A summary of the mechanisms of action and a brief review of clinical data for rofecoxib (Vioxx), zanamivir (Relenza), rizatriptan (Maxalt), and rosiglitazone (Avandia).
In October 2000, Dr Henderson worked with the BCMJ staff and Editorial Board on a medical publishing internship. She was keen to write for the Journal, and as we have been publishing medical student articles regularly for the past few years it wasn’t much of a leap to expand our commitment to international medical students. We identified four drugs recently approved for use in British Columbia, and I asked Dr Henderson to look at the Medical Letter and try to do a better job, which I believe she has. Keep in mind, though, that this is a medical student article, not a consensus paper from a group of pharamacoscientists. That aside, I am confident that the majority of you will find it useful reading.
Rofecoxib is a nonsteroidal anti-inflammatory drug that targets the enzyme cyclooxygenase (COX) and thereby inhibits prostaglandin synthesis. There are two isoforms of this enzyme: COX-1 and COX-2. COX-1 is constitutively expressed and generates prostaglandins that are involved in homeostatic functions such as gastric mucosal protection and platelet activation.[1,2] In contrast, COX-2 is induced by inflammatory mediators, such as growth factors, cytokines, and lipopolysaccharides.[2,3]
Traditional NSAIDs have a blanket effect on prostaglandin synthesis, inhibiting all COX enzymes, not just those involved with inflammation. The resulting change in physiological function can cause substantial morbidity and mortality, particularly in the gastrointestinal tract. A study of more than 8000 patients taking NSAIDs for rheumatoid arthritis found a 1.5% incidence of gastrointestinal complications. Nonsteroidal inhibition of COX-1 can also lead to a decrease in platelet thromboxane production and a corresponding increase in bleeding time. Adverse effects such as these have serious implications for the many people who use NSAIDs.
Based on the hypothesis that inhibition of COX-2 alone accounts for the therapeutic benefits of NSAIDs and the many adverse effects apparent with older style NSAIDs, specific inhibitors have been developed. Rofecoxib is a second generation COX-2 inhibitor licensed for use in Canada in August 2000.
Rofecoxib has been confirmed to be a specific inhibitor of COX-2.[3,6] It is well-absorbed and reaches peak concentrations about 3 hours after administration. It does not have to be taken with food, although a high-fat meal can delay absorption. Metabolism occurs in the liver, and the end-products are excreted renally. The elimination half-life of rofecoxib varies from between 9 and 21 hours and also varies with dose.
Rofecoxib is currently indicated for the relief of osteoarthritis, the management of acute pain in adults, and for the treatment of primary dysmenorrhoea.
This drug is contraindicated in those with a known hypersensitivity to rofecoxib, patients with moderate to severe hepatic insufficiency, and patients who have had asthma, urticaria, and allergic-type reactions after taking aspirin or other NSAIDs. Rofecoxib should not be prescribed during the third trimester of pregnancy.
Possible drug interactions include ACE inhibitors, salicylic acid, frosemide, lithium, methotrexate, rifampin, and warfarin.
Rofecoxib (12.5 mg or 25 mg o.d.) was found to have a clinical efficacy comparable to ibuprofen (800 mg t.i.d.) in the treatment of 736 patients with osteoarthritis of the knee or hip with pain on walking. It also had an effect comparable to that of diclofenac.
According to Jackson and Hawkey, the gastrointestinal profile of rofecoxib is impressive. A double-blind single-centre trial in healthy volunteers showed a lower incidence of upper GI mucosal damage with rofecoxib (12% of the treatment group) compared with ibuprofen (70% of the treatment group). Langman and colleagues studied the incidence of upper GI adverse effects (perforations, bleeding, ulcers) in 5435 patients participating in eight double-blind randomized rofecoxib osteoarthritis trials. Rofecoxib (12.5 mg, 25 mg, or 50 mg o.d.) was found to cause significantly fewer upper GI adverse events (1.3% vs 1.8%, P=0.46) than traditional NSAIDs (either ibuprofen 800 mg t.i.d., diclofenac 50 mg t.i.d., or nabumetone 1500 mg o.d.). This became statistically significant at 6 weeks and remained so up to 12 months. Although the results were significant, it is difficult to assess the outcomes of these studies in combination because of the different dosage regimens and use of differing comparator drugs.
