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Altocor (Extended-Release Lovastatin) Safe and Effective for Alzheimer's Patients

By Rx Sentinel Staff

SAN FRANCISCO, CA -- September 26, 2002 -- Extended-release lovastatin effectively and safely lowers LDL cholesterol in patients with Alzheimer's disease, researchers reported at the American College of Clinical Pharmacology (ACCP).

"The take home message here is that this statin in its extended-release formulation is safe and effective for treatment of patients with Alzheimer's Disease," said researcher Arnold Sterman, Ph.D, executive director of medical affairs and safety at Andrx Labs in Hackensack, New Jersey, who presented the findings here Sept. 22nd.

Altocor has been approved by the FDA as a once-daily adjunct to diet for the reduction of elevated levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglycerides, and to increase levels of high-density lipoprotein cholesterol (HDL-C) in those with primary hypercholesterolemia. Altocor is also indicated to slow the progression of coronary atherosclerosis in patients with coronary artery disease, as part of a cholesterol-lowering treatment strategy.

This was a multicenter, randomized, double blind, placebo controlled, multiple dose, parallel group study of the safety, pharmacokinetics and pharmacodynamics of extended-release lovastatin at daily doses of 20 mg, 40 mg and 80 mg for 28 days in with Alzheimer's disease. The researchers enrolled 35 subjects with a mean Mini-Mental State Exam Score of 20.4 and a mean Clinical Dementia Rating-Memory of 1.29.

Mean change in LDL-C for each dosing was +6.25 percent for placebo, -29 percent for 20 mg, -30 percent for 40 mg and -46 percent for 80 mg. Mean change in triglycerides was +1.7 percent, -18 percent, -24 percent and -31 percent, respectively. Changes in HDL cholesterol for all dosages were minimal.

Mean plasma levels for extended-release lovastatin at Day 28 were 1.4 ng/mL, 7.1 ng/mL and 7.6 ng/mL, respectively. Mean plasma levels for lovastatin acid at Day 28 were 1.8 ng/mL, 8.1 ng/mL and 10.2 ng/mL, respectively.

There were no clinically significant changes in laboratory parameters and no clinically relevant adverse episodes.

"Part of the reason this study is important is because there is more and more epidemiologic data appearing in major journals showing that statins might well have a protective effect in terms of the progression of Alzheimer's disease and that they might substantially reduce the risk of the development of Alzheimer's," said Dr. Sterman. "However, those studies are retrospective studies. This study is a prospective study, and it is one of the few that has been designed as such."

"We tested our hypothesis about extended-release lovastatin, and we made these important findings. This points us in another new direction for the therapeutic possibilities of using this statin with a special population of patients. More studies of extended-release lovastatin with this population are now indicated."

On Sept. 11, 2002, the U.S. Food and Drug Administration approved Altocor for a third indication: the primary prevention of coronary heart disease. In individuals without symptomatic cardiovascular disease, average to moderately elevated triglycerides and LDL cholesterol, and below average HDL cholesterol, Altocor is now indicated to reduce the risk of myocardial infarction, unstable angina, and coronary revascularization procedures.

Andrx Labs supported this research.  


Horrmone Replacement Therapy May Improve Breast Cancer Detection And Survival Rate

Rx Sentinel Staff

Sept. 14, 2002 -- A study at Oregon Health & Science University found that women who use hormone replacement therapy (HRT) have less aggressive tumors and are more likely to be diagnosed through mammograms than other methods. Also, HRT users with breast cancer had significantly better survival rates than non-HRT users. The study is published in the September issue of the journal The Archives of Surgery. About 300 subjects were involved in the research.

Researchers have suspected that HRT use would make it more difficult to detect tumors on mammograms because hormones increase the density of breast tissue, and that tumors in patients who have received HRT might not be detected until they were larger and more advanced. Of 144 study patients using HRT, 84 had their tumors detected by mammogram, while 60 were detected by other methods. Comparatively, of 148 non-HRT users, 63 had their tumors detected by mammogram, while 85 were detected by palpation (feeling for lumps).

Among the subjects whose tumors were detected by mammogram, HRT users had a 100 percent survival rate, while nonusers had only an 87 percent survival rate after six years. The study found significantly fewer cases of invasive tumors among HRT users, and higher incidences of T1 lesions, stage 1 tumors and node-negative tumors--all signs of a less aggressive disease.

"From this data it appears that HRT use had only beneficial effects on breast cancer detection and outcomes, with no visible negative effects," said Rodney F. Pommier, M.D., associate professor of surgery in the OHSU School of Medicine and principal investigator of the study.

