Cladinose analogues of sixteen-membered macrolide antibiotics. I. Synthesis of 4-O-alkyl-L-cladinose analogues via glycosylation.

The synthesis and biological evaluation of sixteen-membered macrolides possessing a 4-O-alkyl-alpha-L-cladinosyl moiety as the neutral sugar are described. The nine novel derivatives have been synthesized by glycosylation with 1-thio sugars. The most active derivative of them showed prolonged antibacterial activity in rat plasma in vitro and improved pharmacokinetics.

[Roxithromycin passage in the cervix mucus]. / Passage de la roxithromycine dans la glaire cervicale.

We studied the diffusion of roxithromycin in the cervix mucus of fifteen healthy normal women, aged 24 to 44 (median 37). They were consulting physician to have an IUD. After this intervention (between the 4 to 7 days of menstrual cycle) they received an antibiotic treatment with the standard dose of roxithromycin: 150 mg bd for a week. At the end of this treatment the cervix mucus was taken 1 to 12 hours after the last antibiotic dose. We dose the roxithromycin by a microbial assay (Bacillus subtilis ATCC 6633, antibiotic medium 1, pH 8) and the acid alpha-1-glycoprotein by an immunodiffusion assay. All women had drug measurable with levels from 0.45 to 2.07 mg/l (median: 0.80 mg/l). The acid alpha-1-glycoprotein levels were quite constant (median: 0.19 mg/l). The antibiotic concentrations observed are above the MIC of the major genital pathogens, mainly C. trachomatis, G. vaginalis, H. ducreyi and U. urealyticum, but lower than the MIC ov N. gonorrhoeae and M. hominis.

Micro-method for the determination of roxithromycin in human plasma and urine by high-performance liquid chromatography using electrochemical detection.

A simple and sensitive high-performance liquid chromatographic micro-method for the determination of roxithromycin in human plasma and urine is described. A dichloromethane extract of the sample was chromatographed on a C18 reversed-phase column with acetonitrile-83 mM ammonium acetate-methanol (55:23:22, v/v) adjusted to pH 7.5 with acetic acid as the mobile phase. Roxithromycin and the internal standard, erythromycin, were detected by dual coulometric electrodes operated in the oxidative screen mode. The applied cell potential of the screen electrode was set at +0.7 V and the sample electrode at +0.9 V. The intra- and inter-assay coefficients of variation were less than or equal to 7.0%. The detection limit (signal-to-noise ratio = 3) was 0.1 microgram/ml for both plasma and urine. A study of drug stability during sample storage at 4, 20 and 37 degrees C showed no degradation of roxithromycin. The method is convenient for clinical monitoring and pharmacokinetic studies.

[Pharmacokinetics of ponsinomycin administered in a syrup form in single 400-800 and 1200 mg doses in healthy volunteers]. / Pharmacocinétique de la ponsinomycine administrée sous forme de sirop en prises uniques aux doses de 400-800 et 1,200 mg chez le volontaire sain.

Ponsinomycin is a new macrolide. Its pharmacokinetics is characterized by an extensive metabolism. Following oral dosing in human, unchanged ponsinomycin is not found in blood, but 3 main metabolites: Mb12, Mb6 and Mb9a can be assayed. Twelve young healthy volunteers received ponsinomycin orally, at doses equal to 400, 800 and 1,200 mg on 3 separate occasions, according to a cross-over design. Metabolites Mb12, Mb6 and Mb9a were measured in plasma by HPLC. The pharmacokinetics of Mb12 was linear in the range of doses administered. A dose-dependent effect leading to a reduction of the apparent elimination rate when dose increased was observed with Mb9a and more importantly with Mb6.

[Influence of food intake on the bioavailability of ponsinomycin administered in a syrup form]. / Influence de la prise d'aliments sur la biodisponibilité de la ponsinomycine administrée sous forme de sirop.

