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PubMed2004

Pharmacokinetics and safety of itraconazole in patients with cystic fibrosis.

OBJECTIVE: To assess the pharmacokinetics of itraconazole and hydroxy-itraconazole in patients with cystic fibrosis. METHODS: Patients were divided into those <16 and >/=16 years of age. All received itraconazole oral solution 2.5 mg/kg twice daily for 14 days. Serial blood samples were taken for itraconazole and hydroxy-itraconazole plasma level measurements. Safety was assessed from biochemistry and haematology data and reported adverse events. RESULTS: Seventeen patients entered the study. Steady-state concentrations were achieved after maximally 8 days of dosing. On day 14 average peak plasma concentrations were 404 +/- 268 ng/mL (<16 years, n = 5) and 779 +/- 470 ng/mL (>/=16 years, n = 11 excluding one patient concurrently receiving oral clarithromycin). A high inter-subject variability in itraconazole pharmacokinetics was seen. Intra-subject variability was low. All the younger patients and 50% of the older patients failed to achieve a plasma steady-state trough concentration of >250 ng/mL. Adverse events were reported by 53% of subjects. Most were mild or moderate in intensity and not considered related to treatment. One patient withdrew from the study because of two severe adverse events. Ten significant laboratory abnormalities were reported in seven of 16 patients with paired data. Six of these were clinically relevant. CONCLUSION: 2.5 mg/kg itraconazole oral solution twice daily in patients with cystic fibrosis achieves steady-state concentrations in maximally 8 days. The pharmacokinetics showed marked inter-subject variability. Plasma concentrations of >250 ng/mL were not reached in the paediatric cohort or in 50% of the adult cohort. The dosage regimen was safe and well tolerated.

Administration, Oral↗
PubMed1983

Use of disulfiram for alcoholics in methadone maintenance programs. A Veterans Administration Cooperative Study.

A multicentered clinical trial studied the efficacy and safety of disulfiram in controlling heavy alcohol consumption by patients on methadone maintenance regimens. The trial was stopped when sample size targets were not achieved. Efficacy comparisons were based on 82 patients who started the study; safety comparisons were based on 35 patients who completed 12 weeks of study. Patients received either disulfiram and methadone or placebo and methadone. Disulfiram was administered at a dosage of 125 mg/day for seven days and 250 mg/day thereafter for 36 weeks. No significant differences between the disulfiram and placebo groups were observed in either the retention in study or any other important end point. Both groups showed improvement in control of drinking during the study. There were no serious adverse reactions that could be attributed to the combined use of the two drugs.

Adult↗
PubMed1997

International variation in anesthesia care during cataract surgery: results from the International Cataract Surgery Outcomes Study.

OBJECTIVES: To describe international variation in anesthesia care and monitoring during cataract surgery and to discuss its implications for cost and safety. METHODS: A standardized questionnaire was sent to random samples of ophthalmologists in the United States, Canada, and Barcelona, Spain, and to all ophthalmologists in Denmark. The survey was conducted in 1993 and 1994. Certified ophthalmologists who had performed 1 or more cataract extractions in the previous year were eligible for enrollment. RESULTS: The response rates were 62% in the United States (n=148), 67% in Canada (n=276), 70% in Barcelona (n=89), and 80% in Denmark (n=82). The anesthetic technique for cataract surgery varied significantly between sites (P<.001). Surgeons reported that retrobulbar blocks were used for 46% of the cataract extractions in the United States, 70% in Canada, 66% in Denmark, and 31% in Barcelona. In Barcelona, general anesthesia was used for 23% of the cataract extractions; it was used for less than 3% of the extractions at the other 3 sites. Peribulbar blocks or topical anesthesia was used for the remaining extractions. In the United States, Canada, and Barcelona, surgeons reported that vital functions were monitored during more than 97% of the extractions and anesthesia surveillance was used during more than 78% of the extractions. In Denmark, ophthalmologists reported that vital functions were monitored and anesthesia surveillance was used for 1% of the cataract extractions (P<.001). CONCLUSIONS: Substantial international variation in anesthesia care and monitoring during cataract surgery was observed. The findings suggest a need for further research to determine whether less intensive monitoring is cost-effective.

Anesthesia↗
PubMed2005

Viscosupplementation for the treatment of osteoarthritis of the knee.

