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PubMed1996

Divalproex sodium in headache: literature review and clinical guidelines.

Divalproex sodium is an anticonvulsant agent approved for use either alone or in combination with other antiepileptic drugs for simple and complex absences seizures and mania. Four double-blind placebo-controlled studies have confirmed that divalproex sodium/valproate is an effective migraine treatment. In all of the clinical studies, whether open, retrospective, or placebo-controlled and double-blind, valproate was an effective preventive treatment for migraine. There was a reduction in the number of migraine attacks, and migraine duration and intensity were also reduced in some instances. It is equally as effective in patients with severe frequent migraines as in those with less severe migraines. In clinical trials, the most frequent adverse events reported by patients treated with divalproex sodium were nausea, asthenia, dyspepsia, dizziness, somnolence, and diarrhea, with most adverse events being mild to moderate in severity.

Chronic Disease↗
PubMedDate not supplied

Antiepileptic drugs in migraine prevention.

Migraineurs may continue to experience attacks, despite daily use of one or more agents from a wide range of drugs, including beta-blockers, calcium channel blockers, serotonin antagonists, tricyclic antidepressants, monoamine oxidase inhibitors, and antiepileptic agents. Divalproex sodium is the only antiepileptic drug approved for migraine prevention. Gabapentin, topiramate, and other antiepileptic agents are being evaluated for migraine prevention and treatment. Prospective, double-blind, placebo-controlled clinical trials of divalproex, gabapentin, and topiramate for migraine prevention generally were composed of a prospective baseline period, a dose titration period, and a fixed-dose treatment period. The primary efficacy variable was a reduction in the 28-day frequency of migraine headache. Patients receiving divalproex for 12 weeks at doses up to 1500 mg/day achieved significant decreases in the migraine frequency (P<.05), corresponding to reductions of 30% to 40% compared with baseline. Nearly half of the divalproex-treated patients had a 50% or more reduction from baseline in headache frequencies (P< or =.05). Asthenia, vomiting, somnolence, tremor, and alopecia were common adverse events associated with divalproex. Significant reductions in migraine frequency were also observed with gabapentin (1800 to 2400 mg/day) when compared with placebo (P<.01), and nearly half of all patients treated at the highest dose experienced a reduction in headache rate of 50% or more. Somnolence was the most commonly reported adverse event among the gabapentin-treated patients. Two single-center, double-blind, placebo-controlled clinical trials evaluated topiramate for migraine prevention. A lower 28-day migraine frequency was seen during 18 weeks of administration at a maximum daily dose of 200 mg (P =.09). In a second study, a significantly lower mean 28-day migraine frequency was observed during 16 weeks of treatment with topiramate (P =.0015). Mean reduction in migraine frequency was also significantly greater in topiramate-treated patients (P =.0037). Paresthesias, diarrhea, somnolence, and altered taste were commonly reported adverse events in the topiramate-treated patients. Unlike some patients given divalproex or gabapentin, some given topiramate reported weight loss. Large, double-blind, placebo-controlled trials may prove the effectiveness of novel antiepileptic drugs in migraine prevention.

Acetates↗
PubMed2001

Efficacy of gabapentin in migraine prophylaxis.