Ponsinomycin is a new macrolide. Following oral administration, ponsinomycin is totally metabolized, even before reaching blood circulation. Metabolite Mb12 is the first compound on the main metabolic route, which can be assayed. The influence of food on ponsinomycin bioavailability has therefore been estimated from measurements of Mb12 plasma levels. Twelve young healthy volunteers received 800 mg of ponsinomycin as a syrup on two separate occasions, 2 hours before and during a standard meal. The Mb12 metabolite was assayed in plasma by High Pressure Liquid Chromatography (HPLC). Plasma peak concentrations and areas under curves were not significantly different but time to peak was significantly shorter when ponsinomycin was administered during meal. The results suggest that ponsinomycin absorption is faster when administered with food but quantitatively unchanged.

[Comparative study of the penetration of penicillin V, amoxicillin, cefaclor and josamycin in the tonsils]. / Etude comparée de la pénétration de la pénicilline V, de l'amoxicilline, du céfaclor et de la josamycine dans les amygdales.

Fourty patients undergoing tonsillectomy for recurrent tonsillitis were administered penicillin V, amoxicillin, cefaclor or josamycin. Antibiotic concentrations in serum and tonsillar tissues were determined by microbiological assay. Cefaclor demonstrated a superior diffusion than penicillin V and amoxicillin, but nevertheless inferior to that of josamycin.

Roxithromycin as a possible agent for prophylaxis of endocarditis: a study in normal volunteers.

A single dose of roxithromycin, 300 mg, was taken by six healthy male volunteers on three occasions at consecutive weekly intervals. It was well tolerated. On the first two occasions, roxithromycin was assayed in serum samples taken at intervals up to 8 h after the administration. The mean peak concentration at 1 h was 3.0 mg/l (range 0.3-7.3). The serum samples from the volunteers showed variable bactericidal activity against a strain of Streptococcus sanguis isolated from a case of bacterial endocarditis. Roxithromycin was not detected in saliva or gingival fluid. Smooth surface plaque samples taken at intervals were investigated for the emergence of streptococci resistant to roxithromycin at 2 and 8 mg/l. Initially two volunteers had small number of roxithromycin-resistant streptococci. At the end of the study all six volunteers had resistant streptococci detectable in their plaque samples and these accounted for 100% of the streptococci in two volunteers. The most resistant isolates (in several cases with MIC greater than 64 mg/l) were Str. sanguis or Str. mitior; individual volunteers tended to yield the same strain on consecutive samplings.

Solid phase extraction and HPLC determination of spiramycin in plasma and vitreous concentrations.

A method for extracting spiramycin by an octadecylsilica cartridge is described for plasma or vitreous samples. The macrolide antibiotic is then measured by reversed-phase HPLC with UV detection. The limit of detection is estimated to be 50 ng/mL. The coefficient of variation for the procedure is 6.1% and 5.2% for the range of concentrations 0.2 micrograms/mL and 10 micrograms/mL respectively. By this method, pharmacokinetic profiles were performed for five adult patients. Spiramycin could be accurately measured in the vitreous humour, allowing the determination of antibiotic at its site of action.

Miokamycin penetration into oral cavity tissues and crevicular fluid.

Diffusion of miokamycin into gum, maxillary-mandibular bone and crevicular fluid was studied in human beings. The antibiotic concentrations were determined in specimens at different times after oral administration of 600 mg in a single dose of miokamycin. Peak serum levels (2.32 +/- 0.67 mcg/ml) were found at the first hour after dosage. In healthy gum tissue the highest antibiotic levels (1.44 +/- 0.34 mcg/gr) were observed at the second hour, while in the inflamed gum miokamycin penetrates more rapidly, being, as in serum at the highest levels detectable during the first hour. In the bone of the maxilla or mandible the highest levels of miokamycin (0.88 +/- 0.13 mcg/gr) were detected at the second hour after treatment. In the crevicular fluid miokamycin showed a similar profile as that in serum, since the peak levels were reached at the first hour (2.4 +/- 0.88 mcg/ml, but the decrease of the antibiotic occurred more slowly than in serum. Miokamycin rapidly penetrates into tissues and fluids of oral cavity. A single oral dose of 600 mg guarantees antibacterial levels against susceptible bacteria over six hours.

High-performance liquid chromatographic analysis of josamycin in serum and urine.