BACKGROUND: Osteoarthritis (OA) is the most prevalent chronic joint disorder worldwide and is associated with significant pain and disability. OBJECTIVES: To assess the effects of viscosupplementation in the treatment of OA of the knee. The products were hyaluronan and hylan derivatives (Adant, Arthrum H, Artz (Artzal, Supartz), BioHy (Arthrease), Durolane, Fermathron, Go-On, Hyalgan, Hylan G-F 20 (Synvisc Hylan G-F 20), NRD-101, Orthovisc, Ostenil, Replasyn, SLM-10, Suplasyn, Synject and Zeel compositum). SEARCH STRATEGY: MEDLINE, EMBASE, PREMEDLINE, Current Contents up to July 2003, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Specialised journals and reference lists of identified randomised controlled trials (RCTs) and pertinent review articles up to April 2004 were handsearched. SELECTION CRITERIA: RCTs of viscosupplementation for the treatment of people with a diagnosis of OA of the knee were eligible. Single and double-blinded studies, placebo-based and comparative studies were eligible. At least one of the four OMERACT III core set outcome measures had to be reported (Bellamy 1997). DATA COLLECTION AND ANALYSIS: Each trial was assessed independently by two reviewers (NB, JC) for its methodological quality using a validated tool. All data were extracted by one reviewer (JC) and verified by a second reviewer (VR). Continuous outcome measures were analysed as weighted mean differences (WMD) with 95% confidence intervals (CI). Dichotomous outcomes were analyzed by relative risk (RR). MAIN RESULTS: Sixty-three trials with a median quality score of 3 (range 1 to 5) were identified. Follow-up periods varied between day of last injection and one year. Thirty-seven trials included comparisons of hyaluronan/hylan and placebo, nine trials included comparisons of intra-articular (IA) corticosteroids, and five trials included comparisons of nonsteroidal anti-inflammatory drugs (NSAIDs). The pooled analyses of the effects of viscosupplements against 'placebo' controls generally supported the efficacy of this class of intervention. In these same analyses, differential efficacy effects were observed for different products on different variables and at different timepoints. Of note is the 5 to 13 week post injection period which showed a percent improvement from baseline of 11 to 54% for pain and 9 to 15% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were noted in comparisons against IA corticosteroids. In general, few adverse events were reported in the hyaluronan/hylan trials included in these analyses. AUTHORS' CONCLUSIONS: Based on the aforementioned analyses, viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection period. It is of note that based on non-randomised groups, the magnitude of the clinical effect, as expressed by the WMD and standardised mean difference (SMD) from the RevMan 4.1 output, is different for different products, comparisons, timepoints, variables and trial designs. However, there are few randomised head-to-head comparisons of different viscosupplements and readers should be cautious, therefore, in drawing conclusions regarding the relative value of different products. The clinical effect for some products, against placebo, on some variables at some timepoints is in the moderate to large effect-size range. Readers should refer to relevant tables to review specific detail given the heterogeneity in effects across the product class and some discrepancies observed between the RevMan 4.1 analyses and the original publications. Overall, the analyses performed are positive for the HA class and particularly positive for some products with respect to certain variables and timepoints, such as pain on weight bearing at 5 to 13 weeks postinjection. In general, sample-size restrictions preclude any definitive comment on the safety of the HA class of products; however, within the constraints of the trial designs employed no major safety issues were detected. In some analyses viscosupplements were comparable in efficacy to systemic forms of active intervention, with more local reactions but fewer systemic adverse events. In other analyses HA products had more prolonged effects than IA corticosteroids. Overall, the aforementioned analyses support the use of the HA class of products in the treatment of knee OA.

Humans↗
PubMed2006

Viscosupplementation for the treatment of osteoarthritis of the knee.