OBJECTIVE: To compare gabapentin with placebo for use as a prophylactic agent in patients with migraine (with or without aura). STUDY DESIGN AND TREATMENT: After screening, a 4-week, single-blind, placebo baseline period was followed by a 12-week, double-blind, treatment period. The 12-week treatment period consisted of a 4-week titration phase and an 8-week stable-dosing phase. During the 4-week titration phase, patients were started on one 300-mg capsule of gabapentin or matching placebo. Patients were titrated weekly from 900 mg/day (end of week 1) to 2400 mg/day (end of week 4) and had to be receiving a stable dose of study medication by the end of the titration period. Study medication was to be given on a three-times-a-day dosing regimen. METHODS: The study hypothesis was defined a priori as a lower 4-week migraine rate during the second stabilization period for the gabapentin-treated patients as compared with the placebo-treated patients. The analyses were performed with the 4-week migraine rate at baseline as a covariate and center as a blocking factor. RESULTS: At seven participating centers, 143 patients with migraine were randomized in a 2:1 ratio and received either gabapentin (n = 98) or matching placebo (n = 45). Thirty-three patients (24.1%) discontinued prematurely from the study, including 24 (24.5%) of 98 gabapentin-treated patients and 9 (20.0%) of 45 placebo-treated patients; the majority of patients discontinued due to adverse events (16 [16.3%] of 98 gabapentin-treated patients; 4 [8.9%] of 45 placebo-treated patients). Patients included in the analysis were evenly balanced for age, sex, race, weight, and height. The majority of these patients were white (80 [92.0%] of 87) and women (72 [82.8%] of 87), with a mean age of approximately 39.4 years and a history of migraine episodes for a mean of about 21 years. At the end of the 12-week treatment phase, the median 4-week migraine rate was 2.7 for the gabapentin-treated patients maintained on a stable dose of 2400 mg/day and 3.5 for the placebo-treated patients (P =.006), compared with 4.2 and 4.1, respectively, during the baseline period. Additionally, 26 (46.4%) of 56 patients receiving a stable dose of 2400 mg/day gabapentin and 5 (16.1%) of 31 patients receiving placebo showed at least a 50% reduction in the 4-week migraine rate (P =.008). The average number of days per 4 weeks with migraine was also statistically significant and favored gabapentin (P =.006) during stabilization period 2. The median change in 4-week headache rate was statistically significant as well (P =.013). The most frequently reported adverse events for both treatment groups were asthenia, dizziness, somnolence, and infection. Adverse events determined by the investigator to be associated with study drug resulted in patient withdrawal in 13 (13.3%) of 98 gabapentin-treated patients and 3 (6.7%) of 45 placebo-treated patients. Somnolence and dizziness accounted for many of the premature withdrawals among those taking gabapentin. CONCLUSION: Gabapentin is an effective prophylactic agent for patients with migraine. In addition, gabapentin appears generally well tolerated with mild to moderate somnolence and dizziness.

Acetates↗
PubMed2001

An open-label dose-titration study of the efficacy and tolerability of tizanidine hydrochloride tablets in the prophylaxis of chronic daily headache.

OBJECTIVE: To assess effectiveness and safety of tizanidine hydrochloride tablets for the prophylaxis of chronic daily headache. BACKGROUND: Tizanidine hydrochloride is an alpha2-adrenergic agonist that inhibits the release and effectiveness of norepinephrine at both central sites (eg, the locus ceruleus) and the spinal cord. It acts as a central muscle relaxant and has antinociceptive effects. Preliminary research and retrospective analyses have suggested efficacy in treatment of both chronic tension-type headache and chronic daily headache with migrainous features. DESIGN: Thirty-nine patients with more than 15 headache days per month (33 with migraine, 5 migrainous, 1 chronic tension-type) completed a 4-week baseline, with 31 completing a planned 12 weeks of treatment with tizanidine. Dosing was titrated from 2 mg at bedtime to a median daily dose of 14 mg (mean, 13.5; SD, 4.3; range, 4 to 20, divided over three doses per day) by treatment week 4. RESULTS: The overall headache index through week 12 (headache frequency x average intensity x duration) declined significantly (P<.00000002), with a corresponding increase in mean percentage improvement from 49% for weeks 1 through 4, to 65% for weeks 5 through 8, and 64% for weeks 9 through 12 (P<.0182). During weeks 9 through 12, 67% had improved more than 50% compared to baseline. Overall headache frequency declined from 22.83 to 15.83 days per month (P<.00001), with frequency of severe headaches dropping from 7.52 to 3.58 days per month (P<.000035). Average headache intensity dropped from 1.83 to 1.07 (1-to-5 scale), peak intensity declined from 2.37 to 1.40, and mean duration was reduced from 6.96 to 4.00 hours per headache (P<.00001). Improvement also occurred on visual analog scales of overall headache status, mood, sleep, quality of life (P<.00001), and sexual function (P<.0075); as well as the Beck Depression Inventory-II (P<.00073). Mild-to-moderate adverse events reported by more than 10% of the patients included somnolence, asthenia, and dry mouth. Only 3 patients discontinued treatment due to adverse events: somnolence and dry mouth alone (n = 1), or in combination with either hyperkinesis (n = 1) or constipation (n = 1). One patient had elevated liver enzymes that returned to normal after the drug was discontinued. CONCLUSIONS: The results provide preliminary support for the efficacy, safety, and tolerability of tizanidine in the prophylaxis of chronic daily headache.