Traditional NSAIDs have been shown to cause increasing blood loss with increased dosage. Clinical trials of rofecoxib have shown no effect on platelet function or bleeding time in healthy volunteers. A recent study reported that rofecoxib (25 mg or 50 mg o.d.) was associated with significantly less fecal blood loss than ibuprofen (800 mg t.i.d.) and was equivalent to that caused by placebo. No significant reduction in serum thromboxane levels have been found in patients administered up to 15 times the recommended dose of rofecoxib.
There is little doubt that rofecoxib is as efficacious as traditional NSAIDs in the treatment of arthritic symptoms[2,8,9,15] but with fewer of the adverse effects. Its specificity provides a significant advantage with regard to its sparing of thromboxane production and consequent lack of effect on bleeding time.
Initially, the outcome of studies assessing gastrointestinal effects of COX-2 inhibitors seems favorable. However, new discoveries are being made that suggest that COX-2 may also be constitutively expressed in the gastric mucosa and it should be noted that COX-2 inhibitors commonly cause abdominal pain, dyspepsia, and diarrhea just like traditional NSAIDs. This has lead to the recommendation that misoprostol be used prophylactically in patients at risk of developing gastrointestinal complications.
Taking economics in to account, it would seem sensible to treat only those patients whose osteoarthritic pain is unresponsive to acetominophen (which does not have gastrointestinal side effects) or who require NSAID therapy for anti-inflammatory purposes but have a history of or are at increased risk of GI problems. Rofecoxib could be considered as a cheaper alternative to a combination of traditional NSAID with a proton pump inhibitor or misoprostol.
There are still many unanswered questions regarding COX-2 inhibitors, which ongoing clinical trials may help to resolve. In the meantime, this is a useful drug whose reduced side effect profile has not yet been properly challenged. The economics of its use should always be weighed against patient benefit, and GI side effects should be carefully watched for in those at risk until rofecoxib has been fully investigated.
Zanamivir, a neuraminidase inhibitor, is one of a new generation of influenza treatments. Unlike amantidine and rimantidine, which target the M2 protein of influenza A viruses only, these drugs inhibit replication of both influenza types A and B. This represents a huge advantage, since the two types cannot be clinically differentiated and may co-circulate.
Neuraminidase is a surface glycoprotein found on the influenza virus, which possesses enzymatic activity essential for viral replication. The structure of the enzyme’s active site is conserved among all influenza neuraminidases. It acts by cleaving an a-ketosidic bond, which causes release of virus from infected cells, facilitates movement through respiratory mucus, and prevents the formation of viral aggregates.[2,4] It is also thought to disrupt the process of viral attachment to epithelial cells of the respiratory tract, a process essential for infection.
Zanamivir is currently only available as a dry powder for inhalation. The bioavailability is between 4% and 17% as systemic absorption is quite low.[2,6] Zanamivir is not metabolized in humans and it is excreted unchanged by the kidneys. It has been found to be more effective if given within 30 hours of the onset of symptoms.
The recommended dosage is two inhalations twice daily for 5 days. Two doses should be taken on the first day of treatment at least 2 hours apart.
Zanamivir can be used to treat uncomplicated acute illness due to influenza A and B virus in adults (and pediatric patients 12 years and older) who have been symptomatic for no more than 2 days.[5,6]
Zanamivir is contraindicated in patients with a known hypersensitivity to any component of the formulation (zanamavir and lactose) or when influenza symptoms have been present in an immunocompromised person for more than 2 days.
Care should be taken when prescribing to patients with respiratory disease. Asthma sufferers should use their bronchodilator before taking zanamivir as bronchospasm and decline in lung function have been reported in some patients receiving zanamivir.
Zanamivir does not have recognized drug interactions of clinical relevance.
