Christian A. Hartman, BSPharm, RPh

Alzheimer's disease is a progressive type of dementia, characterized by a loss of cognitive, intellectual, and functional abilities over time. There are currently more than 4 million Americans living with Alzheimer's disease in the United States, costing the nation approximately $100 billion dollars annually.

 To date, there is no cure for this condition, and underlying causes are not entirely understood. 

There is, however, increasing evidence to suggest that excess activation of the central nervous system 

-methyl- D-aspartate (NMDA) receptors may play an important role in contributing to the symptoms of Alzheimer's disease. Marketed by Forest Laboratories, Namenda (memantine) is the first agent in the class of NMDA receptor antagonists, approved by the FDA for the treatment of Alzheimer's disease. Prior to the approval of Namenda, the only agents indicated for the treatment of this condition were the cholinesterase inhibitors. Unlike Namenda, which was approved for moderate-to-severe Alzheimer's disease, the cholinesterase inhibitors are recommended for mild-to-moderate forms of the disease. 

Overstimulation of NMDA receptors by the excitatory neurotransmitter glutamate has been thought to be a cause of neuronal damage and the subsequent decline in functions of memory and cognition seen in Alzheimer's disease. Namenda exerts its effects by binding to NMDA receptors, resulting in the regulation of glutamate. Namenda is excreted predominantly in the urine, unchanged, and it is not significantly affected by the CYP450 enzyme system. The elimination halflife of Namenda is 60 to 80 hours.

Two randomized, double-blind, placebo-controlled clinical studies of Namenda evaluated the cognitive and day-to-day function of patients with moderate-to-severe Alzheimer's disease. In both studies, cognitive function was measured using the Severe Impairment Battery (SIB), and day-to-day function was assessed using the modified Alzheimer's Disease Cooperative Study?Activities of Daily Living inventory (ADCS-ADL). Both studies showed that patients who were taking Namenda experienced less decline of function in both measures, compared with those taking a placebo.

In the first study, 252 patients with moderate-to-severe Alzheimer's disease were randomized to receive Namenda or a placebo. 

In the second study, 404 patients with moderate-to-severe Alzheimer's disease who had been treated with donepezil for the past 3 months were randomized to receive Namenda or a placebo while still receiving donepezil. At 24 weeks, the mean difference in change in the ADCS-ADL score between the groups, was 1.6 units, and the mean difference in change in the SIB score was 3.3 units.

In clinical trials, the most common adverse events noted were constipation, headache, dizziness, and confusion. Namenda is not recommended for patients with severe renal dysfunction and should be used with caution in those with mild-to-moderate renal dysfunction. 

Namenda is available as 5-mg and 10-mg tablets. The recommended starting dose is 5 mg once daily, with a target dose of 20 mg/day (10 mg twice daily). The dose should be increased in 5-mg increments at intervals of 1 week. Namenda can be taken with or without food. 

Namenda offers an option for patients who have moderate-to-severe Alzheimer's disease, as well as a unique mechanism of action for treating the condition. Further studies are needed to evaluate the effects of Namenda on the prevention or slowing of neurodegeneration, as well as the potential benefits of combination therapy with cholinesterase inhibitors. 

Articles

RxPRODUCT NEWS PROFILE: Namenda

    According to the National Institutes of Health, erectile dysfunction (ED) affects approximately 15 million to 30 million American men.

 ED, also called impotence, is the inability to obtain and keep an erection during sexual intercourse. ED may be caused by disease (diabetes, alcoholism, vascular disease), surgical procedures, and medications. ED traditionally has been treated with psychotherapy, surgery, mechanical vacuum devices, and medications. In March 1998, the FDA approved the first oral medication, sildenafil, for the treatment of ED. Levitra, approved by the FDA in August 2003, is the second oral medication for the treatment of ED. 

    Penile erection occurs by the relaxation of smooth muscle in the corpus cavernosum. Nitric oxide release at the corpus cavernosum activates cyclic guanosine monophosphate (cGMP), which stimulates smooth muscle relaxation. Degradation of cGMP is regulated by phosphodiesterases. Levitra is a selective inhibitor of cGMP-specific phosphodiesterase type 5; thus it increases the amount of cGMP. Levitra has an onset of action of 1 hour and a duration of up to 1 hour.