Adolescent↗
PubMed2002

Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study.

OBJECTIVE: To assess the efficacy of tizanidine hydrochloride versus placebo as adjunctive prophylactic therapy for chronic daily headache (chronic migraine, migrainous headache, or tension-type headache). BACKGROUND: Tizanidine is an alpha2-adrenergic agonist that inhibits the release of norepinephrine at both the spinal cord and brain, with antinociceptive effects that are independent of the endogenous opioid system. Previous open-label studies have suggested the drug may be effective for treatment of chronic daily headache. METHODS: Two hundred patients completed a 4-week, single-blind, placebo baseline period, with 134 fulfilling selection criteria and then randomized to tizanidine or placebo. Ninety-two patients completed at least 8 weeks of treatment (tizanidine, n = 45; placebo, n = 47), and 85 patients completed 12 weeks of treatment (tizanidine, n = 44; placebo, n = 41). Most patients (77%) met the diagnostic criteria for migraine of the International Headache Society; 23% had either chronic migrainous headache or chronic tension-type headache. Tizanidine was slowly titrated over 4 weeks to 24 mg or the maximum dose tolerated (mean, 18 mg; SD, 6.4; median, 20.0; range, 2 to 24), divided equally over three dose intervals per day. Overall headache index ([headache days x average intensity x duration in hours]/28 days) was the primary end point. RESULTS: Tizanidine was shown to be superior to placebo in reducing the overall headache index (P =.0025), as well as mean headache days per week (P =.0193), severe headache days per week (P =.0211), average headache intensity (P =.0108), peak headache intensity (P =.0020), and mean headache duration (P =.0127). The mean percentage improvement during the last 4 weeks of treatment with tizanidine versus placebo was 54% versus 19% for the headache index (P =.0144), 55% versus 21% for severe headache days (P =.0331), 35% versus 19% for headache duration (P =.0142), 35% versus 20% for peak headache intensity (P =.0106), 33% versus 20% for average headache intensity (P =.0281), and 30% versus 22% for total headache days (P =.0593). Patients receiving tizanidine also scored higher ratings of overall headache improvement on a visual analog scale (P =.0069). There was no statistically significant difference in outcome for patients with chronic migraine versus those with only migrainous or tension-type headache. Adverse effects reported by more than 10% of the patients included somnolence (47%), dizziness (24%), dry mouth (23%), and asthenia (19%). Dropouts due to adverse events did not differ significantly between tizanidine and placebo. CONCLUSIONS: The results support tizanidine as an effective prophylactic adjunct for chronic daily headache, including migraine, migrainous headache, and tension-type headache. These results also suggest the possible importance of an alpha2-adrenergic mechanism underlying the pathophysiology of this spectrum of headache disorders.

Adolescent↗
PubMed2001

Long-term safety of tiagabine.