Hormone replacement therapy has been widely criticized in recent months after several studies indicated that long-term use of combination hormone therapies can lead to slight increases in heart disease, stroke and breast cancer among patients.

"Every woman should talk to her physician about her own risks and benefits of taking hormones," said Pommier. "But this data needs to be taken into consideration as well. If we know that HRT can improve survival rates by producing a less aggressive breast cancer, then it's possible that by withholding HRT for the purpose of possibly preventing a few cases of breast cancer, you're going to have a higher death rate among women who were going to get the disease anyway."

The Women's Health Initiative last July canceled its clinical trial on the use of combination estrogen-progestin HRT due to higher reports of associated illnesses. However, there has not been the same association with estrogen-only HRT. The OHSU study, which was a retrospective analysis of patients already diagnosed with breast cancer, included patients who took any form of HRT.

"This study opens an entirely new direction for future research of breast cancers. When we learn how HRT favorably affects the biology of tumors we can then use that information in a therapeutic fashion to improve the outcome of women with breast cancer," said study co-investigator SuEllen Toth-Fejel, Ph.D., research assistant professor of surgery in the OHSU School of Medicine, who led the laboratory work on the project.


Escitalopram Effective as First-Line Treatment of Severe Depression

By RxSentinel Staff

YOKOHAMA, JAPAN --  September 2, 2002 -- The selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro), produced significantly more improved scores on the Montgomery-Asberg Depression Rating Scale (MADRS) than either placebo or citalopram, after one week of use by subjects with severe major depression, researchers report.

Columbia University Medical School researchers presented their findings at the World Congress of Psychiatry in Yokohama.

"Escitalopram is the single isomer responsible for the serotonin reuptake inhibition produced by the racemic antidepressant citalopram. SSRI antidepressants are not usually considered as first-line treatments for the most severely depressed patients. However, escitalopram is the most selective SSRI to date and represents an advance on the SSRI class," the authors wrote.

Escitalopram was approved by the FDA on August 15, 2002, for the treatment of major depressive disorder.

The investigators used three double-blind, placebo controlled trials of similar design to study the efficacy of escitalopram (10-20mg/day) and citalopram (20-40 mg/day) for depressed subjects, including a subset of severely depressed patients.

Following one week of single-blind placebo treatment, the researchers randomly assigned eligible subjects to eight weeks of double-blind treatment. Entry criteria included a baseline MADRAS score = 22. The investigators defined as "severely depressed" those subjects with a baseline MADRS score = 30.

In all three trials, the researchers measured primary efficacy as the mean change in MADRS total score from baseline to endpoint.

There were 520 escitalopram subjects, with 211 in the severely depressed subset, 403 citalopram subjects with 171 in the severely depressed subset and 398 placebo subjects with 166 in the severely depressed subset.

Mean change from baseline MADRS scores for the severely depressed subset was -12.2 for placebo, -14.3 for citalopram and -16.2 for escitalopram (p<0.05 escitalopram vs placebo and p<0.05 escitalopram versus citalopram)

"In the pooled data set, both active treatments significantly improved depressive symptoms relative to placebo. Escitalopram significantly separated from placebo at earlier time points than did citalopram, and escitalopram was statistically significantly superior to citalopram at endpoint. Both active treatments were well tolerated." the authors said

"The data suggest that escitalopram should be considered as a first-line SSRI antidepressant, even in severely depressed patients," they concluded.

The study was supported by Forest Laboratories.

Olanzapine-Fluoxetine for Treatment-Resistant Depression

By RxSentinel Staff

YOKOHAMA, JAPAN, September 2, 2002 -- Olanzapine-fluoxetine combination (OFC) therapy leads to improvement in depressive symptoms with sustained efficacy over eight weeks, and demonstrates greater reduction in depressive symptoms than either drug as monotherapy.

These findings were reported at the World Congress of Psychiatry in Yokohama.

"Current antidepressant treatments do not help every patient with depression," the authors wrote. "Up to 30 percent of patients with major depressive disorder (MDD) are resistant to conventional antidepressant treatment. Subsequent medical therapy may include combinations of antidepressants or various augmentation strategies, such as a combined antidepressant-antipsychotic approach. Atypical antipsychotic agents, such as olanzapine, cause fewer extrapyramidal adverse effects than conventional antipsychotics, and may be an advantageous augmentation strategy for treatment-resistant depression (TRD)."

"The purpose of this meta-analysis was to compare the efficacy of olanzapine/fluoxetine combination (OFC) with component (olanzapine and fluoxetine) monotherapies in TRD (defined as failure to respond to adequate trials of two classes of antidepressants) using data pooled from two studies," the authors added.

