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W R Garnett
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ABSTRACT: Nonsteroidal antiinflammatory drugs (NSAIDs) often are prescribed to patients who are taking concomitant drugs. Cyclooxygenase (COX)-2 inhibitors (coxibs) rofecoxib and celecoxib are highly selective inhibitors of COX-2, differentiating them from nonselective NSAIDs, which substantially inhibit both COX-1 and COX-2. Like nonselective NSAIDs, coxibs are hepatically metabolized: rofecoxib primarily by reduction by cytosolic enzymes and celecoxib by the cytochrome P450 (CYP) enzyme system. Because rofecoxib is not significantly metabolized by CYP, it has fewer confirmed or potential drug interactions than celecoxib. However, potent inducers of CYP, such as rifampin, may decrease rofecoxib concentrations because of induction of general hepatic metabolic activity. Celecoxib is metabolized by CYP2C9 and may be increased or decreased by CYP2C9 modifiers. It also inhibits CYP2D6 and may affect concentrations of CYP2D6 substrates. Similar to NSAIDs, many pharmacodynamic interactions involving coxibs are related to inhibition of production of renal prostaglandins. However, coxibs have no antiplatelet activity and may be preferred to NSAIDs in patients receiving antithrombotic therapy. Nonetheless, when a potential for an interaction exists, standard monitoring is recommended when starting or discontinuing a coxib. Due to lack of data to support these interactions, which are primarily theoretical, additional studies are necessary to establish the drug interaction profiles of coxibs.
Pharmacotherapy 11/2001; 21(10):1223-32. · 2.90 Impact Factor
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ABSTRACT: The role of infliximab in managing Crohn's disease (CD) is described. CD is characterized by chronic transmural inflammation at various sites of the gastrointestinal tract, particularly the ileum and colon. The major symptoms are diarrhea, abdominal pain, enterocutaneous and perianal fistulas, and weight loss. Management goals include alleviating symptoms, inducing remission, promoting healing of the intestinal mucosa and fistulas, and modifying the disease process. Drugs traditionally used to manage CD are aminosalicylates, antimicrobials, immunomodulatory agents, and corticosteroids. Infliximab is a chimeric (human-mouse) monoclonal antibody targeted at human tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine important in the pathogenesis of CD. Infliximab antagonizes the biological activity of TNF-alpha by binding to it on macrophage and T-cell surfaces. Clinical trials have shown infliximab to be effective in producing and maintaining a clinical response in patients with refractory, moderate to severe CD. Treatment helps promote healing of intestinal mucosa and closure of fistulas. Infliximab may act more rapidly than most traditional agents and produces less severe adverse effects. The most frequent adverse effects are headache, nausea, and upper-respiratory-tract infections. The recommended dosage is 5 mg/kg i.v. infused over a two-hour period. Infliximab may be given at eight-week intervals for maintenance or management of flare-ups. Infliximab appears useful in the treatment of CD and may improve patients' quality of life.
American Journal of Health-System Pharmacy 03/2001; 58(4):307-16; quiz 317-9. · 1.96 Impact Factor
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ABSTRACT: Proton pump inhibitors, the treatment of choice for acid-related disorders, are often coadministered with other medications, sometimes with potentially adverse interactions. Although all agents studied may potentially interact with one proton pump inhibitor or another, a literature review documented adverse interactions for 10 medications in particular. Furthermore, 44% of people using proton pump inhibitors received another gastrointestinal drug. Although documented interactions involving these agents have been reported infrequently, the authors advise that physicians and pharmacists should recognize this possibility and watch for potentially problematic combination therapy.
Managed care interface 10/2000; 13(9):71-6, 79.