The primary outcome in efficacy trials is the time to alleviation of major symptoms (defined as absence of fever and headache, muscle ache, sore throat, and cough). A double-blind randomized placebo-controlled trial of 417 adults carried out during the 1994–1995 influenza season reported the median time to primary outcome as 1 day less with zanamivir treatment than with placebo. More recently, the primary outcome in patients with laboratory-confirmed influenza was achieved 2.5 days (median value) earlier in the zanamivir group than with placebo. Combined analysis of six phase III zanamivir clinical trials (involving more than 1000 patients in each treatment arm) also found an overall reduction in the alleviation of symptoms of 1 day.
A greater therapeutic benefit has been found with zanamivir in patients presenting with a fever.[7,8,10] In one study, symptoms were alleviated 3 days earlier in febrile patients receiving zanamivir than in the placebo group. Also, in parallel with symptom reduction, the median peak temperature fell by 0.3°C in the zanamivir group but was unchanged in the placebo group.
The annual occurrence of influenza has serious implications for employers who stand to lose millions of dollars through lost working hours. Increase in productivity (assessed using a questionnaire with 722 individuals with virologically confirmed influenza) was not found to be statistically significant in patients treated with zanamivir. However, zanamivir showed the potential to reduce the cost of influenza to the health service, since only 8% of patients in the zanamivir treatment groups required an unscheduled contact with health care professionals compared with 14% of patients in the placebo group.
Although zanamivir has not yet been licensed for prophylactic use in the prevention of influenza, evidence is accumulating for its effectiveness in this indication. Of a group of 1107 healthy volunteers recruited prior to the influenza season, zanamivir was found to be 84% efficacious in preventing laboratory-confirmed influenza and fever.
Early treatment with zanamivir reduces both the severity of illness and accelerates recovery. The safety and efficacy of this drug has been repeatedly proven in clinical trials.[3,7-9] Viral resistance to amantidine and rimantidine has been found to develop rapidly, whereas clinical resistance to neuraminidase inhibitors has not yet been recognized as a significant problem. However, it should be noted that in practice, this drug will be used in a variety of patients and situations very different from those found in clinical trials, and outcomes may differ from those reported to date.
Treatment with zanamivir should not affect the evaluation of individuals for influenza vaccination. However, administration of the drug should be considered for outbreak control in institutions such as nursing homes, factories, and offices[1,2] or to treat infected individuals who have unstable underlying conditions.
Zanamivir is likely to become a major form of influenza prophylaxis and results of preliminary studies in this area suggest that a licence for this indication may be forthcoming. If so, zanamivir could be used to provide short-term prophylaxis in family settings, for travelers likely to be exposed out of season, or to provide protection for those unable to receive the vaccine (e.g., those with an allergy to eggs).
The use of neuraminidase inhibitors will ultimately depend on patient risk factors and the cost of the drug. According to Chapple and colleagues, the cost of 5 days’ treatment with zanamivir is approximately 3 times that of a 5-day course of rimantidine. However, by reducing the incidence of secondary complications, zanamivir has the potential to reduce the health care costs associated with influenza, which could offset some of the acquisition costs of the drug.
1. Jefferson T, Demicheli V, Deeks J, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults [review]. Cochrane Database Syst Rev 2000;(2):CD001265. PubMed Abstract
2. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet 2000;355:827-835. PubMed Abstract
3. Makela MJ, Pauksens K, Rostila T, et al. Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: A randomized, double-blind, placebo-controlled European study. J Infect 2000;40: 42-48. PubMed Abstract
4. Calfee DP, Hayden FG. New approaches to influenza chemotherapy. Neuraminidase inhibitors. Drugs 1998;56: 537-553. PubMed Abstract
7. Hayden FG, Osterhaus ADME, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group.N Engl J Med 1997;337:874-880. PubMed Abstract
8. MIST Study Group. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet 1998;352:1877-1881. PubMed Abstract
9. Monto AS, Robinson DP, Herlocher ML, et al. Zanamivir in the prevention of influenza among healthy adults. A randomized control trial. JAMA 1999;282: 31-35. PubMed Abstract
10. Monto AS, Webster A, Keene O. Randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: Pooled efficacy analysis. J Antimcrob Chemother 1999;44: 23-29. PubMed Abstract Full Text
11. Aoki FY, Fleming DM, Griffin AD, et al. Impact of zanamivir treatment on productivity, health status, and health care resource use in patients with influenza. Pharmacoeconom 2000;17:187-195. PubMed Abstract
Rizatriptan is a 5-hydroxytriptamine (5-HT) receptor agonist used for the acute treatment of migraine. It is selective for receptor subtypes 1B and 1D.