The investigators performed a meta-analysis of two (eight-week and 12-week) double-blind studies involving 797 subjects diagnosed with nonpsychotic, unipolar, treatment-resistant major depression. Montgomery-Asberg Depression Rating Scale (MADRS) was used at baseline and endpoint to measure efficacy.

OFC patients achieved significantly greater total score improvement (-7.31) at Week 1 than olanzapine subjects (-5.18, p=0.013) or fluoxetine subjects (-5.26, p=0.004). This significant effect abided during the eight weeks of treatment. (Endpoint: OFC -11.60, olanzapine -7.55, p<0.001; fluoxetine, -8.73, p<0.001).

OFC patients had a significantly higher rate of response as a group at endpoint (eight weeks) than olanzapine (37.3 percent vs. 21.1 percent) OFC subjects showed a significantly greater endpoint remission rate than olanzapine or fluoxetine (OFC 24.9 percent, olanzapine 13.1 percent, fluoxetine 15.2 percent).

The authors concluded that, "OFC had robust onset of action within seven days of treatment and maintained treatment effect throughout eight weeks. OFC showed significantly greater improvement in depressive symptoms than olanzapine or fluoxetine monotherapies from weeks one through eight. OFC had a significantly greater response rate that olanzapine, and a significantly greater remission rate than olanzapine or fluoxetine."

The study was supported by Lilly Research Laboratories.


Gabitril (Tiagabine) Demonstrates Efficacy as Augmenting Agent for Treatment of Chronic Pain with Comorbid Anxiety Disorders

By RxSentinel Staff

SAN DIEGO, CA -- August 21, 2002 -- Results of a small open-label study demonstrate that tiagabine (Gabitril®) has efficacy as an augmenting agent for treatment of patients with neuropathic pain alone or with comorbid anxiety disorders.

Daniel M. Gruener, MD, of Jefferson Medical College, in Philadelphia, Pennsylvania, United States, said the results of his small study suggest the need for placebo-controlled clinical trials to investigate the efficacy of tiagabine, a selective GABA reuptake inhibitor, for treatment of neuropathic pain. He presented these results here August 19th at the 10th World Congress on Pain.

His team recruited one patient with neuropathic pain alone and five with comorbid anxiety disorders for the study. They initiated tiagabine at a dose of 2 mg at bedtime for the first three to four days in addition to pain medication and/or anxiolytic/antidepressant therapy. The tiagabine was then increased by 2 mg initially then 4 mg every three to four days, until the optimum response was achieved. The daily range of final tiagabine dose was 4 mg BID to 8 mg BID (mean final dose 12 mg/day).

Efficacy was assessed at baseline and after two and four weeks of treatment using the 11-point Visual Analogue Scale (VAS) for pain and Hamilton Scale for Anxiety (HAM-A).

Dr. Greuner said that treatment with tiagabine resulted in significant improvement in subjective ratings of pain within two weeks of treatment initiation as well as significant improvements in patients' levels of anxiety.

Mean VAS score for all patients decreased from 9.1 (standard deviation [SD] 0.80) at baseline to 6.8 (SD 0.98) after four weeks of treatment. The mean Hamilton-Anxiety score improved from 44.0 (SD 7.07) at baseline to 31.7 (SD 5.79) after four weeks of treatment.

The study was partially funded by Cephalon, Inc., West Chester, Pennsylvania.

Lamotrigine Effective in Refractory Neuropathic Pain

By RxSentinel Staff

SAN DIEGO, CA -- August 21, 2002 -- Lamotrigine appears to be an effective third line treatment for refractory trigeminal neuralgia and peripheral neuropathy, but is not effective for treatment of radiculopathy.

These results, from a chart review of patients who received lamotrigine as third line therapy for refractory neuropathic pain, were presented August 20th at the 10th World Congress on Pain.

M. Gabriela Gregory, MD of Nevada Neurological Consultants, Las Vegas, Nevada, and Marilyn R. Semenchuck, PharmD of GlaxoSmithKline, Tuscon, Arizona, United States, reviewed charts from 33 men and 47 women mean age 60. Twenty-eight had peripheral neuropathy, 18 trigeminal neuralgia, 11 radiculopathy, five had diabetic neuropathy, four had postherpetic neuralgia, four central pain, three atypical head pain, two failed back pain syndrome, and five had other diagnoses.

All patients had failed at least two or more attempts at treatments with other medications including gabapentine, tricyclic antidepressants, narcotics, carbamazepine, oxcarbazepine, tiagabine, topiramate and baclofen.