BACKGROUND: Osteoarthritis (OA) is the most prevalent chronic joint disorder worldwide and is associated with significant pain and disability. OBJECTIVES: To assess the effects of viscosupplementation in the treatment of OA of the knee. The products were hyaluronan and hylan derivatives (Adant, Arthrum H, Artz (Artzal, Supartz), BioHy (Arthrease, Euflexxa, Nuflexxa), Durolane, Fermathron, Go-On, Hyalgan, Hylan G-F 20 (Synvisc Hylan G-F 20), Hyruan, NRD-101 (Suvenyl), Orthovisc, Ostenil, Replasyn, SLM-10, Suplasyn, Synject and Zeel compositum). SEARCH STRATEGY: MEDLINE (up to January (week 1) 2006 for update), EMBASE, PREMEDLINE, Current Contents up to July 2003, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Specialised journals and reference lists of identified randomised controlled trials (RCTs) and pertinent review articles up to December 2005 were handsearched. SELECTION CRITERIA: RCTs of viscosupplementation for the treatment of people with a diagnosis of OA of the knee were eligible. Single and double-blinded studies, placebo-based and comparative studies were eligible. At least one of the four OMERACT III core set outcome measures had to be reported (Bellamy 1997). DATA COLLECTION AND ANALYSIS: Each trial was assessed independently by two reviewers for its methodological quality using a validated tool. All data were extracted by one reviewer and verified by a second reviewer . Continuous outcome measures were analysed as weighted mean differences (WMD) with 95% confidence intervals (CI). However, where different scales were used to measure the same outcome, standardized mean differences (SMD) were used. Dichotomous outcomes were analyzed by relative risk (RR). MAIN RESULTS: Seventy-six trials with a median quality score of 3 (range 1 to 5) were identified. Follow-up periods varied between day of last injection and eighteen months. Forty trials included comparisons of hyaluronan/hylan and placebo (saline or arthrocentesis), ten trials included comparisons of intra-articular (IA) corticosteroids, six trials included comparisons of nonsteroidal anti-inflammatory drugs (NSAIDs), three trials included comparisons of physical therapy, two trials included comparisons of exercise, two trials included comparisons of arthroscopy, two trials included comparisons of conventional treatment, and fifteen trials included comparisons of other hyaluronans/hylan. The pooled analyses of the effects of viscosupplements against 'placebo' controls generally supported the efficacy of this class of intervention. In these same analyses, differential efficacy effects were observed for different products on different variables and at different timepoints. Of note is the 5 to 13 week post injection period which showed a percent improvement from baseline of 28 to 54% for pain and 9 to 32% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were noted in comparisons against IA corticosteroids. In general, few adverse events were reported in the hyaluronan/hylan trials included in these analyses. AUTHORS' CONCLUSIONS: Based on the aforementioned analyses, viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection period. It is of note that the magnitude of the clinical effect, as expressed by the WMD and standardised mean difference (SMD) from the RevMan 4.2 output, is different for different products, comparisons, timepoints, variables and trial designs. However, there are few randomised head-to-head comparisons of different viscosupplements and readers should be cautious, therefore, in drawing conclusions regarding the relative value of different products. The clinical effect for some products, against placebo, on some variables at some timepoints is in the moderate to large effect-size range. Readers should refer to relevant tables to review specific detail given the heterogeneity in effects across the product class and some discrepancies observed between the RevMan 4.2 analyses and the original publications. Overall, the analyses performed are positive for the HA class and particularly positive for some products with respect to certain variables and timepoints, such as pain on weight bearing at 5 to 13 weeks postinjection. In general, sample-size restrictions preclude any definitive comment on the safety of the HA class of products; however, within the constraints of the trial designs employed no major safety issues were detected. In some analyses viscosupplements were comparable in efficacy to systemic forms of active intervention, with more local reactions but fewer systemic adverse events. In other analyses HA products had more prolonged effects than IA corticosteroids. Overall, the aforementioned analyses support the use of the HA class of products in the treatment of knee OA.

Humans↗
PubMed1995

Guidelines for clinical trials in systemic sclerosis (scleroderma). I. Disease-modifying interventions. The American College of Rheumatology Committee on Design and Outcomes in Clinical Trials in Systemic Sclerosis.

OBJECTIVE: To develop guidelines for therapeutic trials designed to improve the overall course of systemic sclerosis (SSc), that is, to reduce the development of significant organ damage or death. METHODS: A committee developed general guidelines for patient inclusion and exclusion criteria, randomization, blinding of patients and physicians, controls, duration of the trial, investigator training, responses, samples size, study dropouts, statistical analyses, data management, and safety monitoring. Delphi and nominal group techniques were used. RESULTS: Briefly, patients with diffuse cutaneous SSc of less than 24 months' duration should be included because they are at greatest risk for the development of severe organ damage and death. Patients should be excluded if they have other connective tissue diseases, SSc-like illnesses related to exposures or ingestions, severe existing internal organ damage, an unacceptable risk of side effects, or concurrent therapies that might independently influence the outcome. Randomized, double-blind, placebo-controlled trials are preferred. The treatment and followup period must be long enough to permit observation of any disease modification, which is likely to require 18-36 months, unless an extraordinarily effective therapy is identified. Responses selected should be quantitative, consistently and accurately reflect activity of SSc in major target organs (not solely the skin), be sensitive to change, and be standardized, with limited variability. An example of a set of responses is given. Surrogate responses are desirable, but none have been validated as correlating with organ damage. CONCLUSION: Guidelines have been established for trials of disease-modifying interventions in SSc. These guidelines will need to be altered as additional information becomes available. Any given protocol will be individualized based on the nature of the intervention and objectives of the study. Nonetheless, each study team should develop a protocol that meets the spirit of these guidelines.