Current understanding of the pathophysiological and pharmacological processes involved in migraine remains incomplete. It is thought that the pain of migraine can be attributed to a complex set of mechanisms involving cerebral vasodilatation, extravasation of dural plasma proteins, and an imbalance of 5-HT. Rizatriptan is believed to cause constriction of the meningeal blood vessels, both by stimulation of the postsynaptic 5-HT receptors and by inhibiting the release of vasoactive neuropeptides from the trigeminal area. Direct action on the trigeminal nucleus caudalis is thought to result in interruption of pain signals from the meninges by blocking depolarization of the trigeminal axons.
Rizatriptan is a second generation 5-HT agonist, originally developed in an attempt to eliminate cardiac symptoms and improve upon the poor bioavailability and high headache recurrence rate[1,6] that had previously been associated with sumatriptan.
Rizatriptan is completely absorbed following oral administration. The oral bioavailability is about 40%, while the peak concentration (Tmax) is reached after 1 hour to 1.5 hours for the tablet formulation and 1.6 hours to 2.5 hours for the wafer. Food has no significant effect on the bioavailability but it does delay the time taken to reach peak concentration by approximately 1 hour.
Rizatriptan is principally metabolized via monoamine oxidase, “A” subtype, and is primarily excreted by the kidneys.
Rizatriptan is marketed in 10-mg and 5-mg dose strengths and is available both in conventional tablet and orally disintegrating freeze-dried wafer formulations.
Rizatriptan is indicated for the acute treatment of migraine attacks with or without aura in adults. It is not intended for the prophylactic therapy of migraine.
This treatment is contraindicated in patients with a diagnosis or symptoms of ischemic heart disease or other significant underlying cardiovascular disease. It should not be given to patients with uncontrolled hypertension.
Clinical trials of rizatriptan have revealed a high rate of adverse events. A long-term trial comparing rizatriptan with usual antimigraine treatment reported an overall incidence of adverse effects of 80% in patients taking 10 mg of rizatriptan. Those adverse events most commonly experienced with this drug include dizziness, somnolence, nausea, and asthenia/fatigue.[9-11] Although high, this figure compares favorably with that reported for alternative treatments. Seventy-eight percent of patients reported side effects when receiving treatments such as NSAIDs, acetaminophen, barbiturates, opiates, or sumatriptan for their migraine.
More serious adverse events such as chest pain have been reported[6,10] but are infrequent. An investigation of clinical trials and reported incidents for sumatriptan, an earlier 5-HT inhibitor, revealed a small risk of myocardial ischemia and recommended the administration of nitrate if it were to induce symptoms suggestive of angina.
The primary measure of efficacy employed in clinical trials was the change in pain levels experienced with a migraine after administration of a drug. Secondary outcome variables included the presence of associated symptoms and the need for escape medication.
There are many published studies illustrating the effectiveness of rizatriptan in the treatment of migraine when compared with placebo.[1,6,9-11] A large double-blind placebo-controlled double-dummy trial conducted at 46 sites worldwide showed that at 2 hours after the initial dose, 71% of patients taking rizatriptan 10 mg experienced significant pain relief compared with only 35% of patients taking placebo.
A study of 1268 patients comparing a single 10-mg dose of rizatriptan with a single 100-mg dose of sumatriptan (the maximum single dose recommended in the Compendium of Pharmaceuticals and Specialties) reported that all active treatment was superior to placebo 2 hours after the initial dose. Significantly more patients were completely relieved of pain when taking rizatriptan 10 mg (40%) compared with sumatriptan (33%) at 2 hours after the first dose. Goldstein and colleagues have suggested that the increased effectiveness of rizatriptan compared with sumatriptan may be due to the more favorable plasma concentration profile of rizatriptan.