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W R Garnett
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ABSTRACT: The goal in treating patients with epilepsy is a cost-effective approach to the elimination of seizures or a reduction in their number and frequency while avoiding drug interactions and side effects, so as to achieve the best possible quality of life. Among the desirable outcomes are an enhanced understanding of epilepsy by patients, caregivers, and society, and a lessening of the psychosocial risks of this disease. Patients fail to achieve their goals and outcomes when they fail to adhere to the drug regimen or when a less-than-adequate drug regimen is prescribed. To help improve adherence, once- or twice-daily formulations should be used. New antiepileptic drugs (AEDs) increase the possibility of effective treatment for a patient who initially fails therapy. Working together, patients and clinicians can maximize the effectiveness of AED therapy and the potential for achieving desired goals and outcomes.
Pharmacotherapy 09/2000; 20(8 Pt 2):191S-199S. · 2.90 Impact Factor
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W R Garnett
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ABSTRACT: Clinical success with an antiepileptic drug (AED) depends primarily on its efficacy and tolerability. Clinicians also need to have a basic understanding of an AED's pharmacokinetic characteristics, particularly those affecting the potential for drug interactions such as hepatic enzyme inhibition or induction and protein-binding displacement. Successful treatment may be complicated by pharmacokinetic characteristics such as a short half-life, nonlinear kinetics, and active metabolites. Pharmacokinetic characteristics that make a drug easy to use may affect patient adherence. In general, newer AEDs such as topiramate (TPM) are simpler to use than traditional AEDs because they have more favorable pharmacokinetic characteristics and fewer drug interactions.
Epilepsia 02/2000; 41 Suppl 1:S61-5. · 3.96 Impact Factor
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ABSTRACT: We evaluated the use of a new, controlled-release capsule form of carbamazepine, Carbatrol capsules, in an open-label, multicenter study of 124 patients with complex partial seizures. Ninety-one percent of the patients successfully completed the 6-month trial with good seizure control, with a significant improvement in quality of life. We conclude that switching patients with complex partial seizures from multiple daily-dose carbamazepine to twice-daily Carbatrol on a milligram-to-milligram basis is relatively safe.
Neurology 01/1999; 51(6):1727-9. · 8.31 Impact Factor
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W R Garnett
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ABSTRACT: The safety of proton-pump inhibitors (PPIs) for long-term use is reviewed. PPIs are being used with increasing frequency to inhibit secretion of gastric acid in order to treat acid-related disorders such as gastroesophageal reflux disease and peptic ulcer disease. Some patients may require long-term acid suppressive treatment to control the symptoms of their disease, which raises questions about the long-term safety of PPIs. A thorough literature search was conducted, and the clinical consequences of sustained hypergastrinemia induced by all antisecretory therapy, the consequences of atrophic gastritis in patients infected with Helicobacter pylori, the effects of hypochlorhydria on bacterial overgrowth and nutrient absorption, and possible interactions of PPIs with other drugs were identified as areas of concern with long-term use of PPIs. Short- and long-term studies showed that PPIs have a wide safety margin and a favorable adverse-event profile with few drug interactions. Available data support the short- and long-term safety of PPIs.
American Journal of Health-System Pharmacy 12/1998; 55(21):2268-79. · 1.96 Impact Factor
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ABSTRACT: To determine the effect of reduced hepatic function on the pharmacokinetics of minoxidil. The pharmacokinetics of antipyrine, lorazepam, and indocyanine green were included as indicators of hepatic function.
Eight mild cirrhotics and eight healthy subjects received antipyrine (po), lorazepam (IV), indocyanine green (IV) and minoxidil 5 mg (po). Blood and urine were sampled for up to 72 h after each drug, and drug concentrations were measured by validated HPLC methods. Blood pressure and heart rate were measured for safety.
For unchanged minoxidil, the serum elimination rate constant was significantly smaller and mean residence time was significantly longer in cirrhotic patients. Urinary elimination rate constant for minoxidil glucuronide was significantly smaller and fraction of dose excreted in urine was significantly higher in cirrhotic patients. Antipyrine elimination was significantly slower for cirrhotic patients. No differences were observed in lorazepam pharmacokinetic parameters.
