Influence of the clindamycin administration route on the magnitude of clindamycin–rifampicin interaction: a prospective pharmacokinetic study

ObjectivesAn important clindamycin–rifampicin pharmacokinetic (PK) interaction has been reported, but the potential influence of the clindamycin administration route on that interaction is unknown. This prospective, observational, comparative PK study was undertaken to characterize and analyse the impact of the route, comparing the rifampicin enzyme-inductor effects on clindamycin clearance (CLclin) for oral versus intravenous (IV) administration.MethodsPatients with bone-and-joint infections (BJIs) were treated with clindamycin monotherapy (n = 20) or clindamycin–rifampicin combination therapy (n = 19). Patients received continuous IV clindamycin infusion for 2–6 weeks, followed by an oral regimen. Liquid chromatography–mass spectrometry was used to measure plasma clindamycin concentrations at the end of IV and after 2 weeks of oral treatment. The ratios of the mean CLclin for the combination and monotherapy groups were calculated for IV (Riv) and oral (Rpo) routes, with the final ratio, Rf = Rpo/Riv, representing the fold change of the rifampicin-inducing effect from the IV to the oral route.ResultsComparing monotherapy with combination-therapy groups, the former's median steady-state concentration was two-fold higher after IV administration (8.49 versus 3.82 mg/L, p < 0.001) and its median AUC_0–8h was 12 times higher after oral intake (37.7 versus 3.1 mg.h/L, p < 0.001). Riv, Rpo and Rf were 2.68, 18.8 and 7.0 respectively.ConclusionThe magnitude of this interaction was markedly increased by oral intake, questioning the use of oral treatment for difficult-to-treat infections like BJIs. Nevertheless, the clindamycin–rifampicin combination seems possible provided that clindamycin is administered by continuous IV infusion.     

Standardized combination antibiotic treatment of Mycobacterium avium complex lung disease

Purpose

The optimal treatment regimen for Mycobacterium avium complex (MAC) lung disease has not yet been fully established. We evaluated the efficacy of standardized combination antibiotic therapy and the factors that might affect unfavorable microbiologic responses in patients with MAC pulmonary disease.

Materials and Methods

This retrospective study reviewed data from 96 patients (56 females; median age 59 years) treated with newly diagnosed MAC lung disease between January 2003 and December 2006.

Results

All patients received standardized combination antibiotic therapy, consisting of clarithromycin, rifampicin, and ethambutol. Streptomycin was additionally given in 72 patients (75%) for a median duration of 4.5 months. The overall favorable microbiologic response rate was 79% (76/96); 20 patients (21%) had unfavorable microbiologic responses, including failure to sputum conversion (n = 13), relapse (n = 3), and MAC-related death (n = 4). A positive sputum acid-fast bacillus smear at the start of treatment was an independent predictor of an unfavorable microbiologic response.

Conclusion

Standardized combination antibiotic therapy consisting of clarithromycin, rifampicin, and ethambutol with or without initial use of streptomycin is effective in treating patients with newly diagnosed MAC lung disease.     

Diffusion of rifampicin into spongy and compact bone tissue during total hip prosthesis operation

Sixty eight patients received either an oral single dose of 300 mg (or 300 mg/12 h), or an oral single dose of 600 mg (or 600 mg/24 h) of rifampicin. In every case samples of serum and bone were collected 3 h, 12 h, and 24 h after the last oral dose. Rifampicin levels measured at 3 h and 12 h in cortical bone samples increased significantly with the dose of the drug. The only dose which determines activity in cortical bone at the 3rd hour was the dose of 600 mg. When the dose was increased from 300 mg/12 h to 600 mg/24 h the ratio spongious bone/serum increased from 0.19 to 0.41 at 3d h and from 0.24 to 0.29 at the 12th hour; the ratio cortical bone serum was 0.20 at the 3rd hour after a dose of 600 mg. In any case tissue levels varied in a parallel direction to serum levels and were superior in spongious bone to the MIC of S. aureus sensitive strains until 12 h after the 600 mg dose. According to these results, it appears that the best dose for treating S. aureus bone infection seems to be 600 mg/12 h.     