Tiagabine (TGB) is now registered in >20 countries, and the total number of treated patients approaches 90,000. Short-term safety data were derived mainly from five placebo-controlled, add-on studies in adults with therapy-resistant partial epilepsy, and two conversion to TGB monotherapy studies. Central nervous system (CNS)-related adverse effects, most frequently dizziness, were common with TGB treatment during the titration period; the risk became similar to placebo rates during fixed-dose periods. Other adverse events that were more frequent in TGB- than in placebo-treated patients were asthenia, nervousness, tremor, concentration difficulties, depressive mood, and language problems. TGB doses should be titrated slowly and taken with food to avoid rapid increases in plasma concentrations, thus minimizing the risks of adverse events. Overall, >2,500 patients have been exposed to TGB during clinical trials, with 1,274 patients treated >12 months, the majority of whom received TGB 24-60 mg/day. No idiosyncratic reactions have been linked to the use of TGB, and no abnormalities in hematology or common chemistry values were reported. In all the epilepsy studies combined, 21% of patients discontinued treatment because of adverse events, usually during the first 6 months of treatment. No adverse effects on cognitive abilities were detected when the neuropsychological effects of TGB add-on therapy and monotherapy were evaluated. TGB does not appear to cause an excess risk of psychosis or increase the incidence of status epilepticus or spike/wave discharges. No evidence of a relationship between visual field constriction and TGB treatment was found in a study of 15 patients converted to TGB monotherapy (mean dose, 22 mg/day; mean duration, 2.5 years) who had a full ophthalmologic evaluation. In conclusion, the characteristics of TGB in the management of partial epilepsy are enhanced by its favorable side-effect profile in the cognitive area.

Anticonvulsants↗
PubMed2001

Tiagabine (gabitril) experience in children.

Tiagabine (TGB) is indicated as adjunctive therapy for partial seizures in adults and children aged 12 years and older. Double-blind, placebo-controlled studies of TGB treatment are under way in younger children with various forms of epilepsy. The results of pediatric pharmacokinetic trials indicate patterns similar to those seen in adults. An open-label study was conducted in the United States in 31 children with refractory complex partial seizures, with doses escalated every 2 weeks by 0.25 mg/kg up to a maximal daily dose of 1 mg/kg. Twenty-nine patients were treated with TGB for >1 year; 26 completed the study, of whom 18 were receiving monotherapy at study completion. A European dose-escalation study evaluated TGB (0.25-1.5 mg/kg/day) as add-on therapy in 52 children aged 2-15 years. TGB appeared to be more effective in localization-related epilepsy syndromes, with 17 of 23 patients with localization-related epilepsy having a 33% median reduction of seizure rate compared with baseline in the fourth month of treatment, and six patients having > or =50% seizure rate reduction. In this study, myoclonic seizures and spasms showed a poor response as opposed to encouraging findings reported by other groups with these seizure types. The adverse effect profile of TGB in children with epilepsy is similar to that in adults. In the U.S. study, most common adverse events were related to the central nervous system (CNS) and decreased over time. In the European study, mostly mild to moderate adverse events, including asthenia (19%), nervousness (19%), dizziness (17%), and somnolence (17%), were reported by 83% of TGB-treated children (39% of children reported adverse events during the single-blind placebo period). In summary, preliminary pediatric data with TGB suggest particular efficacy against epilepsy characterized by partial seizures or other syndromes, and further investigation is warranted.

Adolescent↗
PubMed2002

[Raltitrexed and oxaliplatin in colorectal cancer: in vitro and in vivo study of a synergistic cytostatic combination].

AIM: To evaluate the efficacy of combined raltitrexed and oxaliplatin in vitro using 4 colorectal cell-lines and subsequently in vivo in 36 patients with advanced colorectal cancer failing palliative 5-fluorouracil/leucovorin-based chemotherapy. In the preclinical phase of this study, the efficacy of oxaliplatin and of raltitrexed as well as of 5-FU alone and in combination was evaluated in 4 different human colorectalcarcinoma cell-lines with the MTT-test (Microculture Tetrazolium Assay). In the clinical phase 36 patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after withholding palliative chemotherapy with 5-FU/leucovorin +/- irinotecan were enrolled in this study. Treatment consisted of oxaliplatin 130 mg/m2 and raltitrexed 3.0 mg/m2 both given on day 1 every 3 weeks for a total of 8 courses unless prior evidence of progressive disease. A supraadditive effect was found for the experimental combination of oxalipatin and raltitrexed in 3/4 of cell lines. In the clinical phase the overall response rate was 33.3% for all 36 evaluable patients. Seventeen additional patients (47.2%) had stable disease, and only 7 (19.5%) progressed. The median progression-free survival was 6.5 months (range, 1.2 to 14.0). After a median follow-up time of 12 months, 23 patients (63.8%) are still alive. The tolerance of treatment was acceptable with only 8/36 (22%) experiencing grade 3 or 4 neutropenia. Grade 3 nonhematologic adverse reactions included peripheral sensory neuropathy in 3, asthenia in 1, diarrhea in 2, and clinically insignificant increase in serum transaminases in 2 patients, respectively. Our data suggest that the combination of oxaliplatin and raltitrexed has not only in vitro, but also in vivo in patients with progressive fluoropyrimidine/leucovorine +/- irinotecan pretreated colorectal cancer antitumor activity. Because of its favorable toxicity profile and its convenient 3-weekly outpatient administration schedule, further evaluation of this regimen seems warranted.