Rizatriptan has also been found to be effective in reducing the incidence of associated symptoms of nausea, photophobia, and phonophobia compared with placebo. When directly compared with sumatriptan, rizatriptan shows superior efficacy in both primary and secondary outcome measures.[1,6,9,13]
Migraines associated with menstruation can be effectively treated with rizatriptan. Combined data from two masked placebo-controlled clinical trials involving 2715 patients found that the subgroup of women with menstrually associated migraine were effectively treated when compared with placebo.
Rizatriptan has been shown to be effective for the acute treatment of migraine and has a side effect profile similar to other pharmacological treatments currently on the market. Evidence to date indicates that the efficacy of rizatriptan is superior to sumatriptan for both primary and secondary outcomes.[1,6,15]
However, care should be taken not only with patients with ischemic heart disease, but also with those who are symptom free and have risk factors such as hypertension, hypercholesterolemia, diabetes, or a strong family history of heart disease. Nitrates should be given when a 5-HT antagonist induces symptoms of angina.
Physicians should be aware of the high recurrence rate of migraines, reported to occur in approximately one-third of patients in the first 24 hours after initial pain relief. Although no statistical analysis has been conducted on recurrence rates for this drug, more patients (47%) experienced a repeat episode of migraine when taking rizatriptan 10 mg compared with placebo (40%). However, a comparative study of rizatriptan and sumatriptan documents a 24-hour recurrence rate of approximately one-third of patients for both drugs.
The wafer formulation of rizatriptan has been found to be more convenient for patients wishing to take the drug without water and has been said to have a soothing effect on nausea. However, the rate of absorption is slower than with the tablet formulation. Also, some patients may find the wafer disagreeable to the palate.
1. Goldstein J, Ryan R, Jiang K, et al. Crossover comparison of rizatriptan 5 mg and 10 mg versus sumatriptan 25 mg and 50 mg in migraine. Headache 1998;38: 737-747. PubMed Abstract
2. Deiner H-C, Limmroth V. Acute management of migraine: Triptans and beyond. Curr Opin Neuro 1999;12:261-267. PubMed Abstract
3. Williamson DJ, Shepheard SL, Hill RG, et al. The novel agent rizatriptan inhibits neurogenic dural vasodilation and extravasation. Eur J Pharmacol 1997;328:61-64. PubMed Abstract
4. Cumberbatch MJ, Hill RG, Hargreaves RJ. Rizatriptan has central antinociceptive effects against durally evoked responses. Eur J Pharmacol 1997;328: 37-40. PubMed Abstract
5. Hillis WS, MacIntyre PD. Drug reactions. Sumatriptan and chest pain. Lancet 1993;341:1564-1565. PubMed Citation
6. Tfelt-Hansen P, Teall J, Rodriguez F, et al. Oral rizatriptan versus oral sumatriptan: A direct comparative study in the acute treatment of migraine. Headache 1998; 38:748-755. PubMed Abstract
8. Dahlof CGH, Rapoport AM, Sheftell FD, et al. Rizatriptan in the treatment of migraine. Clin Ther 1999;21:1823-1836. PubMed Abstract
9. Block GA, Goldstein J, Polis A, et al. Efficacy and safety of rizatriptan versus standard care during long-term treatment for migraine. Headache 1998;38:764-771. PubMed Abstract
10. Teall J, Tuchman M, Cutler N, et al. Rizatriptan for the acute treatment of migraine recurrence. A placebo-controlled, outpatient study. Headache 1998;38:281-287. PubMed Abstract
12. Weitzel KW, Thomas ML, Small RE, et al. Migraine: A comprehensive review of new treatment options. Pharmacother 1999;19:957-973. PubMed Abstract
14. Silberstein SD, Massiou H, Le Jeunne C, et al. Rizatriptan in the treatment of menstrual migraine. Obstet Gynecol 2000; 96:237-242. PubMed Abstract
15. Dooley M, Faulds D. Rizatriptan. A review of its efficacy in the management of migraine. Drugs 1999;58:699-723. PubMed Abstract
16. Ferrari MD. Migraine. Lancet 1998;351: 1043-1051. PubMed Citation
17. Adelman JU, Mannix LK, Von Seggern RL. Rizatriptan tablet versus wafer: Patient preference. Headache 2000;40: 371-372. PubMed Abstract
Rosiglitazone is a member of a new class of antidiabetic agents called the thiazolidinediones, which improve glycemic control by increasing insulin sensitivity.