Using machine learning to optimize antibiotic combinations: dosing strategies for meropenem and polymyxin B against carbapenem-resistant Acinetobacter baumannii

ObjectivesIncreased rates of carbapenem-resistant strains of Acinetobacter baumannii have forced clinicians to rely upon last-line agents, such as the polymyxins, or empirical, unoptimized combination therapy. Therefore, the objectives of this study were: (a) to evaluate the in vitro pharmacodynamics of meropenem and polymyxin B (PMB) combinations against A. baumannii; (b) to utilize a mechanism-based mathematical model to quantify bacterial killing; and (c) to develop a genetic algorithm (GA) to define optimal dosing strategies for meropenem and PMB.MethodsA. baumannii (N16870; MIC_meropenem = 16 mg/L, MIC_PMB = 0.5 mg/L) was studied in the hollow-fibre infection model (initial inoculum 10⁸ cfu/mL) over 14 days against meropenem and PMB combinations. A mechanism-based model of the data and population pharmacokinetics of each drug were used to develop a GA to define the optimal regimen parameters.ResultsMonotherapies resulted in regrowth to ~10¹⁰ cfu/mL by 24 h, while combination regimens employing high-intensity PMB exposure achieved complete bacterial eradication (0 cfu/mL) by 336 h. The mechanism-based model demonstrated an SC₅₀ (PMB concentration for 50% of maximum synergy on meropenem killing) of 0.0927 mg/L for PMB-susceptible subpopulations versus 3.40 mg/L for PMB-resistant subpopulations. The GA had a preference for meropenem regimens that improved the %T > MIC via longer infusion times and shorter dosing intervals. The GA predicted that treating 90% of simulated subjects harbouring a 10⁸ cfu/mL starting inoculum to a point of 10⁰ cfu/mL would require a regimen of meropenem 19.6 g/day 2 h prolonged infusion (2 hPI) q5h + PMB 5.17 mg/kg/day 2 hPI q6h (where the 0 h meropenem and PMB doses should be ‘loaded’ with 80.5% and 42.2% of the daily dose, respectively).ConclusionThis study provides a methodology leveraging in vitro experimental data, a mathematical pharmacodynamic model, and population pharmacokinetics provide a possible avenue to optimize treatment regimens beyond the use of the ‘traditional’ indices of antibiotic action.     

Serum lipids and lipoproteins in postmenopausal women receiving transdermal oestrogen in combination with a levonorgestrel-releasing intrauterine device

To compare the effects of a non-oral combination of a transdermal oestradiol patch (50 μg daily) and an intrauterine device (IUD) releasing 20 μg of levonorgestrel daily on the serum pattern of lipids and lipoproteins with an established oral regimen of a daily dose of 2 mg of oestradiol and 1 mg of noretisterone acetate. Methods: An open, randomized study comprised of 40 healthy, early postmenopausal women. Results: During 1 year the concentration of total cholesterol decreased 5.0% in the LNg-IUD group and 10.6% in the oral therapy group; HDL cholesterol decreased 10.9% and 12.8%, respectively, and HDL₂ cholesterol decreased 18.1% and 26.9%, respectively. LDL cholesterol values did not change in the LNg-IUD group, whereas a 10.3% decrease was observed in the oral therapy group. Triglyceride values did not change in either group. There were no significant differences in the serum lipoprotein changes between the groups during the treatment. Conclusions: The use of a non-oral regimen of hormone replacement therapy has been advocated to minimize the effect of steroids on the liver. Its effects on the serum pattern of lipids and lipoproteins, however, did not differ significantly from those induced by a continuous oral treatment regimen.     

Effect of ��2-Adrenergic Receptor Polymorphism in Asthma Control of Patients Receiving Combination Treatment

Purpose

Combination treatment of inhaled corticosteroid (ICS) plus long-acting β2-agonist (LABA) is widely used as a maintenance regimen for the management of asthma. This study evaluated the effect of the β2-adrenergic receptor (ADRB2) polymorphism on lung function and asthma control with regular use of combination treatment of an inhaled ICS plus LABA.

Materials and Methods

43 Korean asthmatics who were symptomatic despite regular ICS use for at least 3 months were enrolled. For a 2-week run-in period, they received ICS (budesonide 800 µg/day) plus terbutaline (5 µg prn). as needed. During the 24-week active treatment period, they received budesonide 160 µg and formoterol 4.5 µg b.i.d. as maintenance and rescue medication. Pulmonary function and quality of life scores were monitored every 8 weeks; morning/evening peak expiratory flow meter (PEFR) was recorded daily. Patients were genotyped for ADRB2 Arg16Gly using single base extension methodology.

