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Biomedical subjects

M LeBel

Publications and source records attributed to M LeBel.

At least 19 recordsLinked to original sources
PubMed2000

Who needs individual bioequivalence studies for narrow therapeutic index drugs? A case for warfarin.

Warfarin is, among drugs, considered to have a narrow therapeutic index for which individual bioequivalence has been suggested. To establish the propriety of "switching," an individual bioequivalence study involving a replicate-design study and three "switchings" in healthy subjects was undertaken using the U.S.-brand warfarin sodium tablet and a generic product. A randomized, single-center, open-label, single-dose, four-way crossover replicate bioequivalence study was performed in 24 healthy male volunteers in which each subject received the same 5 mg warfarin test and reference tablets twice on different occasions under fasting conditions. Concentrations of warfarin in plasma were measured by a validated specific HPLC method. The individual pharmacokinetic parameters obtained with test and reference products were compared using pooled data and Liu's method. Bioequivalence was shown with both average and individual bioequivalence methods. The individual bioequivalence assessment did not show a subject-by-formulation interaction, nor did it add value to the bioequivalence assessment of warfarin.

Adolescent↗
PubMed1999

A multiple-dose safety and bioequivalence study of a narrow therapeutic index drug: a case for carbamazepine.

BACKGROUND AND OBJECTIVES: Carbamazepine is among those drugs that have been considered to have a narrow therapeutic plasma concentration range, that is, a narrow therapeutic index. Although the US Food and Drug Administration has approved new generic products based on standard single-dose bioequivalence studies, several state formularies, including the New Jersey Drug Utilization Review Council, have recently established additional criteria for acceptance of bioequivalence of narrow therapeutic index drugs, limiting the use of some approved generic drugs in specific states. To further validate the adequacy of single-dose studies for the determination of bioequivalence of narrow therapeutic index drugs, a multiple-dose study was conducted that more closely reflected therapeutic use. METHODS: A single-center, multiple-dose, randomized, open-label, 2-way crossover bioequivalence study was conducted in 32 fasting volunteers at steady state. Subjects received the test and reference products as a 200 mg carbamazepine tablet 3 times a day in a crossover fashion. Concentrations of carbamazepine and carbamazepine-10,11-epoxide in plasma were measured by a validated specific HPLC method. RESULTS: A total of 28 subjects completed the study. Pharmacokinetic parameters and measures of fluctuation for both products at steady state were similar, with 90% and 95% confidence intervals falling within 90% and 110%. CONCLUSION: The multiple-dose study provided reliable safety and bioequivalence data under rigorous statistical conditions and confirmed bioequivalence of test and reference products determined by a single-dose study.

Adult↗
PubMed1998

Effects of rifabutin and rifampicin on the pharmacokinetics of ethinylestradiol and norethindrone.

This open-label, randomized, three-way crossover study of 28 healthy premenopausal women was conducted to compare the impact of concomitant rifabutin and rifampicin on the safety, pharmacokinetics, and pharmacodynamics of the oral contraceptives ethinylestradiol and norethindrone (Ortho-Novum 1/35; Ortho Pharmaceutical, Raritan, NJ). Each participant received oral contraceptives daily for 21 days for the first control cycle, then was randomized to one of two sequences to receive oral contraceptives with concomitant rifampicin and rifabutin at equal doses of 300 mg/day for 10 days. Ethinylestradiol, norethindrone, follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, rifampicin, and rifabutin (and metabolite) were measured in plasma over the same time frames in all three cycles. Safety was assessed from before the beginning to the end of each cycle. Twenty-two subjects completed all three cycles. Compared with the control cycle, rifabutin and rifampicin significantly altered the disposition of the oral contraceptive. Area under the concentration-time curve from 0 to 24 hours (AUC0-24) and maximum plasma concentration (Cmax) of ethinylestradiol decreased by 64% and 42%, respectively, after coadministration with rifampicin and by 35% and 20%, respectively, after coadministration with rifabutin. The AUC0-24 of norethindrone decreased by 60% and 20% after coadministration with rifampicin and rifabutin, respectively. Unlike progesterone levels, FSH and LH levels increased during coadministration with rifampicin and rifabutin. The incidence of spotting was significantly higher after coadministration with rifampicin (36.4%) and rifabutin (21.7%) than during the control cycle (3.7%). Although both rifampicin and rifabutin affected the pharmacokinetics of ethinylestradiol and norethindrone, the magnitude of this effect was more pronounced with rifampicin. Likewise, the fact that the highest incidence of spotting occurred with rifampicin was consistent with higher metabolic induction by rifampicin. Despite the fact that there was no change in progesterone levels, it is recommended that patients be advised to use additional contraceptive methods while receiving rifabutin or rifampicin with oral contraceptives to prevent inadvertent pregnancy.