Pharmacokinetic analysis suggests a longer dosage interval may be appropriate in patients with hepatic impairment. In the absence of multiple-dose minoxidil pharmacodynamic studies in this population, minoxidil should be used as in other populations: begin with a modest dose, and adjust the dose based on clinical response.
Biopharmaceutics & Drug Disposition 12/1998; 19(8):501-15. · 2.07 Impact Factor
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ABSTRACT: A new capsule dosage form of carbamazepine (CBZ) has been developed, consisting of three different types of beads (immediate-release, extended-release, and enteric-release) that may be taken sprinkled on food or swallowed for easy administration. We compared the pharmacokinetics of the extended-release dosage form of CBZ (Carbatrol capsules) twice daily with the conventional immediate-release formulation of CBZ four times daily.
The randomized, double-blind, two-way, cross-over study was conducted at two sites, with a planned sample size of 24 adult patients with epilepsy. Each treatment was administered for 2 weeks. At the end of the 2-week period, blood samples were obtained hourly for a 24-h period.
The 90% confidence intervals (CI) of the ratio of the means of the extended-release formulation twice daily to the immediate-release formulation four times daily were within the range of 0.80-1.25 for each of the pharmacokinetic parameters for CBZ and for the summation of CBZ and CBZ-epoxide (CBZ-E). There was no difference in the frequency of seizures between treatment (p = 0.103).
Our results demonstrate that extended-release CBZ twice daily was bioequivalent to immediate-release CBZ four times daily, with regard to CBZ levels and summation of CBZ and CBZ-E levels, based on the pharmacokinetic parameters evaluated. Substituting one formulation for the other did not cause patients to have a significant change in seizure frequency.
Epilepsia 04/1998; 39(3):274-9. · 3.96 Impact Factor
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W R Garnett
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ABSTRACT: The pharmacokinetics of lamotrigine have been studied in single and multiple dose studies in animals, normal volunteers, and patients with epilepsy. Lamotrigine exhibits first-order linear pharmacokinetics. Lamotrigine is well absorbed with bioavailability approaching 100%. The absorption is unaffected by food and there is no first-pass metabolism. The volume of distribution is between 1.25 and 1.47 L/kg and protein binding is about 55%. The half-life of lamotrigine is between 24.1 and 35 hours in drug naive adults but may be altered by enzyme inducing and inhibiting drugs. Clinical trials demonstrated no evidence of autoinduction or saturable metabolism. Younger children (0.17 to 5 years) eliminate lamotrigine faster than older children (5 to 10 years). Children may be more prone to enzyme induction than adults.
Journal of Child Neurology 12/1997; 12 Suppl 1:S10-5. · 1.75 Impact Factor
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ABSTRACT: Fosphenytoin (Cerebyx), is a water soluble prodrug that is rapidly and completely converted to phenytoin. This study reports the injection-site tolerance and safety of intramuscular fosphenytoin (> 10 mg/kg doses) in 60 patients requiring a phenytoin loading dose. Patients received injections at single or multiple sites with volumes ranging from 4 to 30 ml per injection site. The majority of patients had no irritation (erythema, swelling, tenderness, bruising) or complaints of discomfort related to fosphenytoin injection either after injection (95%) or at follow-up (88%). Irritation, when reported, was mild in all cases. Forty of 60 patients (67%) reported transient side effects, primarily involving the central nervous system, such as nystagmus, dizziness or ataxia, which are commonly associated with phenytoin therapy. All patients received prescribed doses; no patient had an injection(s) stopped due to intolerance or side effects. No serious adverse events occurred with intramuscular fosphenytoin. In this study, intramuscular fosphenytoin was demonstrated to be a safe and well tolerated, and in many instances, a preferable alternative to other means of phenytoin loading.
Epilepsy Research 10/1997; 28(3):181-7. · 2.29 Impact Factor
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W R Garnett
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ABSTRACT: To summarize the published data on lansoprazole, a proton pump inhibitor approved by the Food and Drug Administration for use in the treatment of duodenal ulcer, erosive esophagitis, and pathologic hypersecretory conditions (e.g., Zollinger-Ellison syndrome).