Type II diabetes is characterized by an increase in insulin resistance in the target tissues, an overproduction of glucose by the liver, and a decrease in insulin output due to impaired B-cell function. The primary defect is thought to be insulin resistance, which can be detected long before the development of impaired glucose homeostasis. Traditional oral antidiabetic agents such as sulphonylureas and metformin are unable to modulate this defect, having different mechanisms of action and showing secondary failure over time.
The pharmacological action of thiazolidinediones has not yet been fully elucidated. However, they are thought to be potent and selective activators of peroxisome proliferator-activated receptor gamma (PPAR-g) receptors, which regulate the transcription of insulin-responsive genes concerned with the production, transport, and uptake of glucose. They sensitize tissues (such as skeletal muscle and the liver) to the action of insulin, resulting in an increase in glucose uptake and decreased hepatic glucose production. The PPAR-g receptors are also involved in the regulation of fatty acid metabolism. This may be of significance since elevated free fatty acid levels are thought to exacerbate the development of insulin resistance and are known to contribute to the secondary complications of diabetes.
Rosiglitazone was released in the USA in 1999 following the withdrawal of the first agent of this type, troglitazone. In clinical trials, rosiglitazone exhibits the same efficacy, apparently without causing the liver toxicity that lead to the withdrawal of troglitazone.
Peak plasma concentrations of rosiglitazone are achieved approximately 1 hour after oral administration. Metabolism of this drug is catalyzed by the cytochrome P-450 isoenzyme system in the liver, and investigation of excretion using radioactively labeled tablets found 64% of the dose excreted in the urine and 23% of the dose excreted in the feces. This was significantly lower in patients with moderate to severe hepatic impairment. Mild to moderate renal impairment was not found to alter the pharmacokinetics of this drug.
A starting dose of 4 mg once or twice daily is recommended. Treatment should be discontinued if no clinical improvement occurs within 8 to 12 weeks.
Rosiglitazone is indicated for use in patients with type II diabetes as an adjunct to diet and exercise to achieve glycemic control. It has been licensed for use as a monotherapy or in combination with a sulfonylurea or metformin.
This product is contraindicated in patients with a known hypersensitivity to the product (rosiglitazone malleate) or any of its inactive components (hydroxypopyl methylcellulose, lactose monohydrate, magnesium stearate, cellulose, polyethylene glycol, sodium starch glycolate, titanium dioxide, and iron oxides). It should be used with caution in patients with edema or those at risk of cardiac failure, and is contraindicated in type I diabetics as it is only active in the presence of insulin.
Treatment with rosiglitazone should not be initiated in those with impaired liver function. Anovulatory premenopausal woman should take contraceptive precautions since rosiglitazone can induce ovulation and is contraindicated in pregnancy unless the potential benefit justifies the potential risk to the fetus.
Data on drug interactions are limited, and though in vitro studies suggest that rosiglitazone does not inhibit any of the major P-450 enzymes at clinically relevant concentrations, care should be taken when prescribing other agents that are metabolized through the cytochrome P-450 system.
Rosiglitazone was approved for use in the USA in 1999, so trial data is limited, appearing mainly in abstract form. To date, this drug, either as a monotherapy or in combination with metformin or a sulfonylurea, has been found to be safe and well tolerated in patients with type II diabetes mellitus. In a trial of 1000 patients treated for a minimum of 12 months, the incidence of adverse effects was low (less than 5%). It is well tolerated in patients over the age of 65 with type II diabetes.
Troglitazone has been found to cause fluid retention and weight gain. According to Krische, this is a thiazolidinidione class effect, and patients with existing edema may experience an exacerbation of symptoms. Physicians should be aware of this when treating patients with rosiglitazone.