    Hellstrom and colleagues performed a placebo-controlled, randomized, multicenter, 4-arm, parallel-group, fixeddose study evaluating Levitra for the treatment of men with ED. The trial consisted of a 4-week baseline period with no treatment, followed by a 26- week double-blind treatment phase with Levitra 5, 10, or 20 mg or placebo, and then a 1-week follow-up phase for adverse-event monitoring. Men over the age of 18 with the inability to maintain or achieve an erection sufficient for satisfactory sexual intercourse for longer than 6 months were enrolled. The study utilized erectile function (EF) domain scores on the International Index of Erectile Function (IIEF) questionnaire as the primary efficacy measure. 

    After 12 weeks, patients on all doses of Levitra showed significant improvement in EF domain scores, versus placebo, and this improvement was maintained at 26 weeks. EF domain scores were significantly higher for the Levitra 10- and 20-mg groups than for the 5-mg group. These EF domain scores were maintained for all groups at week 26, showing the continued superiority of the higher doses.

    Goldstein and colleagues investigated the efficacy and safety of Levitra in males with ED and diabetes mellitus in a multicenter, fixed-dose, double-blind, placebo-controlled trial. This study randomized patients to Levitra 10 or 20 mg or placebo. Most patients reported severe ED and a mean duration of 3.5 years after diagnosis. Most patients enrolled were identified as having type 2 diabetes and poor glycemic control. The study utilized the domain scores and the global assessment question (GAQ) on the IIEF about erection improvement to assess the efficacy of the drug. 

    After 12 weeks of treatment, patients in the 10- and 20-mg Levitra groups showed a 57% and 72% improvement, respectively, in GAQ results. When EF domain scores were assessed, patients in the 2 treatment groups showed an improved rate of successful penetration and intercourse, compared with placebo. Furthermore, Levitra was able to increase successful intercourse rates for patients at each level of HbA1c and for patients with both type 1 and type 2 diabetes.

    The most common adverse events seen with Levitra were headache, flushing, rhinitis, dyspepsia, sinusitis, flu syndrome, dizziness, increased creatine kinase, and nausea.

 Other less frequent adverse events seen included anaphylaxis, chest pain, myocardial infarction, palpitation, postural hypotension, tachycardia, angina, abdominal pain, myalgia, abnormal or blurred vision, abnormal ejaculation, and priapism.

 Contraindications include concurrent therapy with nitrates or alphablockers. Precaution should be advised in patients with cardiovascular complications or low blood pressure. Levitra is also metabolized by CYP450 3A4/5. Therefore, drugs inhibiting these enzymes reduce the clearance of Levitra and should be used with caution.

    The recommended dose of Levitra is 10 to 20 mg, and the drug should be taken at least 1 hour prior to expected sexual intercourse. Levitra should not be taken more than once daily.

Levitra (vardenafil, Bay 38-9456)

    The Centers for Disease Control and Prevention (CDC) estimates that approximately 42 million people currently live with HIV/AIDS. Of these, an estimated 38.2 million are adults and 3.2 million are children under the age of 15. In 2002, 5 million new cases of HIV infection and 3.2 million deaths due to AIDS were noted.1 

    The current mainstays of therapy include protease inhibitors, nucleoside reverse transcriptase inhibitors, and nonnucleoside reverse transcriptase inhibitors. By targeting replication enzymes, researchers have developed strict regimens for patients to follow. The increasing demands of multidose therapy have led to the development of once-daily highly active antiretroviral therapy medication. Reyataz, manufactured by Bristol-Myers Squibb, was recently approved by the FDA for the treatment of HIV-1 in combination with other antiretroviral agents. 

    Reyataz is an azapeptide HIV-1 protease inhibitor that selectively inhibits the viral processing of Gag and Gag-Pol within the HIV-1 infected cell. This inhibition prevents the formation of mature virions. Reyataz is rapidly absorbed (Tmax, 2.5 hours), with a steady state achieved between days 4 and 8. The mean elimination half-life is approximately 7 hours.2 