Clinical Protocols↗
PubMed1993

AMESFIT: a microcomputer program for fitting linear-exponential dose-response models in the Ames Salmonella assay.

The Ames Salmonella/microsome assay remains the most widely used microbial test for genotoxicity. In this article, we describe a microcomputer program developed to fit a linear-exponential dose-response model to Ames assay data for established mutagens. The model includes a linear term to describe the mutagenic effects of the test agent at low to moderate doses and an exponential attenuation factor to accommodate downturns at high doses due to cytotoxicity. Quasi-likelihood methods are used to obtain estimates of the unknown model parameters, thereby avoiding the need to fully specify the distribution of the experimental data. This method of estimation also allows for extra-Poisson variation that is characteristic of counts of mutant colonies of bacteria observed in the Ames assay. The particular linear-exponential model used here was developed for use in the analysis of a recent large-scale collaborative trial using the Ames assay sponsored by the International Programme on Chemical Safety. The use of our program is illustrated using sample data sets taken from that collaborative study.

Dose-Response Relationship, Drug↗
PubMed1991

Pesticide residues in food crops analyzed by the California Department of Food and Agriculture in 1989.

California spends more than $40 million each year for the nation's most comprehensive program to regulate pesticide use: Pesticides are evaluated before they can be used. Businesses that sell or apply pesticides are licensed. Pesticide specialists enforce restrictions on pesticide use. Water, air, and soil are monitored for pesticide levels. And, as a final check in this integrated network of program, domestic and imported produce is sampled and tested for traces of pesticide residue. Annually, approximately 1% of the samples violate established standards. Because the standards include a safety margin, illegal residues rarely present a health risk, according to leading scientific experts, including the World Health Organization.

California↗
PubMed1992

Local street speed management in Australia--is it "traffic calming"?

A small sample of recent developments in local speed management and safety in Australia is outlined to illustrate conclusions about practice and assessment. This experience seems to support the effectiveness of devices in lowering speeds and reducing accidents, but there is still generally a lack of adequate monitoring and evaluation. Speeds in new residential areas require attention in the planning and design stages; some current fads in neighbourhood planning threaten to perpetuate old traffic problems. The current use of the term traffic calming to mean reduction of car travel demand rather than restraint on driver behaviour and route choice is noted. It is suggested that citywide suppression of traffic goes beyond "traffic calming" as it is commonly understood, into the realm of travel demand management and cultural change.

Accidents, Traffic↗
PubMed2004

Wet and dry deposition patterns of plutonium in Daejeon, Korea.

Plutonium in wet and dry deposition samples collected monthly at the Korea Institute of Nuclear Safety (KINS), Daejeon, Korea was determined during the period from January 2000 to August 2000. Monthly 239,240Pu deposition in Korea showed a maximum in the spring season (March to May), which was several times greater than that in Japan and corresponds to a seasonal cycle of soil dust fallout originating from the East Asian arid areas. The trajectory analysis of dust storms suggests that 239,240Pu deposition in Korea in spring is originating from plutonium-bearing surface soil particles from the East Asian arid areas. A significant part of the 239,240Pu deposition in spring in Korea is attributable to dry deposition.

Air Movements↗
PubMed2000

Knee injuries in motor vehicle collisions: a study of the National Accident Sampling System database for the years 1979-1995.