Adolescent↗
PubMed1996

The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin.

BACKGROUND: Substrates and inhibitors of the cytochrome P450 isozyme CYP2D6 have overlapping structural characteristics. Two prototype serotonin uptake inhibitors, sertraline and fluoxetine, share these structural criteria and have been identified as potent inhibitors of CYP2D6 in vitro. The current study was undertaken to investigate whether genetically determined CYP2D6 activity alters the disposition of sertraline or fluoxetine or both. METHODS: Single doses of sertraline (50 mg) and fluoxetine (20 mg) were administered successively to 20 young men with high (extensive metabolizers; n = 10) and low (poor metabolizers; n = 10) CYP2D6 activity. Blood and urine samples were collected for 5 to 7 half-lives and sertraline, desmethylsertraline, fluoxetine, and norfluoxetine were determined by GC and HPLC techniques. RESULTS: Poor metabolizers had significantly greater fluoxetine peak plasma concentrations (Cmax; increases 57%), area under the concentration versus time curve (AUCzero-->infinity; increases 290%), and terminal elimination half-life (increases 216%) compared with extensive metabolizers. The total amount of fluoxetine excreted in the urine during 8 days was almost three times higher in poor metabolizers than in extensive metabolizers (719 versus 225 micrograms; p < 0.05), whereas the total amount of norfluoxetine excreted in urine of poor metabolizers was about half of that of extensive metabolizers (524 versus 1047 micrograms; p < 0.05). Norfluoxetine Cmax and AUCzero-->t were significantly smaller in poor metabolizers (decreases 55% and decreases 53%, respectively), and the partial metabolic clearance of fluoxetine into norfluoxetine was 10 times smaller in this group (4.3 +/- 1.9 versus 0.4 +/- 0.1 L/hr; p < 0.05). No significant differences between extensive and poor metabolizers were found for sertraline and desmethylsertraline pharmacokinetics. CONCLUSION: These data indicate that poor metabolizers accumulate fluoxetine but not sertraline and that CYP2D6 plays an important role in the demethylation of fluoxetine but not of sertraline.

1-Naphthylamine↗
PubMed1995

Suction-induced blister fluid penetration of cefdinir in healthy volunteers following ascending oral doses.

The pharmacokinetics and suction-induced blister fluid penetration of cefdinir following single oral administrations of 200, 300, 400, and 600 mg were studied in 16 healthy young male volunteers according to a Latin square design. Plasma, blister, and urine samples were assayed by high-pressure liquid chromatography. We observed a nonlinear relationship (P = 0.02) between the dose and the maximum concentration in plasma as well as between the dose and the area under the concentration-time curve (AUC) in plasma (P < 0.001), which may be indicative of a limited absorption process. This resulted in a lower AUC value than expected as well as a smaller fraction of cefdinir excreted unchanged at a dose of 600 mg. Renal clearance decreased with increasing doses (P < 0.006; analysis of variance with the Latin square design and Games-Howell procedure). Maximal cefdinir concentrations in blister fluid were delayed compared with concentrations in plasma. Blister fluid penetration measured by the ratio of the AUC in blister fluid to the AUC in plasma was extensive (92.4 to 108.4%). Cefdinir concentrations in blister fluid remained equal to or higher than the concentrations in plasma from 6 to 12 h following cefdinir administration. On the basis of the concentrations in blister fluid and the in vitro MIC data, we estimated that cefdinir at 200 to 400 mg administered twice daily would be adequate to treat uncomplicated skin infections caused by Streptococcus pyogenes. Seven volunteers experienced episodes of light-to-moderate diarrhea. These adverse events occurred irrespective of dose.