Antineoplastic Agents↗
PubMed1986

Newborn calf intestinal absorption of immunoglobulins extracted from colostrum.

In the newborn calf, colostrum immunoglobulin absorption was compared with absorption of immunoglobulins extracted from colostrum. Reduced absorption of the latter resulted in plasma immunoglobulin levels unable to protect the animals against infections. Adding complete milk powder to the immunoglobulin solution slightly improved the level of absorption. Postprandial plasma alkaline phosphatases levels exhibited changes differing with the nature of the meals. This reinforces the idea that intestinal function was probably disturbed by immunoglobulin solutions. Moreover, reduced appetite for immunoglobulin solution was evident by the second meal, when most of the animals previously subjected to this diet suffered from a variety of problems (scour, asthenia), possibly caused by harmful effects of immunoglobulin solution on their digestive tract.

Alkaline Phosphatase↗
PubMed2003

Carnitine and hemodialysis.

Carnitine, gamma-trimethyl-beta-hydroxybutyrobetaine, is a small molecule widely present in all cells from prokaryotic to eukaryotic. It is an important element in the beta-oxidation of fatty acids. A lack of carnitine in hemodialysis patients is caused by insufficient carnitine synthesis and particularly by the loss through dialytic membranes, leading in some patients to carnitine depletion with a relative increase of esterified forms. The authors found a decrease in plasma-triglyceride and increase of high-density lipoprotein cholesterol (HDL-Chol) in dialysis patients during carnitine treatment. Many studies have shown that L-carnitine supplementation leads to improvements in several complications seen in uremic patients, including cardiac complications, impaired exercise and functional capacities, muscle symptoms, increased symptomatic intradialytic hypotension, and erythropoietin-resistant anemia, normalizing the reduced carnitine palmitoyl transferase activity in red cells. In addition, carnitine supplementation may improve protein metabolism and insulin resistance. Recently, carnitine supplementation has been approved by the US Food and Drug Administration not only for the treatment, but also for the prevention of carnitine depletion in dialysis patients. Regular carnitine supplementation in hemodialysis patients can improve their lipid metabolism, protein nutrition, antioxidant status, and anemia requiring large doses of erythropoietin, It also may reduce the incidence of intradialytic muscle cramps, hypotension, asthenia, muscle weakness, and cardiomyopathy.

Carnitine↗
PubMed2001

Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: We evaluated etanercept, a human soluble tumor necrosis factor receptor: Fc fusion protein, for the treatment of active Crohn's disease. METHODS: Forty-three patients with moderate to severe Crohn's disease were enrolled in an 8-week placebo-controlled trial. Patients were randomized to subcutaneous etanercept 25 mg or placebo twice weekly. The primary outcome measure was clinical response at week 4, defined as a decrease in the baseline Crohn's Disease Activity Index score > or =70 points or a Crohn's Disease Activity Index score <150 points. RESULTS: At week 4, 39% of etanercept-treated patients had clinical response as compared with 45% of placebo-treated patients (P = 0.763). The frequency of common adverse events including headache, new injection site reaction, asthenia, abdominal pain, Crohn's disease-related anemia, and skin disorders was similar in both groups. Likewise, the frequency of severe or serious adverse events was similar in both groups. CONCLUSIONS: Subcutaneous etanercept at a dose of 25 mg twice weekly is safe, but not effective, for the treatment of patients with moderate to severe Crohn's disease. The dose of etanercept administered in this study is that approved for rheumatoid arthritis. Higher doses or more frequent dosing may be required to attain a response in patients with active Crohn's disease.