A detailed study of knee injuries recorded in the 1979-1995 National Accident Sampling System database maintained by the National Highway Traffic Safety Administration was conducted. Injuries to other body regions were also considered in order to illustrate the relative frequency of knee injuries. This study demonstrated that knee injuries constitute approximately 10% of all injuries recorded every year. However, the majority of these injuries were of low severity (i.e. contusions, abrasions, lacerations) with an abbreviated injury score (AIS) of 1. Most knee injuries occurred following a frontal collision with no intrusion. The study also indicated most knee fractures occur in crashes where the vehicle velocity differences (deltaVs) were less than 45 kmph, with some occurring at deltaVs as low as 10 kmph. Serious non-fracture knee injuries (i.e. ligament tears) rated AIS 2 accounted for 20 out of every 1000 injuries and predominantly occurred at deltaVs below 25 kmph. In this study it was noted that women were more likely to experience a knee contusion than men. This study further suggests that knee impact scenarios have remained relatively constant over the years as the knee injury rates showed little variation. The rate of lap and shoulder belt use was lower in occupants who experienced a knee injury vs. the rate in the overall database and airbags were present in only a small number of cases. As this study largely included only vehicles without airbags it provides a good baseline for analysis of the influence of the airbag on knee injury trends in the future.

Accidents, Traffic↗
PubMed1997

A randomized controlled trial of strict glycemic control and tertiary level obstetric care versus routine obstetric care in the management of gestational diabetes: a pilot study.

OBJECTIVES: The purpose of this study was to determine whether strict maternal glycemic control for the treatment of gestational diabetes lessened the risk of fetal macrosomia, birth trauma, neonatal hypoglycemia, and operative delivery. The aim of the pilot study was to prepare for a multicenter trial by assessing patient acceptance of the study, by determining realistic accrual rates, and by detecting any major adverse outcomes in the control group that received routine obstetric care. STUDY DESIGN: The study was a prospective randomized controlled trial comparing fetal-neonatal and maternal outcomes in 300 women with gestational diabetes. Women randomized to the treatment arm were managed by strict glycemic control and tertiary level obstetric care, and women in the control arm received routine obstetric care. RESULTS: Three hundred women with gestational diabetes mellitus were studied. There was no difference in maternal age, weight, or length of gestation between groups. The treatment mean birth weight was 3437 +/- 575 gm compared with 3544 +/- 601 gm in the control group, a difference of 107 gm (not significant). Macrosomia rates were similar. There was no birth trauma in either group. The frequency of neonatal hypoglycemia and other metabolic complications was the same. The mode of delivery also showed similar patterns. The treatment group had significantly lower preprandial and postprandial glucose levels by 32 weeks' gestation, which continued to term. CONCLUSION: This pilot study suggests that intensive treatment of gestational diabetes mellitus may have little effect on birth weight, birth trauma, operative delivery, or neonatal metabolic disorders. It has demonstrated the safety of proceeding to a multicenter trial of sufficient sample size to confirm these findings.

Adult↗
PubMed2003

Mechanical model for theoretical determination of maximum running speed in mammals.

A mechanical model for the determination of maximum speed in terrestrial tetrapods, designed for application to extinct species, is proposed. Only external bone measures and average body mass estimations are used as input data, and the hypothesis is made that leg bones are strong enough to endure the stress of running at maximum speed at a certain universal safety factor. The model is applied to a broad sample of living mammalian species to test its predictive power, and it is found to provide very good estimates of maximum running speed.

Animals↗
PubMed2001

Factors controlling measures of anxiety and responses to novelty in the mouse.

This review focuses on factors influencing behaviour in the elevated plus-maze, the holeboard and the social transmission of food preference. The elevated plus-maze provides independent measures of anxiety (percentage of time spent on open arms) and activity (number of closed arm entries) and can be used in both males and females. Important sex differences emerge in factor loadings, and, whereas in males, anxiety is the primary factor, in females it is activity. On trial 2 in the plus-maze, the nature of the anxiety state is changed and thus this maze can be used to screen for possible genetic alterations in two distinct anxiety states. The holeboard provides independent measures of exploration and locomotor activity and habituation between sessions provides a useful measure of learning. Mice display neophobia and avoid novel foods, but information about their safety can be socially transmitted. A mouse that has sampled a novel food will be actively sniffed by others on its return to the colony. It is important to control for possible changes in social investigation, neophobia, olfactory sensitivity, anxiety and exploration, before it is concluded that a changed performance in this task is due to changes in learning.

Animals↗
PubMed2004

Complementary and alternative medicine education in the United States, China, and Taiwan.