Adult↗
PubMed1995

Self-measurement of blood pressure: benefits, risks and interpretation of readings. The Canadian Coalition for High Blood Pressure Prevention and Control.

The literature on the benefits and risks of self-measurement of blood pressure and interpretation of the readings was reviewed. Self-measurement of blood pressure is useful in selected patients with high blood pressure, can be used to monitor blood pressure closely outside health care facilities, and can determine whether patients have white coat hypertension. The involvement of patients in their own blood pressure management is increased and self measurement may result in more rapid achievement of target blood pressure readings, improvement in adherence to antihypertensive therapy and decreased health care utilization. However, some patients may not be suited to monitor their own blood pressure and some may experience an increase in anxiety regarding their health. With careful training and selection of patients, most can accurately assess their blood pressure. Self-measured readings are generally lower than readings in a physician's clinic (or office) and this must be accounted for in assessing response to therapy and usual levels of blood pressure. Self-measured readings are a valuable supplement to clinic readings in many patients.

Anxiety↗
PubMed1995

Self-measurement of blood pressure: recommendations of the Canadian Coalition for High Blood Pressure Prevention and Control.

OBJECTIVE: To provide health care professionals with guidelines on the use of blood pressure self-measurement. METHODS: Recommendations were devised after consideration of expert reviews and guidelines, personal files, international standards documents, personal communication with investigators and the results of a MEDLINE search (1966-94) using the term 'blood pressure determination'. BENEFITS, HARMS, COSTS: Self-measurement of blood pressure can be used to detect white coat hypertension, monitor changes in blood pressure closely, more rapidly achieve desired blood pressure goals, increase adherence to antihypertensive therapy and improve patient self-reliance. However, self-measured blood pressure readings may be misleading because there is insufficient normative, prognostic and outcome data and because some patients may not take accurate measurements. The use of self-measurement of blood pressure has a relatively small direct cost and may result in an overall reduction in treatment costs. RECOMMENDATIONS: Self-measured blood pressure readings can be a valuable supplement to clinic (or office) blood pressure readings. However, self-measurement is appropriate neither for patients who are physically or mentally incapable of accurate assessment and interpretation of readings nor for those who do not want to participate. Patients who self-monitor blood pressure require careful training in blood pressure measurement and instruction on the recording and interpretation of blood pressure readings. Advice to patients using monitoring equipment must take into account the needs and abilities of the patient. Although only a few electronic devices for the self-measurement of blood pressure have met recommended performance standards, their use may be more appropriate for some patients and the training requirements fewer than if manual devices are used. VALIDATION: The guidelines of several expert groups were examined in the preparation of these recommendations. The recommendations were presented at the World Conference on Hypertension Control in 1995 and were reviewed by the parent societies of the Canadian Coalition for High Blood Pressure Prevention and Control.

Blood Pressure Determination↗
PubMed1994

Optimizing sedation following major vascular surgery: a double-blind study of midazolam administered by continuous infusion.

