Frequent Dosing Regimens Research Articles

Comparative Ocular Bioavailability and Efficacy of Topical Levofloxacin and Ofloxacin in Rabbits

Levofloxacin and ofloxacin are fluoroquinolone antibacterial agents with activity against a broad spectrum of Gram‐positive and Gram‐negative ocular pathogens. Levofloxacin is the pure S‐(−) isomer of ofloxacin, and is approximately twice as active as the R‐(+) isomer. Studies were conducted to measure the pharmacokinetics of levofloxacin and ofloxacin in the cornea and aqueous humor of the intact rabbit eye and also to determine the therapeutic efficacy of the two compounds for the treatment of experimental pseudomonas keratitis. A single ocular dose of 1.5% levofloxacin to intact rabbit eyes produced average maximum concentration (Cmax) values in both cornea and aqueous humor that were approximately five times greater than that of 0.3% ofloxacin. Furthermore, concentrations of levofloxacin in corneas were maintained above the minimum inhibitory concentration 90% (MIC90) for most ocular pathogens for more than 2 hours following a single topical dose. In a rabbit model of pseudomonas keratitis, dosing rabbits for 2 days with either 1.5% levofloxacin every 2 hours, or 0.3% ofloxacin every 30 minutes, resulted in the elimination of viable pseudomonas organisms from all treated rabbits. The results of these bioavailability and efficacy studies support the concept that a less frequent dosing regimen with 1.5% levofloxacin ophthalmic solution (every 2 hours) will be as effective as dosing 0.3% ofloxacin every 30 minutes for treatment of bacterial keratitis.

Efficacy and Safety of Oral Weekly Ibandronate in the Treatment of Postmenopausal Osteoporosis

Adherence to oral daily bisphosphonate regimens in postmenopausal osteoporosis is currently suboptimal. Less frequent dosing regimens are likely to improve patient adherence and thus, potentially, patient outcomes. A multicenter, randomized, double-blind, noninferiority study was conducted in 235 women (53-80 yr old; time since menopause >/==" BORDER="0"> 3 yr) with postmenopausal osteoporosis [lumbar spine (L1-L4) bone mineral density (BMD) T-score </= -2] to demonstrate the noninferiority of an oral weekly (20 mg) ibandronate regimen compared with an oral daily (2.5 mg) ibandronate regimen. All patients received daily calcium (500 mg) and vitamin D (400 IU). The primary analysis was the relative change in lumbar spine (L1-L4) BMD from baseline after 48 wk in the per- protocol population. Daily and weekly ibandronate significantly increased spinal BMD by 3.47 and 3.53%, respectively, and provided substantial and similar decreases in biochemical markers of bone turnover. In the primary analysis, noninferiority of the weekly regimen to the daily regimen was demonstrated, with the boundary of the one-sided confidence interval, -0.96%, within both the -1.65% prespecified margin and a more stringent margin of -1.10%. These results demonstrate that oral weekly ibandronate provides the same efficacy and safety as oral daily ibandronate in women with postmenopausal osteoporosis.

Epoetin alfa as a supportive measure in hematologic malignancies

Anemia is prevalent among cancer patients with hematologic malignancies, with fatigue and weakness, major symptoms of anemia, contributing to diminished quality of life (QOL). Data from several randomized, placebo-controlled clinical trials and three large community-based studies in patients with hematologic malignancies indicate that recombinant human erythropoietin (r-HuEPO, epoetin alfa) can correct anemia, reduce transfusion requirements, and improve QOL. Moreover, a positive relationship has been found between increased hemoglobin (Hb) levels and improvements in QOL assessments, regardless of disease state, with the greatest incremental improvement occurring when Hb increases from 11 g/dL to 12 g/dL (range, 11 to 13 g/dL). This suggests that patients with mild-to-moderate anemia may achieve the greatest QOL benefit from epoetin alfa therapy. Evidence from community-based studies suggests that epoetin alfa administered once weekly has a similar safety and efficacy profile as three-times-weekly administration. Further research is ongoing with less frequent dosing regimens. The beneficial effects of epoetin alfa therapy have been reported in studies involving patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. Evidence also exists that epoetin alfa can benefit patients with myelodysplastic syndromes (MDS), although these results have not been as impressive. Combining epoetin alfa with other cytokine growth factors may confer some additional benefit in these patients, but more rigorous investigation is required. Semin Hematol 39(suppl 3):25-31. Copyright 2002, Elsevier Science (USA). All rights reserved.