Published data on lansoprazole identified by MEDLINE searches (1985-1996), as well as other pertinent literature.
Clinical efficacy trials discussed were limited to multicenter, double-blind, parallel group, prospective studies, where possible.
Lansoprazole inhibits gastric acid secretion via inhibition of gastric hydrogen/potassium adenosine triphosphatase (H+,K(+)-ATPase), an enzyme of the gastric parietal cell membrane that forms part of the proton pump that performs the final step in the acid secretory process. Lansoprazole binds covalently to parietal cell H+,K(+)-ATPase, rendering it nonfunctional and inhibiting the secretion of gastric acid. In clinical trials, lansoprazole has been shown to be more effective than placebo and standard doses of histamine (H)2-receptor antagonists and as effective as standard doses of omeprazole for the treatment of peptic ulcer disease, gastroesophageal reflux, Zollinger-Ellison syndrome, and nonsteroidal antiinflammatory drug-induced lesions.
Lansoprazole is safe and effective for the treatment of acid-related disorders. It is more effective than the H2-receptor antagonists and comparable to omeprazole for these indications. The choice between lansoprazole and omeprazole is likely to be institution-specific and pharmacoeconomic.
Annals of Pharmacotherapy 01/1997; 30(12):1425-36. · 2.13 Impact Factor
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W R Garnett
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ABSTRACT: Adverse GI effects of NSAIDs include dyspepsia, occult bleeding, overt bleeding and ulcer disease. Consequences of NSAID-induced GI toxicity include anemia, hospitalization, and death. External factors, such as drugs and alcohol, can disrupt the gastric barrier that protects the GI tract from erosive substances. Pharmacists should counsel patients who frequently use non-prescription analgesics and determine whether further medical evaluation is needed. In contrast to NSAIDs, acetaminophen has not been associated with GI toxicity of increased risk of GI tract bleeding.
Journal of the American Pharmaceutical Association 10/1996; NS36(9):565-72.
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W R Garnett
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ABSTRACT: Fluvastatin, the newest member of the class of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, is structurally different from the fungal metabolites (lovastatin, pravastatin, and simvastatin) and is wholly synthetic. Fluvastatin has a distinct biopharmaceutical profile, including a short systemic exposure time (half-life of 1.2 hours) and virtually no active circulating metabolites. Fluvastatin is targeted to the liver, where it is rapidly metabolized; 98% of fluvastatin is protein bound. Double-blind, placebo-controlled studies have demonstrated that fluvastatin at daily dosages of 20-40 mg produces significant decreases from baseline in low-density lipoprotein (LDL) cholesterol on the order of 22-31% in patients with severe primary hypercholesterolemia (mean baseline LDL cholesterol 227 mg/dL) and decreases of 19-25% in patients with familial hypercholesterolemia (mean baseline LDL cholesterol 270 mg/dL). Interim results of a titrate-to-goal, 20-week study in patients with moderate hypercholesterolemia (LDL cholesterol >= 160 mg/dL and triglycerides <= 350 mg/dL) demonstrate that fluvastatin, 20 mg/day, lowers LDL cholesterol by 21% within 6 weeks. Long-term results indicate that the lipid-lowering effects of fluvastatin are sustained for 96 weeks. Further, 1 study has shown that the combination of low-dose fluvastatin plus niacin decreased LDL cholesterol levels 40% without untoward adverse events, suggesting that this combination is effective and safe for patients needing intensive lipid-lowering therapy. Asymptomatic, reversible increases in hepatic transaminase levels occur in fluvastatin-treated patients at a frequency comparable to that reported for other HMG-CoA reductase inhibitors. The 20-30% reduction in LDL cholesterol required by the majority of patients with hypercholesterolemia can be achieved with fluvastatin at 20 or 40 mg/day as well as with the other available HMG-CoA reductase inhibitors at their most commonly prescribed doses. Fluvastatin, priced 40% lower than other statins, provides the most cost-effective means of safely achieving goal LDL cholesterol levels in these patients.