Analysis of 3455 patients treated with rosiglitazone prior to its approval found no evidence of hepatotoxicity. However, two cases of hepatic failure have recently been reported.[14,15] The first was probably due to hepatic necrosis caused by an inadequate blood supply in an already unwell patient. However, the second event occurred in a 61-year-old man who developed anorexia, vomiting, and abdominal pain 2 weeks after starting rosiglitazone therapy. Liver function tests indicated severe hepatocellular injury. Symptoms improved and liver enzymes returned to normal after rosiglitazone was stopped. The authors claim that this pattern of symptom development was typical of drug-induced hepatotoxicity.
A randomized double-blind study of 369 patients with type II diabetes found both a statistically and clinically significant reduction in fasting glucose after treatment with rosiglitazone. Eight weeks of treatment with a once-daily dose of rosiglitazone (dose range 4 mg to 12 mg) demonstrated a mean reduction in fasting plasma glucose (FPG) levels of 35.7 mg/dl for an 8 mg dose. Patients given placebo actually experienced a small increase in FPG levels of 7.4 mg/dl. These results were improved by adopting a twice-daily dosing schedule. The patient group taking 4 mg rosiglitazone two times a day showed a mean reduction in FPG levels of 42.5 mg/dl. However, it is difficult to assess the comparability of these studies solely from the information provided in an abstract.
Rosiglitazone exhibits increased efficacy when administered in combination with sulfonylureas and metformin. A multicentre, randomized, double-blind placebo-controlled trial reported in April 2000 demonstrated a significant decrease of 0.78% in HbA1c levels in those simultaneously treated with metformin (2.5 g per day) and rosiglitazone (8 mg per day). This compared favorably with the decrease of 0.45% in HbA1c seen in patients taking metformin in combination with a placebo drug. The results imply that the rosiglitazone actually complements the actions of metformin and can therefore be used in combination to achieve optimal glycemic control.
Rosiglitazone has been shown to significantly reduce both FPG[17,18] and, in the longer term, HbA1c levels[19,20] in patients with type II diabetes. However, published data is limited and mainly in abstract form, making a critical appraisal of these trials difficult to conduct.
Many physicians will be aware of the hepatotoxicity problems associated with the use of the first thiazolidinedione, troglitazone. Forty-three cases of acute hepatic failure were reported, leading to the removal of this drug form the market in the United Kingdom. Initial clinical trials with rosiglitazone show no evidence of this adverse event. However, two case studies of hepatic failure associated with the use of this drug have recently been published.[14,15] It remains to be seen whether patients using rosiglitazone will experience adverse liver reactions.
In the meantime, more frequent liver function testing (once a week for the first month, followed by monthly testing) and the encouragement of patients to promptly report any adverse symptoms have been recommended. Therapy should be stopped if patients present with symptoms of anorexia, fatigue, abdominal pain, nausea, or jaundice, and liver enzymes measured.[1,14]
The availability of thiazolidinediones should not alter the initial, traditional management of patients when they first present with type II diabetes. Exercise, diet control, and weight loss are all important and are recommended in the rosiglitazone prescribing information since they help to improve insulin sensitivity. However, for patients who do not achieve adequate control with these measures, rosiglitazone provides an effective additional treatment. Alternatively, it can be added to an existing treatment regimen involving other oral antidiabetics to provide superior glycemic control.
2. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1996;45:1661-1669. PubMed Abstract
4. UK Prospective Diabetes Study (UKPDS) Group. UK Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: A progressive disease. Diabetes 1995;44:1249-1258. [Published erratum in Diabetes 1996;45:1249-1583.] PubMed Abstract
5. Lehmann JM Moore LB, Smith-Oliver TA, et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma. J Biol Chem 1995;270:12953-12956. PubMed Abstract Full Text
6. Samraj GPN, Kuritzky L, Quillen DM. Improving management of type 2 diabetes mellitus: 5. Thiazolidinediones. Hosp Pract 2000;15 Jan:123-132. PubMed Citation
8. King AB. A comparison in a clinical setting of the efficacy and side effects of three thiazolidinediones. Diabetes Care 2000;23:557. PubMed Citation
11. Kreider M, Miller E, Patel J. Rosiglitazone is safe and well-tolerated as monotherapy or combination therapy in patients with type 2 diabetes mellitus. Poster, American Diabetes Association Meeting, 19–22 June 1999, San Diego.