Results

During the run-in period, there were no significant between-group differences in lung function; after 8 weeks of active treatment, Arg/Arg patients had significantly higher forced expiratory volume in 1 secord (FEV₁) and maximal mid-expiratory flow (MMEF) (p = 0.023 and p = 0.021, respectively), and better asthma control and quality of life after 24 weeks (p = 0.016 and p = 0.028, respectively). During treatment, there was a greater improvement in morning/evening PEFR in Arg/Arg patients.

Conclusion

Asthmatic patients with the Arg/Arg genotype at codon 16 of ADRB2 achieve better asthma control with long-term regular use of combined budesonide and formoterol treatment, suggesting that the ADRB2 genotype may dictate choice of treatment strategy.     

Effects of bolus injection of 5-fluorouracil on steady-state plasma concentrations of 5-fluorouracil in Japanese patients with advanced colorectal cancer

Objectives: The irinotecan (CPT-11) + 5-fluorouracil (5-FU)/leucovorin (LV) + UFT/LV chemotherapy, in which repetitive oral administration of UFT/LV replaces the infusion of 5-FU/LV in the FOLFIRI regimen, has been proposed previously. In this study, five of 10 patients were injected with a bolus of 5-FU and the other were not injected with it in order to examine the effect of omitting it in terms of pharmacokinetics of 5-FU.Methods: The treatment consisted of the intravenous infusions of CPT-11 at 100 mg/m² and l-LV at 15 mg/m², and the injection of a bolus of 5-FU at 500 mg/m² on day 1, and the repetitive oral administration of UFT/LV (300 mg/m²/day as tegafur + 75 mg/day of LV) on days 1-5. A total of 13 measurements of the plasma concentrations of uracil, 5-FU and tegafur were made per patient within 48 hr after the start of chemotherapy and the value of area under the concentration-time curve (AUC_0-48) was evaluated. The plasma concentration was also determined at 2 weeks to assess long-term exposure to 5-FU.Results: The plasma concentrations of 5-FU at 24 hr after the start of treatment were 27.4 ng/mL and 9.4 ng/mL in the patients with and without the bolus injection, respectively. At 48 hr, they were 31.3 ng/mL and 10.4 ng/mL with the AUC_0-48 values of 22.16 mg*h/L and 0.65 mg*h/L, respectively. The 5-FU was detected in the plasma at 226 hr after the last administration of UFT/LV for the patients with the bolus injection, but not for those without.Conclusion: A bolus of 5-FU on day 1 provided long-term exposure to 5-FU.     

Liver involvement in patients with brucellosis: results of the Marmara study

Brucellosis is a zoonotic disease that primarily affects the reticuloendothelial system. But, the extent of liver damage in due course of the disease is unclear. This study included 325 brucellosis patients with significant hepatobiliary involvement identified with microbiological analyses from 30 centers between 2000 and 2013. The patients with ≥5 times of the upper limit of normal for aminotransferases, total bilirubin level ≥2 mg/dl or local liver lesions were enrolled. Clinical hepatitis was detected in 284 patients (87.3 %) and cholestasis was detected in 215 (66.1 %) patients. Fatigue (91 %), fever (86 %), sweating (83 %), arthralgia (79 %), and lack of appetite (79 %) were the major symptoms. Laboratory tests showed anemia in 169 (52 %), thrombocytopenia in 117 (36 %), leukopenia in 81 (25 %), pancytopenia in 42 (13 %), and leukocytosis in 20 (6 %) patients. The most commonly used antibiotic combinations were doxycycline plus an aminoglycoside (n?=?73), doxycycline plus rifampicin (n?=?71), doxycycline plus rifampicin and an aminoglycoside (n?=?27). The duration of ALT normalization differed significantly in three treatment groups (p?<?0.001). The use of doxycycline and an aminoglycoside in clinical hepatitis showed better results compared to doxycycline and rifampicin or rifampicin, aminoglycoside, doxycycline regimens (p?<?0.05). However, the length of hospital stay did not differ significantly between these three combinations (p?>?0.05). During the follow-up, treatment failure occurred in four patients (1 %) and relapse was seen in three patients (0.9 %). Mortality was not observed. Hepatobiliary involvement in brucellosis has a benign course with suitable antibiotics and the use of doxycycline and an aminoglycoside regimen seems a better strategy in select patients.     

International Active Surveillance Study of Women Taking Oral Contraceptives (INAS-OC Study)

Background  

A 24-day regimen of contraceptive doses of drospirenone and ethinylestradiol (DRSP/EE 24d) was recently launched. This regimen has properties which may be beneficial for certain user populations (e.g., women suffering from premenstrual dysphoric disorder or acne). However, it is unknown whether this extended regimen has an impact on the cardiovascular risk associated with the use of oral contraceptives (OCs). The INternational Active Surveillance study of women taking Oral Contraceptives (INAS-OC) is designed to investigate the short- and long-term safety of the new regimen in a population which is representative for the typical user of oral contraceptives.     