A high-performance liquid chromatographic assay for the analysis of josamycin in human serum and urine is presented. The assay involves a simple solid-phase extraction procedure coupled with a phase separation step, separation on a reversed-phase C18 column with UV detection by a multi-wavelength programmable detector. The mobile phase was acetonitrile-0.015 M phosphate buffer, pH 6.0 (5:2) at a flow-rate of 1.2 ml/min. The column temperature was maintained at 35 degrees C. Linear calibration curves over the concentration ranges 0.1-2.0 mg/l (serum) and 0.5-5 mg/l (urine) were obtained with correlation coefficients of 0.9983 and 1.0000, respectively. The relative standard deviations of five replicate samples at the upper and lower limits of each calibration curve were below 7%. The recoveries at the upper and lower ends of the calibration range for serum were 77% and 70%, respectively, and those for urine were 76% and 80%, respectively.

[Studies on the absorption and excretion of rokitamycin in infant beagle dogs. Comparison with adult beagle dogs].

Absorption and excretion of rokitamycin (RKM) were studied after oral administration of 50 mg/kg to fasted infant and adult Beagle dogs. In infant Beagle dogs, the mean plasma level of RKM reached its peak of 6.53 micrograms/ml in 15 minutes after administration. The area under the curve (AUC) value was 11.04 micrograms.hr/ml. In adult Beagle dogs, the mean plasma level of RKM reached its peak of 8.62 micrograms/ml in 30 minutes after administration. The AUC value was 18.25 micrograms.hr/ml. Ratios of Cmax and AUC value in infant Beagle dogs to those in adults were about 75% and 60%, respectively. In infant Beagle dogs, urinary excretion of RKM was 2.55% of the dose within 24 hours. In adult Beagle dogs, urinary excretion of RKM was 3.03% of the dose within the same period. The excretion ratio of RKM in infant Beagle dogs was about 85% of the adults' value.

Spiramycin concentrations in female pelvic tissues, determined by HPLC: a preliminary report.

An automated high performance liquid chromatographic method with remote controlled column switching was used to measure the concentration of spiramycin in pelvic tissues and plasma after oral administration of the antibiotic. Three oral doses of 2 g spiramycin were given to patients scheduled for elective gynaecological surgery over the 14 h before 6 a.m. on the day of surgery. Spiramycin concentrations in serum ranged from 7.4 to 12.5 mg/l between 3 h 20 min and 9 h 20 min after the last dose of spiramycin. Spiramycin pelvic tissue concentrations were determined in five of the eleven females and ranged from 4.4 to 33.3 mg/kg. The highest concentrations were observed in the Fallopian tube. These preliminary results suggest that spiramycin has good diffusion into female pelvic tissues.

[Studies on plasma levels and clinical efficacy of rokitamycin in pediatrics].

Pharmacokinetic and clinical evaluations of rokitamycin (RKM, TMS-19-Q), a new macrolide antibiotic, were carried out. RKM was administered orally to 14 patients with congenital heart diseases before cardiocatheterization and angiography. Peak plasma levels of RKM were observed at 30 minutes after the administration at dosages of 5, 10, 15 mg/kg. Although the reason is not clear, there were great variations among plasma levels. Peak plasma levels of patients with relatively good absorption were high enough against bacteria such as beta-hemolytic Streptococcus, Mycoplasma pneumoniae and Chlamydia trachomatis. Clinical responses were evaluated in 5 children comprising 2 cases of mycoplasmal pneumonia, 2 cases of Chlamydia infection and 1 case of beta-hemolytic streptococcal tonsillitis. All of these cases had excellent or good responses without any side effect. Furthermore, no child refused to take RKM dry syrup.

Prostatic tissue concentrations and serum levels of Myocamicin in human subjects.

The diffusion of Myocamicin in the prostatic tissue of patients undergoing prostatectomy after a single oral dose of 600 mg has been studied. The maximum concentration of antibiotic in the prostatic tissue and the serum peak are reached at the first hour with mean values respectively of 3.8 micrograms/g and 2.6 micrograms/ml. The concentrations of Myocamicin remain more elevated in the prostatic tissue compared with the serum levels, at the second, fourth and sixth hours. Myocamicin has shown itself to be an antibiotic with optimal capabilities of diffusion in the prostatic tissue, where it rapidly reaches good therapeutic concentrations.