A randomized, double-blind study was undertaken to determine the dose requirements, recovery characteristics, and pharmacokinetic variables of midazolam given by continuous infusion for sedation in patients following abdominal aortic surgery. Thirty subjects, 50-75 yr, scheduled to undergo aortic reconstructive surgery, entered the study. Following a nitrous oxide-isoflurane-opioid anaesthetic technique, patients were randomly allocated to receive one of three loading doses (0.03, 0.06 or 0.1 mg.kg-1) and initial infusion rates (0.5, 1.0 or 1.5 micrograms.kg-1.min-1) of midazolam, corresponding to groups low (L), moderate (M) and high (H). The infusion of midazolam was adjusted to maintain sedation levels of "3, 4 or 5," which permitted eye opening in response to either verbal command or a light shoulder tap, using a seven-point scale ranging from "0" (awake, agitated) to "6" (asleep, non-responsive). Additionally morphine was given in increments of 2.0 mg iv prn for analgesia. On the morning after surgery, midazolam was discontinued, and the tracheas were extubated when patients were awake. Blood samples were taken during, and at increasing intervals for 48 hr following discontinuation of the infusion, and analyzed by gas chromatography. The desired level of sedation was maintained during more than 94% of the infusion period in all three groups, with a maximum of three dose adjustments per patient, for treatment which lasted 16.3 +/- 0.6 hr. There was, however, an increase in both the infusion rates and mean plasma concentrations from Group L to Group H (P < 0.05), which corresponded to an inverse relationship of morphine requirements during the period of sedation (P < 0.05, Group H vs Group L). Optimal midazolam infusion rates and resulting plasma concentrations at the times the infusions were discontinued (in parentheses) were as follows-Group L: 0.60 +/- 0.18 microgram.kg-1.min-1 (76 +/- 32 ng.mL-1), Group M: 0.90 +/- 0.52 microgram.kg-1.min-1 (133 +/- 71 ng.mL-1), and Group H: 1.34 +/- 0.69 microgram.kg-1.min-1 (206 +/- 106 ng.mL-1). Times to awakening were longer in Group H: 3.1 +/- 3.4 hr, than in Group L: 1.1 +/- 0.8 h, P < 0.05. Pharmacokinetic variables were found to be dose-independent over the range of infusion rates. Mean values were t1/2 beta = 4.4 +/- 1.5 hr, CL = 5.94 +/- 1.69 mL.min-1.kg-1, Vd = 3.13 +/- 1.07 L.kg-1.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1994

Caffeine metabolism in cystic fibrosis: enhanced xanthine oxidase activity.

STUDY OBJECTIVE: To characterize the activities of the P450 mixed-function oxidase CYP1A2 as well as the cytosolic enzymes N-acetyltransferase and xanthine oxidase using caffeine as a probe in children with cystic fibrosis compared to age-matched healthy control subjects. METHODS: After administration of caffeine (cola beverage) to 12 children with cystic fibrosis (age range, 5 to 11 years) and 12 healthy control subjects (age range, 5 to 12 years), urine was collected for 4 hours. Caffeine metabolites were determined by HPLC, and urinary caffeine metabolite ratios were computed to determine liver enzyme activities. In addition, a blood sample was used to detect cystic fibrosis mutant alleles by polymerase chain reaction. RESULTS: The indexes for CYP1A2, N-acetyltransferase, and 8-hydroxylation were similar in both groups of subjects. In contrast, there was a significant difference in the frequency distribution of the xanthine oxidase activity between the two groups. Nine of 12 patients with cystic fibrosis but only one of 12 healthy volunteers had xanthine oxidase activities above 0.42 (Kolmogorov-Smirnov two-sample test, p < 0.01). CONCLUSIONS: Differences in xanthine oxidase may have clinical implications with regard to interindividual variation in xenobiotic biotransformation and the exposure to lung tissue-damaging oxygen radicals. Hepatic enzyme activities appear to be selectively altered in patients with cystic fibrosis.

Alleles↗
PubMed1993

Intravenous ciprofloxacin disposition in obesity.

The pharmacokinetics of ciprofloxacin and its metabolite 1 (desethyleneciprofloxacin) were studied in 17 obese men (mean age, 29.2 +/- 7.5 years; mean weight, 110.7 +/- 20.2 kg; mean body mass index, 36.4 +/- 3.9 kg/m2) and 11 control subjects (men of normal weight; mean age, 25.0 +/- 5.1 years; mean weight, 71.8 +/- 9.9 kg; mean body mass index, 23.3 +/- 2.4 kg/m2). Each subject received a single 400 mg intravenous dose of ciprofloxacin infused over 1 hour. Ciprofloxacin total clearance was significantly increased in obese subjects compared with control subjects (897.44 +/- 159.57 versus 744.44 +/- 120.51 ml/min, respectively; p < 0.05). Ciprofloxacin renal clearance in obese subjects (637.58 +/- 128.89 ml/min) was 29% higher than in control subjects (495.47 +/- 137.85 ml/min; p < 0.05). The elimination half-life values of ciprofloxacin and desethyleneciprofloxacin were not statistically different between groups. Ciprofloxacin steady-state volume of distribution (Vss) was significantly larger in obese group (269.17 +/- 51.64 versus 219.03 +/- 35.80 L; p < 0.01) compared with the control group, and when it was normalized by total body weight, obese subjects exhibited lower Vss/kg than control subjects (2.46 +/- 0.42 versus 3.06 +/- 0.31 L/kg; p < 0.001). These findings indicate that ciprofloxacin is distributed less to adipose tissue than to other tissues, but partial distribution to adipose tissue does occur. To normalize the volume of distribution of obese subjects to that of normal weight subjects, 45% of excess weight (total body weight minus ideal body weight) must be added to the ideal body weights of obese subjects.