Teicoplanin dosing strategy for treatment of Staphylococcus aureus in Korean patients with neutropenic fever

Purpose

The present study was conducted to determine and compare the target attainment rate (TAR) between microorganism-nonspecific (C_trough) and microorganism-specific (AUC₂₄/MIC) targets over two weeks of teicoplanin administration according to several dose regimens for the treatment of Staphylococcus aureus in Korean patients with neutropenic fever.

Materials and Methods

One thousand virtual concentrations were obtained for each dose using the population pharmacokinetic parameters of teicoplanin adopted from a published study. Simulation of 1,000 virtual MICs was performed using the MICs of 78 clinical isolates of S. aureus collected from a hospital in Korea. Thereafter, these simulated MICs were randomly allocated to 1,000 virtual patients in whom the TARs for AUC₂₄/MIC >125 [or 345] and C_trough >10 [or 20] mg/L were determined. The relationship of the maintenance dose with the steady-state TAR was predicted with respect to the AUC₂₄/MIC >125 [or 345] using logistic analysis.

Results

The standard dose regimen of teicoplanin showed TARs of about 70% [or 33%] and 70% [or 20%] at steady-state in cases with AUC₂₄/MIC >125 [or 345] and C_trough >10 [or 20] mg/L, respectively.

Conclusion

The current standard dose regimen was predicted to be insufficient to adequately treat S. aureus in Korean patients with neutropenic fever. To assure at least an 80% TAR in this population, dose adjustment of teicoplanin should be considered.     

The in vitro activity of moxifloxacin against Haemophilus influenzae and Moraxella catarrhalis explored using a pharmacodynamic model

ObjectiveTo assess the antibacterial action of moxifloxacin on Haemophilus influenzae and Moraxella catarrhalis using an in vitro pharmacodynamic model of infection.MethodsSerum concentrations in humans associated with doses of 400 mg once a day for 48 h were simulated and the antibacterial effect measured by the log change in viable count at intervals through the simulation compared to time zero and also the area under the bacterial kill curve (AUBKC). Wild- type strains of H. influenzae and M. catarrhalis with varying β-lactam susceptibilities (moxifloxacin MICs ≥0.1 mg/L) and laboratory-generated mutants with moxifloxacin MICs of 0.5–1.0 mg/L were tested.ResultsH. influenzae strains with MICs of ≥0.06 mg/L were eradicated by 12 h; strains with MICs of 0.5–1.0 mg/L were eradicated by 24–36 h. M. catarrhalis strains with MICs of ≥0.08 mg/L were eradicated by 24–36 h, while the less susceptible laboratory mutant (MIC 1.0 mg/L) was not eradicated even at 48 h. Although we used only a single dosing simulation, the AUC/MIC ratio was strongly related to the AUBKC.ConclusionsThese data indicated that once daily dosing of moxifloxacin holds promise for the treatment of infection due to H. influenzae or M. catarrhalis but bacterial killing is related to MIC.     

24-Month adherence,tolerance and efficacy of once-a-day antiretroviral therapy with didanosine,lamivudine, and efavirenz in African HIV-1 infected children: ANRS 12103/12167

Background

There is no data on long-term benefit of once-a-day antiretroviral therapy (ART) with combination of DDI, 3TC and EFV to allow its use in future therapeutic strategies.

Objectives

To assess 24-month immuno-virological, adherence, tolerance, and effectiveness of a once-a-day ART with DDI, 3TC and EFV.

Methods

A phase 2 open trial including 51 children aged from 30 months to 15 years, monitored a once-a-day regimen for 24 months from 2006 to 2008 in the Departement de Pediatrie du CHUSS, at Bobo-Dioulasso in Burkina Faso. We tested immunological and virological response, adherence, tolerance and resistance of the treatment.

Results

Children with CD4 >25% at 24 months were 67.4% (33/49) CI 95% [54%, 80%]. The proportion of children with viral plasma RNA <300 cp / ml at 24 months of treatment was 81.6 % (40/49) CI [68.0% 91.2%]. Good adherence was obtained with more than 88% adherence > 95% over the 24 months. Drugs were well tolerated.