Adult↗
PubMed2003

Feasibility of amifostine administration in conjunction with high-dose rate brachytherapy.

This ongoing study was initiated to determine the feasibility of administering amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD) with monomodal high-dose rate (mHDR) brachytherapy and to assess the tolerability and side effects of this combination. To date, 18 patients suitable for prostate implant brachytherapy (<or=T2aN0; prostate-specific antigen <or= 10 ng/mL; Gleason score <or= 6) have been treated with mHDR brachytherapy, receiving four 9-Gy fractions administered twice daily for 2 days. Amifostine (500 mg) is administered subcutaneously on the day before implant and 30 to 60 minutes before the first and third mHDR treatments. All 18 patients have received amifostine and brachytherapy as planned. Nausea was manageable with oral prochlorperazine in the pretreatment phase and our standard antiemesis protocol (intravenous promethazine, with granisetron if needed) during the implant; hypotension and asthenia were not problematic. During the 2-week post-treatment phase, grade 1 cystitis occurred in eight of 18 patients; grades 1 and 2 proctitis occurred in six of 18 and five of 18 patients, respectively. Six patients developed urinary obstruction symptoms. Preliminary results support the feasibility and tolerability of subcutaneous amifostine in conjunction with mHDR brachytherapy. Total accrual goal is 50 patients to assess long-term efficacy. Additional studies of HDR with amifostine are planned for patients with recurrent prostate and gynecologic cancer.

Amifostine↗
PubMed2004

Gemcitabine plus docetaxel administered every other week as first-line treatment of metastatic breast cancer: preliminary results from a phase II trial.

The purpose of this study was to assess the toxicity and efficacy of gemcitabine and docetaxel administered every other week as first-line therapy in metastatic breast cancer. Fifty-one patients with histologically confirmed metastatic breast cancer were enrolled. Patients received docetaxel 65 mg/m(2) followed by gemcitabine 2,500 mg/m(2), both on day 1 of a 14-day cycle, for 10 cycles without granulocyte-colony stimulating factor support. Thirty-five patients were evaluable for toxicity and 32 for efficacy. Median age was 65 years (range, 37 to 72 years), and median performance status was 90 (range, 60 to 100). The number of disease sites was 2 or > or =3 in 39% and 44% of patients, respectively, with visceral involvement in the liver and/or lung in 44% of patients. A total of 45% had received prior adjuvant chemotherapy. So far, 267 cycles have been administered. Twenty-five percent of the docetaxel and gemcitabine doses were reduced or delayed due primarily to neutropenia, giving a median dose intensity of 90% of the planned dose for both drugs. Grade 3/4 toxicities were mainly hematologic, with neutropenia in 46% of patients (two patients experienced neutropenic fever). Other toxicities were asthenia, diarrhea, transaminase elevation, and nausea. Overall response rate was 66% (four complete responses, 17 partial responses), with 22% of patients achieving stable disease. Responses were observed in all disease sites, including lung (60%) as well as liver (37.5%). In conclusion, preliminary evaluation from our phase II study shows that the combination of docetaxel and gemcitabine given every 2 weeks is a tolerable and highly active combination in patients with metastatic breast cancer. These data compare favorably with those obtained with other docetaxel schedules.

Adult↗
PubMed2000

A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. The Hepatitis C Intervention Therapy Group.