Adult↗
PubMed1993

Stability of famotidine in polyvinyl chloride minibags and polypropylene syringes and compatibility of famotidine with selected drugs.

OBJECTIVE: (1) to determine the stability of famotidine 200 micrograms/mL in admixtures with dextrose 5% injection (D5W) and NaCl 0.9% injection (NS) in polyvinyl chloride (PVC) minibags and polypropylene syringes, at room temperature (22 degrees C), protected and unprotected from light for 15 days; and (2) to evaluate the visual compatibility of famotidine with 34 selected drugs for four hours at room temperature. DESIGN: Concentration of famotidine samples was determined on day 0 and again on days 3, 6, 9, 12, and 15 by a stability-indicating HPLC. Inspection for visual and pH changes was also performed at these time intervals. RESULTS: More than 95 percent of the day 0 famotidine concentration remained in all samples over the 15-day study period. During this period, all samples remained clear and colorless and no change in absorbance at 450 and 540 nm was observed. The pH of the samples also remained unchanged. Famotidine 2000 micrograms/mL was found to be compatible with 33 selected drugs; only furosemide was found to be incompatible. A white precipitate was observed when an equal volume of famotidine 2000 micrograms/mL in NS was mixed with furosemide 3000 micrograms/mL in D5W. The concentration of famotidine in the supernatant gradually decreased during the 4-hour study period. At 0.5, 1.0, 2.0, and 4.0 hours after mixture of famotidine with furosemide, famotidine concentrations were 97.5, 23.6, 21.7, and 17.2 percent of the initial famotidine concentration, respectively. CONCLUSIONS: Our results show that famotidine 200 micrograms/mL was stable in admixture with D5W and NS in PVC minibags and polypropylene syringes when these solutions were stored at room temperature, protected and unprotected from light for 15 days. Famotidine 2000 micrograms/mL in NS was compatible with 33 of the drugs, and was incompatible with furosemide.

Analysis of Variance↗
PubMed1992

Comparative study of pharmacokinetics and serum bactericidal activities of cefpirome, ceftazidime, ceftriaxone, imipenem, and ciprofloxacin.

We compared the pharmacokinetics and the serum bactericidal activities of cefpirome, ceftazidime, ceftriaxone, imipenem, and ciprofloxacin. Fifteen healthy volunteers received 1 g of cefpirome, ceftazidime, and ceftriaxone intravenously, 500 mg of imipenem-cilastatin intravenously, and 500 mg of ciprofloxacin orally. High-performance liquid chromatographic assays were used to quantitate unchanged antibiotic in plasma and urine. Serum bactericidal activities were determined against six clinical isolates each of Staphylococcus aureus, Enterobacter cloacae, and Pseudomonas aeruginosa by using a modified microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977). Overall, cefpirome exhibited pharmacokinetics similar to those of ceftazidime: half-life (t1/2), 1.95 h; concentration at 1 h (C1h), 47 to 49 micrograms/ml for both antibiotics. Ceftriaxone displayed the longest t1/2 (7.65 h) and the highest C1h (137.8 micrograms/ml), while we observed the shortest t1/2 (1.05 h) and the lowest C1h (19.85 micrograms/ml) with imipenem. At 1 h, cefpirome and, even more so, imipenem showed significantly better serum bactericidal activities against S. aureus (1:273 and 1:80) than did the other antibiotics (P less than 0.0005; analysis of variance with randomized block design and Bonferroni correction). Against E. cloacae, we observed the highest serum bactericidal titers at 1 h with cefpirome, and this superiority vis-à-vis the other antibiotics tested was maintained for up to 8 h after dosing. Ceftazidime remained the most active agent tested against P. aeruginosa (serum bactericidal activity titers, 1:43 at 1 h) up to 8 h. In summary, the study showed that cefpirome and imipenem provide more potent serum bactericidal activities than do broad-spectrum cephalosporins against S. aureus; thus, both of these antibiotics should be adequate against serious S. aureus infections. In addition, cefpirome appears to be a promising alternative for treatment of infections caused by E. cloacae and P. aeruginosa.