Conclusions

Given the limited number of antiretroviral drugs available in Africa and the inadequacy of laboratory monitoring in support program, once-a-day treatment and especially the DDI-based combination strategies could be an attractive operational option.     

Ciprofloxacin and Rifampicin Versus Doxycycline and Rifampicin in the Treatment of Brucellosis

 The present study was undertaken to evaluate the efficacy, safety, and patient tolerability of two antibiotic regimens for the treatment of brucellosis: rifampicin 600 mg/day and doxycycline 200 mg/day for 45 days (group 1), versus rifampicin 600 mg/day and ciprofloxacin 1 g/day for 30 days (group 2). Forty patients were diagnosed with brucellosis based on clinical and microbiological findings. The two groups were comparable regarding age and sex distribution. The average number of days without fever and symptoms was lower in group 2 patients than in group 1 patients (mean±SD: 3.85±1.98 for group 1 vs. 2.78±1.03 for group 2, P=0.044). During the 1-year follow-up period, three (15%) patients in group 2 and two (10%) patients in group 1 had clinical relapses; these rates were not significantly different. Ciprofloxacin and rifampicin treatment for brucellosis is as effective as the standard regimen of doxycycline and rifampicin and offers the advantage of a shorter duration of treatment.     

Efficacy of 2- and 4-week rifampicin treatment on the <Emphasis Type="Italic">Wolbachia</Emphasis> of <Emphasis Type="Italic">Onchocerca volvulus</Emphasis>

The microfilaricidal and temporarily sterilizing drug ivermectin is used for mass treatment of filarial infections. Filariae containing Wolbachia endobacteria can also be treated by the antibiotic doxycycline. The loss of Wolbachia results in sterilization of Onchocerca volvulus and macrofilaricidal effects. Besides doxycycline, other antibiotics may be effective in depleting Wolbachia. A preliminary study on the effects of rifampicin on the endobacteria, embryogenesis and microfilariae production of O. volvulus was carried out in the year 2000 in Ghana. Twenty-six onchocerciasis patients were treated for 2 or 4 weeks with 10 mg/kg/day rifampicin. From 17 treated and nine untreated patients, all palpable nodules were extirpated 1 or 18 months after the start of the study and examined for Wolbachia and embryogenesis using immunohistology. One and 18 months after rifampicin treatment, the proportion of Wolbachia-positive worms was significantly reduced compared to the untreated group. In patients treated 4 weeks with rifampicin, only 21% and 18% of living female filariae contained Wolbachia after 1 and 18 months, respectively, compared to 92% in the untreated patients. The reduction of Wolbachia after 2 weeks rifampicin was less but also significant. Embryogenesis and microfilariae production were reduced after 4 weeks rifampicin treatment, rendering rifampicin an antibiotic with anti-wolbachial efficacy in human onchocerciasis. This treatment is less efficient than treatment with 6 weeks doxycycline, but might be an alternative for cases that cannot be treated with doxycycline, e.g. children, or might be further developed for combination therapy.     

Synthetic modifications of the immunomodulating peptide thymopentin to confer anti-mycobacterial activity

Effective global control of tuberculosis (TB) is increasingly threatened by the convergence of multidrug-resistant TB and the human immunodeficiency virus (HIV) infection. TB/HIV coinfections exert a tremendous burden on the host's immune system, and this has prompted the clinical use of immunomodulators to enhance host defences as an alternative therapeutic strategy. In this study, we modified the clinically used synthetic immunomodulatory pentapeptide, thymopentin (TP-5, RKDVY), with six arginine residues (RR-6, RRRRRR) at the N- and C-termini to obtain the cationic peptides, RR-11 (RKDVYRRRRRR-NH₂) and RY-11 (RRRRRRRKDVY-NH₂), respectively. The arginine residues conferred anti-mycobacterial activity to TP-5 in the peptides as shown by effective minimum inhibitory concentrations of 125 mg/L and killing efficiencies of >99.99% against both rifampicin-susceptible and -resistant Mycobacterium smegmatis. The immunomodulatory action of the peptides remained unaffected as shown by their ability to stimulate TNF-α production in RAW 264.7 mouse macrophage cells. A distinct change in surface morphology after peptide treatment was observed in scanning electron micrographs, while confocal microscopy and dye leakage studies suggested bacterial membrane disruption by the modified peptides. The modified peptides were non-toxic and did not cause hemolysis of rat red blood cells up to a concentration of 2000 mg/L. Moreover, RY-11 showed synergism with rifampicin and reduced the effective concentration of rifampicin, while preventing the induction of rifampicin resistance. The synthetic peptides may have a potential application in both immunocompetent and immunocompromised TB patients.     

