% risk of meningitis. A low initial infusion rate of 0.1 microg/hour and limiting infusion rate increases to 2-3 times/week are now recommended. Patients responsive to intrathecal ziconotide require an implanted infusion system to receive long-term therapy.

Dose-Response Effects of Tiagabine on the Sleep of Older Adults

To evaluate the dose- response effects of tiagabine on sleep and safety measures in healthy older adults. Randomized, double-blind, Latin-square design. Sleep laboratory. Twenty-four healthy older adults (11 men, 13 women; mean age 68.0 +/- 6.2 years) Tiagabine 2, 4, or 8 mg, or placebo, each given on two consecutive nights. Polysomnography revealed that compared with placebo, tiagabine 4 mg increased total sleep time, reduced wake after sleep onset, and increased minutes of slow-wave sleep. Tiagabine 8 mg decreased wake after sleep onset, increased slow-wave sleep, and improved a sleep-continuity index. No differences were seen between the 2-mg dose and placebo. Subjective ratings indicated fewer awakenings with the 8-mg dose. Central nervous system adverse events were somewhat higher in the 8-mg condition only. Measures of morning performance were minimally affected. Research with tiagabine at dosages of 8 mg or less appears warranted in elderly clinical populations.

Safety and Feasibility of Convection-enhanced Delivery of Cotara for the Treatment of Malignant Glioma: Initial Experience in 51 Patients

We report the safety and feasibility of using convection-enhanced delivery to administer Cotara (Peregrine Pharmaceuticals, Inc., Tustin, CA), a novel radioimmunotherapeutic agent, to patients with malignant glioma. Between April 1998 and November 2002, 51 patients with histologically confirmed malignant glioma received Cotara by convection-enhanced delivery. Most patients (88%) were treated with Cotara targeting tumor volume-dependent, single or multiple administrations of activity ranging from 0.5 to 3.0 mCi/cm3 of baseline clinical target volume. Two weeks after infusion, single-photon emission computed tomographic imaging determined the spatial distribution of Cotara. Patients were followed for as long as 41 months (average follow-up, 5 mo). Safety was evaluated on the basis of incidence of procedure-related, neurological, and systemic adverse events. Feasibility was evaluated in a subset of patients on the basis of the correlation between the prescribed activity and the actual activity administered to the targeted region. Fifty-one patients, 37 with recurrent glioblastoma multiforme, 8 with newly diagnosed glioblastoma multiforme, and 6 with recurrent anaplastic astrocytomas, were treated. Average tumor volume was 36 +/- 27.6 cm3 (range, 5-168 cm3). Of the 67 infusions, 13 (19%), 52 (78%), and 2 (3%) delivered less than 90%, 100 +/- 10%, and more than 110%, respectively, of the prescribed administered activity to the targeted region. Treatment-emergent, drug-related central nervous system adverse events included brain edema (16%), hemiparesis (14%), and headache (14%). Systemic adverse events were mild. Several patients had objective responses to Cotara. The majority of Cotara infusions delivered between 90 and 110% of the prescribed administered activity to the targeted region. This method of administration has an acceptable safety profile compared with literature reports of other therapeutics delivered by convection-enhanced delivery.