Adult↗
PubMed1991

Fluoroquinolones in the treatment of cystic fibrosis: a critical appraisal.

While the appropriate usage of antibiotics in cystic fibrosis patients is still a matter of debate, the introduction of oral antipseudomonal antibiotics such as fluoroquinolones represents an eagerly awaited addition to the therapeutic armamentarium. Ciprofloxacin is the single agent most often studied and used in this population for treatment of pulmonary exacerbations. Altered pharmacokinetics of fluoroquinolones have been described in cystic fibrosis patients as for other drugs, and a higher dosage than usual is recommended. Open clinical trials have shown good efficacy of ciprofloxacin in acute infection. A few comparative trials have demonstrated that ciprofloxacin is as effective clinically as conventional intravenous agents. As with other agents, a lack of correlation between clinical improvement and bacteriologic evaluation has been observed. Ciprofloxacin (and possibly ofloxacin) are considered useful alternatives to parenteral agents in therapy of cystic fibrosis patients older than 18 years of age with exacerbations of pulmonary infection. Intermittent therapy with ciprofloxacin alternating with other conventional treatment appears to be a rational approach; clinical trials evaluating the alternation of fluoroquinolones with intravenous anti-pseudomonal therapy are necessary. Considering the potential for emergence of resistance and the not completely elucidated implication of increasing MICs during ciprofloxacin therapy, the duration of treatment should be limited to 2 to 4 weeks. In older children (12 to 18 years old), ciprofloxacin provides an alternative to intravenous agents when clinically justifiable. In view of the possibility of fluoroquinolone associated-arthropathy in younger children, ciprofloxacin should be used judiciously when no alternative agents are available or in life-threatening situations.

Adolescent↗
PubMed1991

Comparative study of pharmacokinetics and serum bactericidal activity of ceftizoxime and cefotaxime.

Single 2-g intravenous doses of ceftizoxime (CZX) and cefotaxime (CTX) were given over 30 min to 10 adult volunteers in a crossover manner on two separate occasions. Concentrations of CZX, CTX, and the primary metabolite of CTX, desacetylcefotaxime (dCTX), in serum, suction-induced-blister fluid, and urine were determined by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by using an extended least-squares modeling program (MKMODEL). CZX exhibited a half-life in serum (2.05 h) longer than that of CTX (1.43 h) but comparable to that of dCTX (2.02 h). The percentage of penetration in blister fluid, estimated by area under the curve ratios, was significantly higher for CZX (164.4%) than for CTX (60.8%). Serum bactericidal activity, determined for volunteer samples at 1, 6, 8, and 12 h after patients were dosed, against clinical isolates of the Bacteroides fragilis group, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and Morganella morganii were significantly higher for CZX than those for CTX against members of the family Enterobacteriaceae at all times. Serum bactericidal titers against B. fragilis were also higher for CZX than for CTX at 1 h postinfusion. Neither CZX nor CTX exhibited any bactericidal activity at any other time against the B. fragilis group. In conclusion, the serum bactericidal activity of CZX was greater and more-prolonged than that of CTX against tested strains in spite of the in vitro synergistic contribution of dCTX to CTX, equal serum elimination half-lives of dCTX and CZX, and similar antibacterial activity and similar instability under microbiological testing for CZX and CTX.

Adult↗
PubMed1991

Bioavailability and pharmacokinetics of oral ofloxacin formulations in normal subjects.