14. Forman LM, Simmons DA, Diamond RH. Hepatic failure in a patient taking rosiglitazone. Ann Intern Med 2000; 132:118-121. PubMed Abstract
15. Al-Salman J, Arjoman H, Kemp DG, et al. Hepatocellular injury in a patient receiving rosiglitazone. A case report. Ann Intern Med 2000;132:121-124. PubMed Abstract
16. Fried J, Everitt D, Boscia J. Rosiglitazone and hepatic failure. Ann Intern Med 2000;132:164. PubMed Citation
17. Nolan JJ, Jones NP, Patwardhan R, et al. Once-daily rosiglitazone is effective in the treatment of type 2 diabetes mellitus. Poster, American Diabetes Association Meeting, 19–22 June 1999, San Diego.
19. Gomis R, Jones NP, Vallance SE, et al. Low-dose rosiglitazone (RSG) provides additional glycemic control when combined with sulphonylureas in type 2 diabetes (T2D). Poster, American Diabetes Association Meeting, 19–22 June 1999, San Diego.
20. Fonseca V, Rosenstock J, Patwardhan R, et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus. JAMA 2000;283:1695-1702. PubMed Abstract
1. Jackson LM, Hawkey CJ. COX-2 selective nonsteroidal anti-inflammatory drugs: Do they really offer any advantages? Drugs 2000;59:1207-1216. PubMed Abstract
2. Cannon GW, Caldwell JR, Holt P, et al. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium. Arthritis Rheum 2000;43:978-987. PubMed Abstract
3. Van Hecken A, Schwartz JI, Depre M, et al. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol 2000;40:1109-1120. PubMed Abstract
4. Peterson WL, Cryer B. COX-1-sparing NSAIDs—Is the enthusiasm justified? JAMA 1999;282:1961-1963. PubMed Citation
5. Silverstien FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. Ann Intern Med 1995;123:241-249. PubMed Abstract
6. Depre M, Ehrich E, Van Hecken A, et al. Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans. Eur J Clin Pharmacol 2000;56:167-174. PubMed Abstract
9. Saag K, Fisher C, McKay, et al. MK-0966, a specific COX-2 inhibitor, has clinical efficacy comparable to ibuprofen in the treatment of knee and hip osteoarthritis in a 6-week controlled clinical trial [abstract]. Arthritis Rheum 1998;41:S196.
10. Cannon G, Caldwell J, Holt P, et al. MK-0966, a specific COX-2 inhibitor, has clinical efficacy comparable to diclofenac in the treatment of knee and hip osteoarthritis in a 26-week controlled clinical trial [abstract]. Arthritis Rheum 1998;41: S196.
11. Lanza F, Simon T, Quan H, et al. Selective inhibition of cyclooxygenase-2 (COX-2) with MK-0966 is associated with less gastroduodenal damage than aspirin or ibuprofen. Gastroenterol 1998;112: Abstract 194.
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Janet Henderson, MB, BCh
At the time of writing, Dr Henderson was a fifth-year medical student out of Bristol, England, doing a medical publishing internship with the BC Medical Journal. She has since completed her degree in medicine and is now a house officer in general medicine at St. Richard’s Hospital in Chichester, West Sussex.
Above is the information needed to cite this article in your paper or presentation. The International Committee
of Medical Journal Editors (ICMJE) recommends the following citation style, which is the now nearly universally
accepted citation style for scientific papers:
Halpern SD, Ubel PA, Caplan AL, Marion DW, Palmer AM, Schiding JK, et al. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.
About the ICMJE and citation styles
The ICMJE is small group of editors of general medical journals who first met informally in Vancouver, British Columbia, in 1978 to establish guidelines for the format of manuscripts submitted to their journals. The group became known as the Vancouver Group. Its requirements for manuscripts, including formats for bibliographic references developed by the U.S. National Library of Medicine (NLM), were first published in 1979. The Vancouver Group expanded and evolved into the International Committee of Medical Journal Editors (ICMJE), which meets annually. The ICMJE created the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals to help authors and editors create and distribute accurate, clear, easily accessible reports of biomedical studies.
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