A systematic review of the associations between dose regimens and medication compliance

Background: Previous reviews of the literature on medication compliance have confirmed the inverse relationship between number of daily doses and rate of compliance. However, compliance in most of these studies was based on patient self-report, blood-level monitoring, prescription refills, or pill count data, none of which are as accurate as electronic monitoring (EM). Objective: In this paper, we review studies in which compliance was measured with an EM device to determine the associations between dose frequency and medication compliance. Methods: Articles included in this review were identified through literature searches of MEDLINE ®, PsychInfo ®, HealthStar, Health & Psychosocial Instruments, and the Cochrane Library using the search terms patient compliance, patient adherence, electronic monitoring, and MEMS (medication event monitoring systems). The review was limited to studies reporting compliance measured by EM devices, the most accurate compliance assessment method to date. Because EM was introduced only in 1986, the literature search was restricted to the years 1986 to 2000. In the identified studies, data were pooled to calculate mean compliance with once-daily, twice-daily, 3-times-daily, and 4-times-daily dosing regimens. Because of heterogeneity in definitions of compliance, 2 major categories of compliance rates were defined: dose-taking (taking the prescribed number of pills each day) and dose-timing (taking pills within the prescribed time frame). Results: A total of 76 studies were identified. Mean dose-taking compliance was 71% ± 17% (range, 34%–97%) and declined as the number of daily doses increased: 1 dose = 79% ± 14%, 2 doses = 69% ± 15%, 3 doses = 65% ± 16%, 4 doses = 51% ± 20% ( P < 0.001 among dose schedules). Compliance was significantly higher for once-daily versus 3-times-daily ( P = 0.008), once-daily versus 4-times-daily ( P < 0.001), and twice-daily versus 4-times-daily regimens ( P = 0.001); however, there were no significant differences in compliance between once-daily and twice-daily regimens or between twice-daily and 3-times-daily regimens. In the subset of 14 studies that reported dose-timing results, mean dose-timing compliance was 59% ± 24%; more frequent dosing was associated with lower compliance rates. Conclusions: A review of studies that measured compliance using EM confirmed that the prescribed number of doses per day is inversely related to compliance. Simpler, less frequent dosing regimens resulted in better compliance across a variety of therapeutic classes.

Efficacy and safety of dry powder fluticasone propionate in children with persistent asthma

Flovent Diskus is a powder formulation of the inhaled corticosteroid fluticasone propionate (FP) delivered via a breath-actuated, multidose inhaler. To determine the efficacy and safety of dry powder FP administered once or twice daily (200 microg per day) to children with persistent asthma. Twelve-week, randomized, double-blind, placebo-controlled, multicenter trial with a 52-week, open-label extension. Children aged 4 to 11 were required to have pulmonary function 50% to 85% of predicted values. The population was stratified for baseline therapy (inhaled corticosteroid/cromolyn or bronchodilators only). After a 2-week placebo run-in, 242 patients received dry powder FP 200 microg each morning, dry powder FP 100 microg BID, or placebo for 12 weeks; 192 were rerandomized to the QD or BID regimen for an additional 52 weeks of open-label treatment. Primary endpoints were mean changes in FEV1 and morning PEF recorded at clinic visits. Both dry powder FP regimens significantly improved FEV1, evening PEF, and asthma symptoms at the double-blind phase endpoint (P < or = .017 compared with placebo). The BID regimen also significantly improved morning PEF and nighttime awakenings due to asthma (P < or = .005). Among patients previously treated with inhaled corticosteroids/cromolyn, improvements observed with the QD and BID regimens were similar. Patients switched from BID to open-label QD treatment showed additional improvements at week 52 generally comparable to patients who received the BID regimen during both phases. Fluticasone propionate was well tolerated for up to 64 weeks with few reports of drug-related adverse events or morning plasma cortisol abnormalities. Once daily dosing of dry powder FP 200 microg is an effective and convenient alternative for children whose asthma is controlled with a more frequent dosing regimen of inhaled corticosteroids.