The relative bioavailability and pharmacokinetics of ofloxacin tablets and a reference oral solution of ofloxacin were compared in 32 normal male subjects using a randomized two-way crossover design. After an overnight fast, subjects were randomized to receive a single 200 mg or 300 mg dose of ofloxacin (tablet or solution) and blood samples were obtained prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours after the dose. After a 5-day wash-out period, subjects were administered the same dose but of the other formulation, and blood samples were collected in an identical manner. Plasma concentrations of ofloxacin were determined by high-pressure liquid chromatography. The results showed that ofloxacin tablets were more slowly absorbed when compared to the solution and mean peak plasma concentrations were obtained in about 1.5 hours for the tablet preparation. Maximum plasma concentrations were higher after administration of the solution (Cmax = 2.24 micrograms/ml, 200 mg; Cmax = 3.25 micrograms/ml, 300 mg) compared to the tablet (Cmax = 1.74 micrograms/ml, 200 mg; 2.61 micrograms/ml, 300 mg). The bioavailability of ofloxacin tablets was greater than 98% compared to the solution. The other pharmacokinetic parameters were similar between the two dosage formulations. Ofloxacin tablets revealed an apparent volume of distribution of 1.5 l/kg, an elimination half-life of 5.6 hours, and a total clearance of 251 ml/min. In addition, a linear increase in plasma concentrations was observed when the dose of ofloxacin was increased. In summary, ofloxacin tablets was found to be reliably bioavailable and bioequivalent to the reference solution.

Administration, Oral↗
PubMed1991

Meta-analysis of quinolone-theophylline interactions.

Several fluoroquinolones currently under investigation or on the market potentially interact with theophylline. In this study, meta-analysis methodology was used to evaluate the significance of findings from quinolone-theophylline interaction studies. Two major databases were searched: Index Medicus (from 1986 to March 1990) and Current Content/Clinical Medicine (from 1985 to March 1990). A total of 32 studies were retrieved; 20 of these met the inclusion criteria. With a large effect size (ES) value of 2.26, enoxacin is the strongest inhibitor of theophylline metabolism of this family. The fail-safe N value was 135, indicating that 135 studies enrolling an average of 8 patients and showing no interaction (i.e., ES = 0) would be required to lower the ES to the threshold value of 0.1, which we considered a priori to render the results nonsignificant. Other fluoroquinolones showed a degree of interaction that can be considered significant: ciprofloxacin (ES = 0.50, fail-safe N = 26), norfloxacin (ES = 0.31, fail-safe N = 10). Ofloxacin (ES = 0.13, fail-safe N = 4), lomefloxacin (ES = 0.12, fail-safe N = 2), and fleroxacin (ES = 0.06, fail-safe N = 2) provided the weakest evidence of interaction based on effect size and power. Among the fluoroquinolones studied, ofloxacin, lomefloxacin, and fleroxacin, when available, should be the fluoroquinolones of choice when the patient also is receiving theophylline.

Ciprofloxacin↗
PubMed1990

Influence of the menstrual cycle on the absorption and elimination of D-xylose.

Thirteen healthy female volunteers with regular menstrual cycles (28 +/- 2 days) received 25 gm oral and 5 gm intravenous doses of D-xylose on 2 successive days during the follicular, ovulatory, and luteal phases of two consecutive menstrual cycles. The ovulation time was characterized by luteinizing hormone levels, body basal temperatures, and progesterone and estradiol serum levels. D-Xylose was assayed in plasma and urine with a phloroglucinol-based colorimetric method. The findings of this study indicated that menstrual cycle did not significantly affect D-xylose absorption. After oral administration, the total clearance was significantly increased in cycle 2 during the luteal phase (p = 0.004). After intravenous administration in both cycles, D-xylose total clearance was also significantly faster during the luteal phase (p = 0.038 and p = 0.041, respectively). After oral administration, the renal clearance tended to be higher during the luteal phase in both cycles studied. After intravenous administration, this parameter was increased during the luteal phase by 24% and 25% in cycle 1 and by 8% and 12% in cycle 2. These findings are consistent with those of others showing an increase in glomerular filtration rate (GFR) during the luteal phase of the menstrual cycle. The findings of this study seem to be explained by the hormonal changes occurring during the menstrual cycle. Further investigations are warranted with use of specific probes of renal processes (GFR, renal reabsorption and tubular secretion) to confirm our findings and to elucidate the underlying mechanisms.

Absorption↗