    Study AI424-034 was a randomized, double-blind, multicenter trial comparing Reyataz with efavirenz in patients who had not had prior antiretroviral therapy. In that study, 810 participants were randomized to receive Reyataz 400 mg once daily or efavirenz 600 mg once daily, along with a fixed-dose combination of lamivudine 150 mg and zidovudine 300 mg twice daily. Response was based on subjects achieving and maintaining confirmed HIV RNA <400 copies/mL through all 48 weeks. Results at 48 weeks yielded a comparable response in the Reyataz (67%) and the efavirenz (62%) treatment groups. Additionally, the mean CD4 cell count increase from baseline was 176 cells/mm3 in the Reyataz arm and 160 cells/mm3 in the efavirenz arm.3 

    Study AI424-043 is an ongoing randomized, open-label, multicenter trial comparing Reyataz with lopinavir/ritonavir in patients who did have prior antiretroviral therapy. Participants were randomized to receive Reyataz 400 mg once daily or lopinavir/ritonavir 400/ 100 mg twice daily, along with 2 nucleoside reverse transcriptase inhibitors. Preliminary results?presented at the 2nd International AIDS Society Conference in Paris in July 2003?from 229 patients at 24 weeks showed a higher percentage responding to the lopinavir/ ritonavir therapy. Mean changes in CD4 (cells/mm3) from baseline were 101 for the Reyataz group versus 121 for the lopinavir/ritonavir group. Additionally, data presented showed that 54% of participants in the Reyataz group responded to treatment (HIV RNA <400 copies/mL), compared with 75% of those in the lopinavir/ ritonavir group.4 

    The most frequent adverse events reported with Reyataz among patients in clinical trials were nausea, headache, rash, abdominal pain, vomiting, diarrhea, peripheral neuropathy, depression, drowsiness, insomnia, and fever. Increases in indirect bilirubin, prolonging of the PR interval, increases in lactic acid, and increases in blood sugar also have been reported with the use of Reyataz. Conditions and medications that exacerbate these conditions should be monitored with caution when administering Reyataz.2 Reyataz is contraindicated with drugs that are dependent on CYP3A for clearance. Caution should be used with coadministration of Reyataz and sildenafil due to the chance of increased sildenafil concentrations. Concomitant administration of Reyataz with lovastatin, simvastatin, and/or St. John?s wort is not recommended. Additionally, caution should be used when other HMG-CoA agents metabolized by CYP3A are used concomitantly with Reyataz.2 

    The recommended dose of Reyataz is two 200-mg capsules once daily (400 mg/day) with food in combination with other antiretroviral medications. The drug is supplied as 100-, 150-, or 200-mg capsules. It should be stored at room temperature. 

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. D. Ryan, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: dryan@mwc.com.

Reyataz (Atazanavir sulfate, BMS-232632)

    Coronary heart disease (CHD) is the number-1 cause of death in both men and women in the United States.1 Evidence suggests that low-density lipoprotein cholesterol (LDL-C) blood levels are directly correlated with CHD events. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (RIs), also called statins, have proven to be the best agents available for reducing LDL-C.2 Literature indicates, however, that only 18% of patients are treated to their goal LDL-C levels as defined by the National Cholesterol Education Program?Adult Treatment Panel III (NCEP-ATP III) guidelines.3 The introduction of a statin with improved efficacy at its starting dose, decreased drug interactions, and minimal adverse effects would be optimal for control of cholesterol levels. Rosuvastatin (Crestor), developed by Shionogi & Co and licensed to AstraZeneca, is a third-generation (pure enantiomer) HMG-CoA RI recently approved by the FDA for the treatment of hypercholesterolemia. 

    Statins decrease the production of cholesterol by inhibiting the rate-limiting enzyme HMG-CoA reductase. As a result, there is an upregulation of LDL receptors by hepatocytes, increasing the clearance of LDL-C.4 Crestor is a relatively hydrophilic (polar methane sulfonamide group) synthetic HMG-CoA RI. It has a half-life of about 20 hours, making its cholesterol-lowering capability equal when given at any time during the day. 