The impact of dosing frequency on the efficacy of 10-day penicillin or amoxicillin therapy for streptococcal tonsillopharyngitis: A meta-analysis.

The recommended dosing frequency of oral penicillin for the treatment of acute streptococcal tonsillopharyngitis has long been 3 to 4 times daily. In 1994, treatment guidelines included twice-daily (BID) dosing for the first time, a recommendation that could significantly increase the ease of compliance. This meta-analysis was performed to determine whether overall cure rates differed between BID or once-daily (QD) versus more frequent dosing schedules in the treatment of streptococcal tonsillopharyngitis. Candidate studies for this meta-analysis included all clinical trials of therapy for streptococcal tonsillopharyngitis published through August 1998 and identified using Medline, Dissertation Abstracts, conference proceedings, and bibliographies of all retrieved articles. A study was eligible for inclusion if it was a randomized clinical trial that compared the efficacies of different dosing frequencies of 10-day penicillin or amoxicillin in the treatment of streptococcal tonsillopharyngitis. Of the 30 articles initially identified, 6 studies met eligibility criteria. The measure of interest was the difference in proportion cured between the BID or QD dosing group and the comparison group with more frequent dosing. The results of this analysis suggest that BID dosing of 10-day penicillin is as efficacious as more frequent dosing regimens in the treatment of streptococcal tonsillopharyngitis. This result also holds true in a subgroup analysis confined to pediatric cases and does not vary with total daily dose of the regimen. QD dosing of penicillin is associated with a cure rate that is 12 percentage points lower than more frequent dosing (95% confidence interval: 3-21). In contrast, this decreased efficacy is not found with QD dosing of amoxicillin. This meta-analysis supports current recommendations for BID dosing of penicillin in treating streptococcal tonsillopharyngitis. QD penicillin is associated with decreased efficacy and should not be used. Simplified regimens of amoxicillin of shorter duration or of less frequent dosing should be further investigated.

Functional properties of regenerating skeletal muscle following LIF administration.

We tested the hypothesis that periodic systemic administration of the myogenic cytokine leukemia inhibitory factor (LIF) enhances the functional recovery of regenerating skeletal muscle following bupivacaine-induced degeneration. LIF had no effect on functional capacity or regenerating myofiber size in rat muscles at 7, 14, or 21 days post-injury. The results do not support exogenous administration of LIF as a treatment for acute muscle injury, but a more frequent dosing regimen should be tested.

Famciclovir (FAMVIR®)

Famciclovir is an antiviral with efficacy and safety comparable to aciclovir, but famciclovir's more favorable pharmacokinetic profile enables a less frequent dosing regimen. Future trials will likely determine famciclovir's role in the suppression of HBV.

Once‐Daily Dosing of Aminoglycosides

OBJECTIVE: To review the pharmacodynamic rationale for once‐daily dosing of aminoglycosides and to summarize thee results of comparative trials in animals and humans. DATA SOURCES: Published articles on the pharmacodynamics of aminoglycosides and those comparing the therapeutic efficacy and toxicity of once‐daily administration will more frequent closing regimens. DATA SELECTION: Fourteen randomized studies in infected patients that compared the efficacy and toxicity of once‐daily aminoglycoside dosing with twice‐ or thrice‐daily dosing regimens were available for review. Ten studies comparing the efficacy and toxicity of different an1inoglycoside dosing regimens in animal models were also reviewed . DATA EXTRACTION: Frequency of clinical response, nephrotoxicity and ototoxicity with each dosing regimen were compared graphically and by x2 for statistical significance (P&lt;0.05). DATA SYNTHESIS: Once‐daily dosing was consistently less toxic than more frequent dosing in animals. When human pharmacokinetics were simulated in animals, efficacy of once‐daily dosing was similar or enhanced over more frequent dosing regimens. Once‐daily dosing in patients, compared with twice‐ or thrice‐daily administration, was statistically more effective in two studies, less nephrotoxic in six studies, and less ototoxic in one study. Similar efficacy and toxicity were observed in all the oilier studies. CONCLUSIONS: Once‐daily dosing of aminoglycosides has the potential to enhance efficacy, reduce toxicity and lower administration costs for this drug class. The once‐daily dosing regimen deserves serious consideration for routine use of the aminoglycosides.