The objectives of this study were to assess the safety, pharmacokinetics, and efficacy of pegylated interferon alfa-2b (PEG-Intron) plus ribavirin in patients with chronic hepatitis C. A total of 72 patients (35 men/37 women, age range 20-68 years) with clinically compensated chronic hepatitis C virus (HCV) were enrolled into this open-label, randomized, active controlled study. Patients received either PEG-Intron 0.35, 0.7, or 1.4 microg/kg subcutaneously weekly for 24 weeks alone, or in combination with ribavirin 600, 800, or 1,000 to 1,200 mg orally daily. Patients were evaluated during treatment and after a 24-week follow-up period for safety and efficacy. Detailed pharmacokinetic assessments were performed at weeks 1 and 4. PEG-Intron alone produced expected dose-related reductions in white cells, neutrophils and platelets. Addition of ribavirin reduced hemoglobin levels in a dose-related manner, did not further reduce PEG-Intron-induced decreases in neutrophil or white cell count, and increased platelet counts. Neutrophil function tests (C5a and FMLP migration, killing curves) were unaltered. Reported adverse events (flu-like symptoms, asthenia) were qualitatively similar in all dose groups. Anti-HCV activity, as measured by loss of detectable serum HCV RNA (i.e. <100 copies/mL) at the end of treatment (week 24) and after 24 weeks of follow-up (week 48) showed dose-response trends for PEG-Intron. At each PEG-Intron dose level, anti-HCV activity was higher in patients coadministered ribavirin than in patients treated with PEG-Intron monotherapy. There was no evidence of pharmacokinetic interactions with either drug. We conclude that the safety and tolerability of combined PEG-Intron/ribavirin and PEG-Intron alone were comparable. Combined PEG-Intron/ribavirin showed dose-related synergistic anti-HCV effects, which were numerically superior to those obtained with PEG-Intron monotherapy.

Adult↗
PubMed2001

Biopsy-negative giant cell arteritis: clinical spectrum and predictive factors for positive temporal artery biopsy.

OBJECTIVES: To examine the frequency and features of patients with biopsy-negative giant cell arteritis (GCA), establish differences with biopsy-proven GCA, and identify the optimal set of predictors for a positive temporal artery biopsy (TAB) in patients with GCA. METHODS: Retrospective study of an unselected population of patients with GCA diagnosed at the reference hospital for a defined population between 1981 and 1998. Patients were classified into biopsy-proven GCA if a TAB was positive for GCA, or biopsy-negative GCA if they fulfilled the American College of Rheumatology 1990 criteria for the classification of GCA (Hunder GG, et al Arthritis Rheum 1990; 33:1122-8) despite having a negative TAB. RESULTS: One hundred ninety Caucasian patients were diagnosed with GCA. Twenty-nine of them (15.3%) had a negative TAB. In these biopsy-negative patients, headache and polymyalgia rheumatica were frequent presenting symptoms. In contrast, jaw claudication, abnormal temporal artery on physical examination, and constitutional syndrome (asthenia, anorexia, and weight loss of 4 kg or more) were less common. They also had lower biologic markers of inflammation. The best predictive model of biopsy-proven GCA included a history of constitutional syndrome (OR = 6.1), an abnormal temporal artery on physical examination (OR = 3.2), and the presence of visual complications (OR = 4.9). CONCLUSIONS: In GCA, a subset of patients have a high likelihood of having a negative TAB. This subset seems to have less severe ischemic complications than that of biopsy-proven GCA. In patients without visual manifestations, abnormal temporal artery on examination or constitutional syndrome the risk of having an abnormal TAB is low.

Aged↗
PubMed2000

A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy.

The aim of this study was to determine the tolerability and efficacy of two oral regimens of levetiracetam, 1000 mg and 2000 mg twice daily, as add-on treatment without titration in patients with refractory epilepsy. After a 1- to 4-week baseline, 119 patients were randomized to receive levetiracetam 2000 mg daily, 4000 mg daily, or placebo for a 24-week double-blind period, then levetiracetam 4000 mg daily in a 24-week open-label phase. Somnolence was the most common reason for discontinuation, and along with asthenia, occurred more frequently with levetiracetam than placebo. Responder rates were higher with levetiracetam 2000 mg and 4000 mg daily (48.1% [P < 0.05] and 28.6% [NS], respectively) than placebo (16.1%). In the open-label phase, the overall responder rate was 43.0%. Switching from placebo to levetiracetam increased the overall responder rate from 16.7% to 44.0%. No such increase was observed with patients initiated on levetiracetam 2000 mg daily. Levetiracetam initiated at doses of 2000 mg or 4000 mg daily without titration is well-tolerated and effective as add-on therapy in patients with partial and/or generalized seizures. The higher dose may be related to an increased incidence of somnolence and is not necessarily more effective than the lower dose.