    Several clinical trials have compared Crestor with marketed statins, with Crestor showing favorable results. One randomized, double-blind, placebocontrolled, multicenter study compared the effectiveness of Crestor with that of atorvastatin in 516 patients with type IIa or type IIb hypercholesterolemia. Patients included in the study had an LDL level of 160 to 250 mg/dL and a triglyceride level 400 mg/dL. The study compared the effectiveness of Crestor 5 mg, Crestor 10 mg, atorvastatin 10 mg, and placebo for 12 weeks, with the primary end point of reducing LDL-C. Both Crestor doses showed a statistically significant greater reduction in LDL-C than atorvastatin. Additionally, Crestor was significantly more effective than atorvastatin in increasing high-density lipoprotein cholesterol levels, in decreasing total cholesterol levels, and in the percentage of patients reaching their LDL-C goals as defined by the NCEP-ATP III guidelines.5 

    Crestor undergoes minimal hepatic metabolism (~10%), mostly by isoenzymes 2C9 and 2C19, and it has essentially no metabolism via the 3A4 pathway. 6 In clinical trials, drug?drug interactions with cyclosporine, warfarin, and gemfibrozil have been evident. The majority of the parent compound is excreted unchanged in the feces. The adverse-effect profile of Crestor has been shown to be similar to that of the other statins. Rare occurrences of rhabdomyolysis have been reported with higher-than-recommended doses (80 mg) of Crestor. Additionally, uncomplicated myalgia has been reported in the Crestor-treated patients, and they should be monitored for this side effect. 

    Like other statins, Crestor has been related to biochemical liver abnormalities. Liver function tests should be done prior to initiation of therapy, 12 weeks following initiation, at dosage increases, and periodically thereafter. Crestor is classified as a pregnancy category X drug and should not be initiated in women who are pregnant or may become pregnant. 

    Crestor is available as 5-, 10-, 20-, and 40-mg tablets. Although each therapy should be individualized, the suggested starting dose of Crestor is 10 mg once daily. In clinical trials, Crestor was shown to be more effective than marketed statins in a variety of dosing ranges. With its increased potency, Crestor may have an advantage over marketed products in achieving NCEPATP III goals. 

    For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. D. Ryan, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: dryan@mwc.com.

Crestor (Rosuvastatin, ZD4522)

Lung cancer is the leading cause of cancer death among men and women in the United States, with approximately 157,000 deaths per year.

The Ameri-can Society of Clinical Oncology estimates that 172,000 new cases of lung cancer are diagnosed each year, 80% of which are deemed non?small cell lung cancer (NSCLC). Survival rates at 1 year for people with lung cancer are 42%.

Among the major risk factors for lung cancer are tobacco smoking (including cigarettes, cigars, pipes, and environmental smoke), asbestos, and radon. Currently, treatment for lung cancer includes surgery, radiation, and chemotherapy. The mainstays of chemotherapy have included platinum-based regimens and docetaxel. With low rates of 1-year survival, researchers have investigated new avenues for the treatment of lung cancer. Iressa, manufactured by AstraZeneca and recently approved by the FDA, is indicated as monotherapy for the treatment of locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies.

Iressa is thought to inhibit the intra-cellular phosphorylation of tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). Expression of EGFR has been widely reported in human tumors and has been associated with metastasis, late-stage disease, resistance to chemotherapy, and poor prognosis.

Iressa is absorbed slowly, with peak plasma levels occurring 3 to 7 hours after dosing. The mean oral bioavail-ability of Iressa is 60%, which is not significantly altered by food. Iressa undergoes extensive hepatic metabolism in humans, predominantly by CYP3A4. Excretion occurs mostly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose. The elimination half-life of Iressa is approximately 48 hours.

The Iressa Dose Evaluation in Advanced Lung cancer study (IDEAL-2) evaluated the efficacy of Iressa (250 mg vs 500 mg) as third-line therapy in 142 patients who had failed platinum and docetaxel therapies due to toxicity or lack of efficacy on these agents. In the group receiving the recommended dose of 250 mg/day, response rates (defined as at least 50% tumor shrinkage lasting at least 1 month) were reported to be 13.6% (n = 66). Patients receiving 500 mg/day were reported to have a 7.9% (n = 76) response rate and to have experienced a greater incidence of adverse effects. The overall combined response rate for the 250-and 500-mg doses was 10.6%.

The Iressa NSCLC Trial Assessing Combination Treatment (INTACT I & II) trials were large, placebo-controlled, randomized studies examining the use of Iressa as first-line therapy for chemotherapy-naive patients with stage III or IV NSCLC. Patients (n = 2130) were randomized to receive Ires-sa 250 mg, 500 mg, or placebo, all in combination with platinum therapy. The results showed no statistically significant differences in overall survival. Thus, there was no benefit from adding Iressa to standard platinum-based chemotherapy.