Patients were started on lamotrigine at a dose of 50 mg/day for two weeks, increased to 100 mg/day for two weeks and titrated upward by 50 mg/day at weekly intervals. The target dose was 200 mg/day. Maximum dose prescribed was 600 mg/day.

Of 68 evaluable patients 38 percent responded to lamotrigine. Lamotrigine was most effective in patients with diabetic neuropathy, followed by postherpetic neuralgia, trigeminal neuralgia, peripheral neuropathy and central pain. Most patients with radiculopathy were non-responders as were patients with atypical head pain and failed back syndrome.

The average dose of lamotrigine in responders was 300 mg/day while the average dose in non-responders was 160 mg/day. Four patients discontinued due to side effects.

The study was funded by GlaxoSmithKline.


Gabapentine Effective for Severe Back Pain and Restless Leg Syndrome Associated with Rapid Opioid Detoxification

By RxSentinel Staff

SAN DIEGO, CA -- August 21, 2002 -- Rapid opioid detoxification is associated with a number of neurological symptoms including intense back pain and restless leg syndrome (RLS), but new research suggests that administering gabapentine following rapid opioid detoxification (ROD) can eliminate these symptoms.

Enno Freye, MD, of the University of Düsseldorf, Düsseldorf, Germany and colleagues from the Department of Anesthesia, Jewish Hospital Berlin, Berlin, Germany, and the Department of Anesthesia and Pain Therapy, Nordwest Hospital, Frankfurt/Main, Germany, presented findings from a study of 21 patients who received gabapentine following ROD. The results were presented August 20th at the 10th World Congress on Pain.

In an interview, Dr. Freye said that ROD patients are "often very difficult to handle. They are coming out of the fog and all types of stimuli are hitting them at once. These are not easy patients to handle, and when they experience back pain or RLS, they are usually thrashing about and very, very difficult." These symptoms do not respond to standard treatment.

He also said that in addition to using gabapentine for symptom control, "these patients need to be closely watched for at least 24 hours. Some centers do ROD and then just send the patients home. That is a mistake."

The 21 patients underwent ROD using naltrexone and simultaneous administration of clonidine and somatostatin. Aside from amplitude height of late SSEPs (somatosensory-evoked potentials) (SSEPs >100ms), individual tolerance to an increase in electrical stimuli (mA) to the forearm was measured when the patients were awake, during anesthesia, and before and after receiving 1200 mg of gabapentine.

Data was analyzed using Friedman's test for repeated measures of variance on ranks, and the Student-Newman-Keuls test for multiple comparison.

Following ROD, amplitude in the SSEP increased (8.4±2.5 to 12.3±3.3 µV; p< 0.01) which dropped below control (3.5±1.5 µV; p <0.01) after gabapentine. Simultaneously, tolerance to electrical stimuli decreased from 10.2±1.2 mA to 4.4±1.2 mA. After gabapentine, tolerance increased to 19.5±4.8 mA.

There was an inverse linear correlation of amplitude height of SSEP and tolerance to electrical stimuli (r2=0.88), but inverse linear correlation of tolerance to electrical stimuli and latency of SSEP was less. (r2= 0.61).

Zonegran (Zonisamide) May Be Effective Second-line Treatment for Neuropathic Pain

By RxSentinel Staff

SAN DIEGO, CA -- August 21, 2002 -- Results of a small study of patients with neuropathic pain suggest that zonisamide (Zonegran®), a novel antiepileptic drug, may be effective when satisfactory pain control is not achieved with first line medications.

Janet Kunz, RN, MS, and Misha-Miroslav Backonja, MD, from the department of neurology, University of Wisconsin Hospital and Clinics, in Madison, Wisconsin, United States, presented the results August 20th at the 10th World Congress on Pain.

The researchers enrolled 14 women and four men with neuropathic pain. Nine patients had complex regional pain syndrome, four had peripheral neuropathy, and five had various other types. Mean age was 46.9 years. Sixteen patients were taking at least one other medication for neuropathic pain. The mean pre-zonisamide pain rating was 6 (range 3.5 to 10).

Patients were treated with zonisamide 100 to 500 mg per day and rated their pain on a 0-10 scale (0=no pain, 10=worst pain imaginable) at baseline and after reaching maintenance dosage, Dr. Backonja said.

Eight patients (44.4 percent) experienced a mean 3.2-point decrease in pain symptoms on zonisamide and six patients experienced a 1 to 2 point decrease in pain symptoms. Two patients had no improvement in pain symptoms and two patients had an increase in pain symptoms while taking zonisamide.