Adolescent↗
PubMed2002

Other secondary sequelae of treatments for myeloproliferative disorders.

Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic disorders for which there are no medical cures. Clinical sequelae of PV and ET fall into three categories: primary, such as thrombosis and hemorrhage; secondary, resulting from disease progression or treatment. The decision whether to treat the patient is based on the sequelae of no treatment versus short- and long-term toxicities of the three classes of drugs available for treatment: hydroxyurea, interferon-alpha, and anagrelide. Thrombosis is the most common short-term sequelae of untreated disease; the risk increases with age and after the first thrombotic complication. Hydroxyurea, a nonalkylating myelosuppressive agent, is mutagenic and probably leukemogenic over 5 to 15 years, which makes it unsuitable for treating most younger patients. Interferon-alpha, a cytokine that is myelosuppressive and immunomodulatory, has been shown to have a therapeutic effect in both PV and ET. Tolerance to the initial flu-like symptoms of interferon-alpha is usually developed, but dose-limiting symptoms of anorexia, asthenia, and neuropsychiatric disease can occur, along with exacerbation or development of autoimmune diseases. Anagrelide, a quinazoline that inhibits cyclic nucleotide phosphodiesterase, inhibits platelet aggregation and has an idiosyncratic effect of inhibiting megakaryocyte maturation and platelet budding at doses below those that affect platelet function. This agent is a vasodilator with positive inotropic activity and a side-effect profile that may include palpitations, forceful heartbeat, tachycardia, and headache. One in four patients develop fluid retention and/or edema that are controllable with diuretic therapy. Dizziness is frequent, but mild. Because these side effects usually abate in 2 to 4 weeks, successful management of patients taking anagrelide depends on encouraging them to maintain therapy. The availability of these three classes of drugs with differing modes of action suggests that combination therapy may offer the opportunity to achieve better control of proliferation while reducing short-term side effects as well as the risks of dose-related cumulative sequelae.

Antineoplastic Agents↗
PubMed2002

Preliminary data of the GORTEC 2000-02 phase III trial comparing intravenous and subcutaneous administration of amifostine for head and neck tumors treated by external radiotherapy.

A prospective randomized study is comparing intravenous (IV; arm A) versus subcutaneous (SC; arm B) administration of amifostine in patients receiving radiotherapy for head and neck cancer. Main eligibility criteria were newly diagnosed squamous cell head and neck cancer, inclusion of at least 75% of both parotid glands within radiation fields that would receive at least 40 Gy, and no evidence of distant metastasis. Prophylactic use of pilocarpine and concomitant chemotherapy were prohibited. Intravenous administration of amifostine is 200 mg/m2/d in a short 3-minute infusion 15 to 30 minutes before each fraction of radiotherapy. Subcutaneous administration is 500 mg/d in two, slow 1.25-mL injections at two different sites 20 to 60 minutes before each radiotherapy fraction. Antiemetic treatment and blood pressure monitoring are required in both arms. As of April 25, 2002, 111 of the 292 required patients were included. Data are available for the first 54 patients. Acute toxicity included nausea/vomiting (12% for arm A; 13% for arm B), hypotension (6% in arm A; 0% in arm B), skin rash (15% in arm A; 16% in arm B), and asthenia (4% in arm A; 0% in arm B). Compliance with amifostine administration was 70% in arm A (IV) and 80% in arm B (SC). The rate of acute xerostomia (> or = grade 2) was 23% in arm A and 19% in arm B. These preliminary results indicate that tolerance is better with SC than IV administration, particularly because of the absence of hypotension. The absence of hypotension with SC administration facilitates patient monitoring and management in radiotherapy departments. More patients and data are required to assess the long-term efficacy of SC administration on acute and late xerostomia.

Amifostine↗