Low-dose methotrexate therapy for intravenous immunoglobulin-resistant Kawasaki disease

Purpose

The aim of this study was to evaluate the efficacy of low-dose oral methotrexate (MTX) as a treatment for patients with Kawasaki disease (KD) which was resistant to intravenous immunoglobulin (IVIG).

Patients and Methods

The patients who had persistent or recrudescent fever after treatment with IVIG were subsequently treated with low-dose oral MTX [10 mg/body surface area (BSA)] once weekly.

Results

Seventeen patients developed persistent or recrudescent fever after treatment of KD with IVIG and were consequently given MTX. The proportion of children with coronary artery lesions (CALs) was 76%. The median value of maximum body temperatures decreased significantly within 24 hours of MTX therapy (38.6℃ vs. 37.0℃, p < 0.001). The median CRP (C-reactive protein) level was found to be significantly lower 1 week after administering the first dose of MTX (8.9 mg/dL vs. 1.2 mg/dL, p < 0.001). The median duration of fever before MTX treatment was shorter in CALs (-) group than in CALs (+) group (7 days vs. 10 days, p = 0.023). No adverse effects of MTX were observed.

Conclusion

MTX treatment for IVIG-resistant KD resulted in quick resolution of fever and rapid improvement of inflammation markers without causing any adverse effects. MTX therapy should further be assessed in a multicenter, placebo-blinded trial to evaluate whether it also improves coronary artery outcome.     

Investigations of allergic status and blood counts in Chinese patients receiving daily or intermittent rifampicin in Hong Kong

In a controlled trial in Hong Kong, 575 Chinese patients with pulmonary tuberculosis whose treatment with first-line regimens had failed were allocated at random to the following retreatment regimens of chemotherapy. (1) Rifampicin plus ethambutol daily (ER₇). (2) Rifampicin plus ethambutol twice a week (ER₂). (3) Rifampicin plus ethambutol once a week (ER₁). (4) Rifampicin plus ethambutol daily for 2 months and then once a week (ER₇ER₁). (5) Ethionamide plus pyrazinamide plus cycloserine daily for 6 months and then ethionamide plus pyrazinamide daily (EtZC), as a control regimen. Answers to a questionnaire on allergic disease, the results of prick tests with standard allergens, ABO blood grouping, size of tuberculin response during chemotherapy, and a rifampicin patch test showed no associations with the occurrence of adverse reactions to daily or intermittent rifampicin. Mantoux testing during chemotherapy provided no evidence of an immuno-suppressive effect of rifampicin. Mean platelet counts at 12 months were significantly lower than those at 3 months on the two once-weekly regimens (ER₁, ER₇ER₁) and on the control regimen (EtZC), although still within normal limits. At 3 months, but not at 12 months, mean platelet counts on the two once-weekly regimens were significantly lower 6 hr after a dose of the regimen than they were before the dose.     

Continuous intrauterine compared with cyclic oral progestin administration in perimenopausal HRT

OBJECTIVES: Two hormone replacement therapy (HRT) regimens of combined oral estradiol with either continuous intrauterine or cyclic oral progestin were compared for 2 years. METHODS: 200 perimenopausal women randomly received an intrauterine system with continuous levonorgestrel release (20 microg/24 h) combined with oral estradiol (2 mg daily), or a cyclic oral regimen of norethisterone acetate (1 mg on day 13-22) and estradiol (days 1-21; 2 mg, days 22-28; 1 mg). Efficacy on endometrial protection, vaginal bleeding patterns, blood loss and practical use were compared during 26 cycles. RESULTS: Endometrial protection was adequate in both regimens. The cyclic regimen induced a more regular bleeding pattern. The continuous local administration induced a reduction in bleeding (P=0.001) with an initial period of prolonged and frequent bleeding. 38% became amenorrhoeic. Women found both regimens acceptable. CONCLUSIONS: Continuous intrauterine Levonorgestrel administration by using an intrauterine system can well be recommended for use in combination with oestrogen replacement therapy in perimenopausal women.     

Pharmacokinetics of oral and intravenous rifampicin during chronic administration

Summary We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic first-pass effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.Abbreviations AUC area under the serum concentration-time curve - Cl clearance - RMP rifampicin - t 1/2 half-life - Vd_area volume of distribution Dedicated to Professor Dr. Hans J. Dengler on the occasion of his 60th birthday