Some pharmacokinetic data on miocamycin. I: Serum, urinary and prostatic levels.

The pharmacokinetics of miocamycin were studied in ten healthy male volunteers after three different administrations: the first group received 600 mg in a single oral dose; the second received 1200 mg divided into two administrations of 600 mg, each one every 12 h; the third received 1200 mg in a single oral dose. Prostatic levels of miocamycin were recorded after the administration of 1200 mg, divided into two administrations of 600 mg every 12 h. The pharmacokinetic analysis was carried out by applying a single-compartment kinetic model with zero-order absorption. The apparent duration of absorption (T) was about 0.55 h for all subjects. The area under the curve was 7.5767 +/- 0.2511 mg/h/l in the first group; 6.7333 +/- 0.6058 mg/h/l in the second group; and 18.6825 +/- 15.1555 mg/h/l in the third. The prostatic levels were five times higher than those in the serum at the same time.

Penetration of roxithromycin in bronchial secretions.

Roxithromycin sputum and serum concentrations after administration of therapeutic doses (150 mg in a single dose) were evaluated in six patients. Blood samples and pooled sputum samples were collected at corresponding time intervals up to 24 h after drug administration. Roxithromycin sputum levels were found to be almost always above serum concentrations, the highest sputum levels being 5.85 +/- 2.5 micrograms/ml in the interval ranging from 2 to 4 h after drug administration. Due to its antibacterial spectrum and favourable pharmacokinetic properties, roxithromycin, like other macrolide antibiotics, seems to be particularly indicated in the treatment of respiratory tract infections.

[Fetomaternal therapeutic follow-up of spiramycin during pregnancy]. / Suivi thérapeutique foetomaternel de la spiramycine en cours de grossesse.

In the preventive treatment of congenital toxoplasmosis it is admitted that spiramycin is concentrated in the placenta and crosses the placental barrier at the end of pregnancy. However, little is known about its entry in the fetal circulation. We studied fetal spiramycin blood levels during the 2nd and 3rd trimesters of pregnancy in women who, having presented with toxoplasmosis during the 1st trimester, had been given spiramycin until delivery. Microbiological titrations of spiramycin were performed--in the maternal blood at the onset of treatment, at the time of fetal blood sampling and during delivery), in the fetal blood at the time of prenatal diagnosis of toxoplasmosis, in cord blood and placenta at birth. We were able to confirm transplacental crossing of spiramycin. Fetal blood levels during the 2nd trimester were about 47% of the maternal ones and there was no correlation between maternal and fetal levels. Levels at birth showed that (1) there was no accumulation in the course of treatment, (2) spiramycin was concentrated in placenta and (3) there was a correlation between fetal and maternal levels during the 3rd trimester.

Tylosin concentrations in rat serum and lung tissue after administration in drinking water.

Tylosin has low in vitro minimum inhibitory concentrations against Mycoplasma pulmonis but levels attainable in rat serum or lung tissue have not been reported previously. Tylosin levels in rat serum and lung tissue were determined after administration of tylosin in the drinking water. Rats were given water mixed with a commercially available preparation of tylosin base, vitamins, and dextrose. Although the calculated amount of tylosin added to the water was intended to provide a concentration of 500 mg/L, the concentration attained was 70-79 mg/L and decreased rapidly with time. Bioassay of serum and lung tissue after 1-10 days of continuous medication revealed no detectable tylosin concentrations (less than 0.1 microgram/ml) in serum, while lung tissue from all treated rats contained tylosin (means = 10.69 +/- 2.66 micrograms/gm tissue, range = 3.93 to 18.14, n = 59). These concentrations are over ten times the reported in vitro minimum inhibitory concentrations against M. pulmonis which indicates that tylosin administration in drinking water may be useful in the treatment of M. pulmonis pneumonia in rats.