A Comparison of Cefpodoxime Proxetil and Cefaclor in the Treatment of Acute Exacerbation of COPD in Adults

In this multicenter, observer-blinded study, 301 patients with signs and symptoms of acute bacterial exacerbation of COPD were randomized (2:1) to receive either cefpodoxime proxetil (200 mg, bid) or cefaclor (250 mg, tid) for 10 days. Clinical and microbiologic evaluations were performed before treatment, during therapy (study days 3 to 5), at the end of therapy (3 to 7 days posttreatment), and at long-term follow-up (4 weeks posttreatment). The most common pretreatment isolates were Haemophilus influenzae, Haemophilus parainfluenzae, and Streptococcus pneumoniae. Significantly (p < 0.001) more bacterial isolates were susceptible in vitro to cefpodoxime (233 of 256, 91 percent) than to cefaclor (215 of 255, 84 percent). There were no statistically significant differences between the two drug regimens in eradication of the initial pathogen (cefpodoxime, 116 of 128, 91 percent; cefaclor, 59 of 64, 92 percent) or end-of-therapy clinical response (cure + proved; cefpodoxime, 99 of 100, 99 percent; cefaclor, 45 of 49, 92 percent) rates for evaluable patients. Both drug treatments were well-tolerated, with a similar incidence of drug-related adverse events (cefpodoxime 11 percent, cefaclor 12 percent). Cefpodoxime (bid) was as safe and effective as cefaclor (tid) in the treatment of acute exacerbation of COPD. The less frequent dosing regimen of cefpodoxime may improve patient compliance compared to those antibiotics that require three or four daily doses.

Glyceryl trinitrate (nitroglycerin) and the organic nitrates. Choosing the method of administration.

Nitrate usage worldwide is on the increase as the indications for therapy expand. Present indications for nitrate therapy include chronic stable angina pectoris, unstable angina pectoris, complications of acute myocardial infarction, and 'unloading' therapy for acute and chronic congestive heart failure. Nitrates are also being used in the operating suite by anaesthesiologists to control systolic blood pressure during various surgical procedures. New nitrate delivery systems have recently become available which provide considerable dosing flexibility, further increasing the interest in this group of compounds. The dominant action of nitrates is a direct effect on vascular smooth muscle, producing vasodilation of the veins and arteries. These drugs decrease myocardial work by lowering systolic blood pressure, systemic vascular resistance, and reducing intracardiac dimensions. In addition, nitrates have a potent effect on cardiac preload as a result of systemic venodilatation. There is also some evidence that nitrates exert direct effects on the coronary circulation (vasodilatation of coronary arteries and coronary collateral vessels, and direct atherosclerotic stenosis dilatation). These actions may play a role in relieving myocardial ischaemia. Adverse sequelae of nitrate therapy are well known and serious adverse reactions are uncommon. Headache and dizziness are the most frequent side effects. Nitrate tolerance is a definite problem - present evidence indicates that long acting formulations, high doses, or frequent dosing regimens are particularly likely to induce vascular tolerance to nitrates. Consequently, provision of a nitrate-free interval has taken on increasing significance as a strategy to avoid tolerance. Nitrate delivery systems are numerous. Although availability varies from country to country, in most countries there are a wide variety of formulations of glyceryl trinitrate (nitroglycerin) available, including sublingual and oral tablets, oral spray, topical ointment as well as discs or patches for transdermal administration, a transmucosal tablet and an intravenous formulation. Similar formulations of isosorbide dinitrate, except buccal tablets, are available in some countries. Isosorbide 5-mononitrate, a potent metabolite of isosorbide dinitrate, is achieving increasing popularity as an antianginal drug. Optimum nitrate therapy requires a good understanding of the properties of the various formulations, particularly onset and duration of action and propensity to induce tolerance.(ABSTRACT TRUNCATED AT 400 WORDS)