The American Journal of Cardiology 10/1996; 78(6A):20-5. · 3.37 Impact Factor
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ABSTRACT: Safety, tolerability, and pharmacokinetics of fosphenytoin sodium, a water-soluble phenytoin prodrug, were investigated after a temporary substitution of intramuscular fosphenytoin for oral phenytoin sodium in 240 epileptic or neurosurgical patients taking oral phenytoin sodium (100-500 mg/d).
Patients were randomly assigned to 1 of 2 parallel groups. During screening and follow-up, patients were maintained on a regimen of oral phenytoin at an individualized dose. During treatment, the phenytoin-treated patients received intramuscular placebo and their prescribed dose of oral phenytoin; the fosphenytoin-treated patients received oral placebo and intramuscular fosphenytoin equimolar to their phenytoin dose.
Both groups had similar types and frequencies of mild to moderate adverse events. Fosphenytoin was as well tolerated as intramuscular placebo at the injection site. Intramuscular fosphenytoin equimolar to a patient's oral phenytoin dose produced equal or greater plasma phenytoin concentrations.
Dosing adjustments are not required when intramuscular fosphenytoin is temporarily substituted or oral phenytoin therapy is resumed. Intramuscular fosphenytoin is a safe and well-tolerated alternative to oral phenytoin when oral administration is not feasible.
Archives of Neurology 09/1996; 53(8):764-8. · 7.58 Impact Factor
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W R Garnett
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ABSTRACT: Drug-drug, drug-food, and drug-disease interactions involving hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are reviewed. The four available HMG-CoA reductase inhibitors-lovastatin, simvastatin, pravastatin, and fluvastatin-have different potentials for drug interactions, probably because of their different pharmacokinetic characteristics. Interactions of some of these cholesterol-lowering agents with cyclosporine, erythromycin, high-dose niacin, or gemfibrozil may produce myopathy with or without rhabdomyolysis. Interactions with other commonly prescribed agents, such as bile acid sequestrants, coumarin anticoagulants, and cardiovascular drugs, may alter the pharmacokinetics of either drug, but the clinical significance is generally minor. Food may affect plasma lovastatin concentrations, systemic pravastatin bioavailability, and the maximum serum concentration (Cmax) and time to achieve Cmax for fluvastatin. Hepatic dysfunction may influence the pharmacokinetics of pravastatin; all HMG-CoA reductase inhibitors are contraindicated in patients with liver disease or unexplained elevations in serum aminotransferases. Severe renal insufficiency may necessitate dosage modification in lovastatin recipients. Renal dysfunction seems to affect the pharmacokinetics of pravastatin, simvastatin, and fluvastatin only minimally, but caution is still warranted. Although the HMG-CoA reductase inhibitors rarely have severe adverse effects, they may interact, in some cases dangerously, with other drugs, with food, and with disease states.
American Journal of Health-System Pharmacy 09/1995; 52(15):1639-45. · 1.96 Impact Factor
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W R Garnett
American Journal of Health-System Pharmacy 02/1995; 52(1):88-91. · 1.96 Impact Factor
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ABSTRACT: A double-blind, randomized, crossover study assessed the effects of a single 40-mg dose of fluvastatin on the steady-state pharmacokinetics of digoxin in chronically treated patients. After demonstrating consistent digoxin serum concentrations as part of the inclusion criteria, 18 patients received a single dose of either fluvastatin or placebo, with a 1-week washout period between crossover to the other treatment. For each patient, 14 serum samples were drawn and urine collected over 24 hours; all samples were assayed for digoxin using a fluorescence polarization immunoassay. The following pharmacokinetic parameters were determined using noncompartmental techniques: area under the curve for 24 hours (AUC24); time to maximum concentration after digoxin (tmax); maximum concentration after digoxin dosing (Cmax); concentration at 24 hours after fluvastatin or placebo (Cmin); total amount excreted in the urine over 24 hours (U24); and urinary clearance (Clren). The pharmacokinetic data were analyzed for sequence, patient nested with sequence, and period and treatment differences using ANOVA, Schuirmann's two one-sided testing approach, confidence intervals, and power analysis. The AUC24, Cmax, and tmax for digoxin were considered bioequivalent with the two treatments. The differences in Cmax, U24, and Clren were statistically significant but were not considered to be clinically relevant due to the low magnitude of the difference (< 20%). There were no clinically significant adverse reactions attributable to either digoxin or fluvastatin.