Eleven patients experienced adverse events, including dizziness, nausea/vomiting, mental cloudiness, tiredness, constipation, heat intolerance/sweating, decreased sense of taste and sedation.

Based on these results, double-blind, placebo-controlled studies of zonisamide for neuropathic pain are warranted, Dr. Backonja concluded.

Elan Pharmaceuticals, Inc. funded the study.

Switch from Nelfinavir to Atazanavir Lowers Cholesterol Levels in HIV Patients

By RxSentinel Staff

BARCELONA, SPAIN -- July 12, 2002 -- Switching patients from the protease inhibitor (PI) nelfinavir to a new investigational drug called atazanavir appears to result in improved blood lipid profiles, researchers said at the 14th International AIDS Conference taking place here this week.

"Data from this study demonstrate a significant reduction in cardiovascular risk factors when switching from nelfinavir to atazanavir," said Robert Murphy, MD, professor of medicine and director of HIV clinical research at Northwestern University School of Medicine, Chicago, Illinois, United States.

Dr. Murphy and colleagues enrolled 346 subjects (217 men and 129 women) into a 76-week study of atazanavir, the first PI being developed for once-a-day dosing. Of those subjects, 63 people were switched from a daily treatment of nelfinavir, stavudine, and lamivudine to a regimen that exchanged atazanavir for nelfinavir.

When the researchers looked at the lipid profiles of this cohort after 12 weeks of treatment with atazanavir, they found a 16 percent decline in totoal cholesterol, 21 percent decline in LDL cholesterol, and a 28 percent decline in triglycerides. All the differences seen were statistically significant to the p<0.0001 level.

The switch also decreased the number of patients with undesirable cholesterol levels -- those with 240 mg/dl cholesterol or higher -- from 32 percent of the sample to 10 percent of the group. The percentage of patients with elevated LDL levels -- equal to or greater than 130 mg/dl -- decreased from 55 percent to 22 percent.

Dr. Murphy said that the lack of increases in lipid profiles that have been seen in earlier studies with atazanavir -- now in Phase III clinical development -- make its use attractive in patients who develop the elevated cholesterol levels often seen in PI-based regimens. He noted that high blood levels of lipids such as cholesterol and triglycerides are risk factors for cardiovascular diseases as well as other disorders.

The study was supported by Bristol-Myers Squibb Company, Princeton, New Jersey, United States.


Lidocaine Patch Treats HIV-associated Peripheral Neuropathy

By Rx Sentinel Staff

BARCELONA, SPAIN -- July 12, 2002 -- A lidocaine patch appears to effectively treat HIV-associated peripheral neuropathy, according to a pilot study reported here this week at the 14th International AIDS Conference.

"Since the beginning of the HIV epidemic, peripheral sensory neuropathy has been recognized as a complication of HIV infection," said Stephen Berman, MD, from the Veterans Affairs (VA) Long Beach Healthcare System in California, United States. "Peripheral neuropathy is one of several HIV-associated conditions which is seen as frequently, if not more frequently, since the advent of highly active antiretroviral therapy."

Doctors led by Dr. Berman enrolled 10 patients in a study to determine if lidocaine patches could bring some measure of relief to HIV patients suffering from painful peripheral neuropathy. During the four-week, open-label study, the patients were allowed to use analgesics already prescribed in addition to the patches, but they were not allowed to change those medications. The patches were worn for 12 out of every 24 hours. The study employed Lidoderm® (lidocaine patch 5 percent, Endo Laboratories) patches, and the trial was supported by internal funding sources.

The patients filled out validated instruments that assessed pain and quality of life issues. One patient dropped out of the study due to perceived increase of pain from the patch, although there were no physical signs that the patch had caused irritation, Dr. Berman said.

With the lidocaine patches, the patients reported significant improvements in the intensity and sharpness of the pain as well as in how "hot" the pain felt, how sensitive their skin was to touch, how unpleasant the pain was, how deep the pain felt, and how intense the surface pain felt.

The use of the patch also decreased the extent that peripheral neuropathy interfered with the patients' self-reported ability to work and walk. The patients also said that by using the patch they were able to sleep better.

Two of the nine patients said their condition was "very much improved"; five of the patients said their condition was "much improved"; one patient reported minimal improvement; and one other patient reported no change from use of the patch.

Dr. Berman acknowledged that the small numbers of patients in the study limits its generalization. Nevertheless, he said, "the analysis clearly indicates that the patch produced symptomatic relief for the majority of the patients enrolled."



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