As public demand for complementary and alternative medicine increases,it is important for physical medicine and rehabilitation physicians to have some basic understanding of complementary and alternative medicine or at least to appreciate some of the approved indications so that appropriate referrals can be made. Because the concept of evidence-based medicine is essential for a successful physical medicine and rehabilitation practice in either academic or private facilities, well-developed research projects, such as randomized, controlled trials of large sample size, are needed to investigate the efficacy and safety of complementary and alternative medicine therapy.

China↗
PubMed2002

Determination of fish community composition in the untempered regions of a thermal effluent canal--the efficacy of a fixed underwater videography system.

High flows and deep waters associated with thermal discharge canals invoke safety concerns and preclude the use of conventional fish sampling methodologies. Despite these challenges, it is critical that assessments of thermal effects from power generation do not rely solely on data collected in the plume, but also focus on fish living in the canal, particularly in regions above the zone of tempering influence. We deployed a fixed underwater videography apparatus to monitor the community composition and abundance patterns of fish in the Nanticoke thermal generating discharge canal on the north shore of Lake Erie from February 1, 1999 until July 31, 1999. We also compared the number of species observed using video to angling surveys, visual observations through the air/water interface and two modified netting procedures. Our results indicate that videography permitted the detection of the most species and the highest number of individuals. Variable visibility was the largest limitation of this approach. The addition of infrared lighting for low light conditions and a series of cameras positioned at several depths would be a cost effective, safe, and efficient method of assessing community structure and behaviour of fish in thermal discharge canals.

Animals↗
PubMed1995

Systemic treatment with epidermal growth factor induces anaemia in Goettingen minipigs.

1. From two independent experimental studies conducted in 48 minipigs with oesophageal sclerotherapy and concomitant treatment with epidermal growth factor, blood samples together with bone marrow biopsies were analysed for safety data. 2. Four to five weeks of systemic treatment with epidermal growth factor induced a decline in blood haemoglobin concentration in a time- and dose-dependent and reversible manner but without an effect on leucocyte or platelet counts. 3. The bone marrow expressed decreased amounts of haematopoietic tissue and reduced numbers of erythropoietic cells. 4. Four to five weeks of systemic treatment with epidermal growth factor induced reversible increases in serum concentrations of creatinine and urea, most likely reflecting renal impairment. 5. Groups in which creatinine and urea were not increased also had reduced blood haemoglobin concentrations. 6. These findings suggest that epidermal growth factor selectively impaired the erythropoiesis and stress the importance of risk-benefit analysis concerning the potential therapeutic applications of epidermal growth factor.

Anemia↗
PubMed2003

Topiramate and lamotrigine pharmacokinetics during repetitive monotherapy and combination therapy in epilepsy patients.

PURPOSE: To determine at steady state (in the same group of patients): (a) the pharmacokinetics (PK) of lamotrigine (LTG) with LTG monotherapy, (b) the PK of LTG concomitantly administered with topiramate (TPM) at three escalating TPM doses (100, 200, and 400 mg/day), (c) the PK of TPM at three escalating TPM doses while receiving fixed-dose LTG therapy, and (d) the PK of TPM with TPM monotherapy. METHODS: This was an open-label, sequential, single-group, dose-escalating PK study in which 13 patients with epilepsy not optimally controlled with LTG received stable-dose LTG monotherapy for 2 weeks, followed by stable-dose LTG therapy combined with escalating doses of TPM for </=16 weeks, stable-dose TPM therapy combined with tapered-dose LTG therapy for 4 weeks, and stable-dose TPM monotherapy for 2 weeks. Serial blood and urine samples were collected before and during TPM dosing, and safety data were collected throughout the study. RESULTS: The exposure, or area under the plasma LTG concentration-time curve within a dosing interval at steady state (AUCss), did not change in the presence of TPM, with mean AUCss values ranging at each TPM dose level between 66 and 81 mg x h/L with concomitant LTG/TPM therapy compared with 77 mgxh/L with LTG monotherapy. No significant change was found in the steady-state peak (Cmax) and trough (Cmin) plasma levels of LTG in the presence and absence of TPM. The mean (+/-SD) oral clearance (CL/F) of TPM (400 mg/day) was 2.6 +/- 1.1 L/h when given alone and 2.7 +/- 0.7 L/h when given with LTG. The similarity of CL/F values also was reflected by the similar exposure (AUCss), Cmax, and Cmin values of TPM in the absence, and presence of LTG. CONCLUSIONS: The results of this study show that no PK interaction between TPM and LTGwas observed at the doses used in this study.

Adult↗