The American Journal of Medicine 06/1994; 96(6A):84S-86S. · 5.43 Impact Factor
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W R Garnett
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ABSTRACT: The phases of therapy for gastroesophageal reflux disease (GERD) and the efficacy, safety, and cost of the various drugs used are discussed. The therapeutic goals for patients with GERD are to relieve pain, promote healing, avoid complications, and prevent recurrence. Sustained inhibition of gastric acid secretion is necessary to facilitate healing of eroded esophageal mucosa. Phase 1 treatment involves lifestyle changes to remove factors that may help to precipitate reflux, such as overeating, alcohol, and tobacco. Phase 2 involves pharmacologic manipulation of the secretion, concentration, and transport of gastric acid. The drugs used are antacids, alginic acid, the histamine H2-receptor antagonists, the prokinetic agents, sucralfate, and omeprazole. While all of these agents may provide symptomatic relief, only the H2 antagonists and omeprazole have been convincingly shown to relieve symptoms and promote healing. The H2 antagonists differ in potency, pharmacodynamic effect, pharmacokinetics in certain patient groups, drug interactions, and adverse effects. The H2 antagonists may not be effective at standard dosages in patients who secrete especially large quantities of gastric acid. Because of its mechanism of action, omeprazole provides greater inhibition of gastric acid than any other antisecretory drug. Omeprazole may also be the most cost-effective treatment. The availability of omeprazole may reduce the number of patients for whom clinicians must resort to phase 3 treatment, surgery. Although many drugs provide symptomatic relief in patients with GERD, the healing that is necessary to break the cycle of damage and symptoms is promoted only by the H2 antagonists and omeprazole.
American journal of hospital pharmacy 05/1993; 50(4 Suppl 1):S11-8.
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ABSTRACT: General principles of antiepileptic drug (AED) therapy are reviewed, current issues involving the use and monitoring of AEDs are examined, promising investigational agents are briefly reviewed, and situations that require potentially difficult decisions about long-term care are discussed. The initial treatment should be monotherapy with a first-line AED for the particular seizure disorder. The usual approach is to maximize seizure control and minimize the adverse effects of AED therapy. Current issues involving the pharmacokinetics, use, and monitoring of the conventional AEDs phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, ethosuximide, benzodiazepines, and acetazolamide are discussed. AED therapy may have adverse effects on behavior and cognition. The risk of teratogenicity with well-monitored AED therapy is probably low, and severe hepatotoxicity is uncommon. Because carbamazepine, phenobarbital, phenytoin, and primidone all have enzyme induction properties, a number of clinically important interactions are possible. Issues related to discontinuing AED therapy, serum concentration monitoring, and generic interchange of AED products are addressed. Whether AEDs should be used to prevent recurrent febrile seizures, alcohol withdrawal seizures, or seizures in patients with head trauma or stroke must be considered. The treatment of seizure disorders is a complex process involving identification of the seizure disorder, selection and monitoring of an appropriate AED(s), and consideration of adverse effects and drug interactions. Whether therapy should be discontinued after a prolonged seizure-free period, compliance issues, and whether to treat certain conditions prophylactically also must be considered.
Clinical pharmacy 06/1991; 10(5):335-58.