Cases of interstitial lung disease have been observed in patients receiving Ires-sa at an overall incidence of about 1% (2% in Japan and 0.3% in the United States), one third of these cases being fatal. The most frequent adverse effects reported with Iressa include diarrhea (48%), rash (43%), acne (25%), dry skin (13%), nausea (13%), and vomiting (12%).

In clinical trials, 2% of patients stopped taking Iressa because of an adverse drug reaction. Iressa is metabolized by CYP3A4; therefore, inducers and inhibitors of this enzyme should be used with caution if taken concomitantly. 

The recommended dose of Iressa is a single 250-mg tablet daily. Iressa appears to be useful as a last-line agent for the treatment of NSCLC after all traditional treatment options have failed. Continued long-term safety analysis and phase 4 studies are warranted with regard to the drug?s clinical application.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. D. Ryan, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: 

Iressa (Gefitinib, ZD1839)

According to the National Institute of Allergy and Infectious Diseases, approximately 42 million people in the world are living with HIV/AIDS. In 2002, an estimated 5 million new HIV infections occurred worldwide (~14,000 infections per day).

Among the 14,000 new patients, an estimated 2000 were children under the age of 15 and 6000 were between 15 and 24 years of age. In the United States alone, the Centers for Disease Control and Prevention estimates that 850,000 to 950,000 people are living with HIV/AIDS and that 40,000 new infections are occurring each year.

Although the epidemiology is astounding, antiretroviral therapy has markedly improved within the last 15 years, leading to a decrease in AIDS-related deaths during the past 5 to 6 years. The introduction of highly active antiretroviral therapy has principally targeted the enzymes reverse transcrip-tase and protease for the treatment of HIV-1. Unfortunately, a number of clinically relevant drug-related adverse effects and an increase in drug resistance have been noted with such agents.

Fuzeon (enfuvirtide) injection, manufactured by Roche/Trimeris and recently approved by the FDA, represents a new class of agents known as fusion inhibitors. 

Fuzeon, a synthetic 36 amino-acid peptide, binds to the glycoprotein 41 subunit (gp41) of HIV-1. The binding of Fuzeon to gp41 blocks the necessary conformational changes required for the fusion of the virus to the CD4+ cell membrane, and eventually the entry of the virus into the host cell.

The T-20 plus Optimized Regimen Only 1 (TORO-1) study was an open-label, randomized trial investigating the use of Fuzeon when added to optimized background (OB) regimens. Subjects (n = 501) from the United States, Canada, Mexico, and Brazil were randomized 2:1 to receive Fuzeon 90 mg twice daily plus an OB regimen of 3 to 5 antiretroviral medications or OB alone. The primary end point was a change in HIV-1 RNA from baseline at week 24. The results showed a decrease in plasma HIV-1 RNA of 1.696 for the Fuzeon group and a log

Clotet and colleagues presented data from the TORO-2 study at the XIV International AIDS Conference. TORO-2 was an open-label, randomized, international study (in Europe and Australia) investigating the use of Fuzeon when added to OB regimens. Subjects (n = 504) were randomized 2:1 to receive Fuzeon 90 mg twice daily plus an OB regimen of 3 to 5 antiretro-viral medications or OB alone. The primary end point was a change in HIV-1 RNA from baseline at week 24. The results showed a decrease in plasma HIV-1 RNA of 1.43 log

for the Fuzeon group and a decrease of 0.65 log

The most common adverse events reported in pooled safety analysis of both TORO-1 and TORO-2 were injection site reactions, diarrhea, nausea, fatigue, headache, insomnia, and vomiting. Additionally, an increased rate of bacterial pneumonia, with 1 death reported, was shown in clinical trials. 

Fuzeon is indicated for combination therapy with other antiretroviral agents for the treatment of HIV-1 infection in adults. The recommended adult dose of Fuzeon is 90 mg subcutaneously twice daily (at rotating sites). The recommended pediatric (age 6-16 years) dose is 2 mg/kg subcutaneously twice daily.

In addition to augmenting current therapy, Fuzeon may possibly assist in decreasing drug resistance and adverse effects associated with antiretroviral therapy. Despite positive clinical data, Fuzeon?s cost (~$20,000 per year), limited production, and parenteral administration are its setbacks. Further studies evaluating naive patients are warranted. 