Miocamycin-containing triple therapy for H. pylori infection.

INTRODUCTION: In Northern Sardinia, one-week triple standard therapies containing a proton-pump inhibitor and two antibiotics for H. pylori infection have an average cure rate of 57% largely due to a high prevalence of antimicrobial resistance. The efficacy of miocamycin-containing treatment for 10 days was evaluated. MATERIALS AND METHODS: Patients referred to the endoscopy service for dyspeptic symptoms were enrolled. H. pylori infection was defined as a positive rapid urease test, presence of the bacteria on gastric biopsies, and a positive 13C-UBT. Treatment consisted of 10 days with omeprazole 20 mg, miocamycin water-soluble 900 mg, and tinidazole 500 mg all bid. Success was evaluated 40-50 days after the end of therapy and defined by a negative 13C-UBT. Compliance was considered good if at least 90% of the total number of the pills were taken. Fluorescent in situ hybridization (FISH) technique was applied on paraffin-embedded gastric tissue sections to test susceptibility to clarithromycin of the bacteria. RESULTS: 50 patients were enrolled (mean age; 52, 36% men). Miocamycin-containing therapy cured 86% (42/49; 95% CI = 72-94%) of infected patients by PP analysis. Susceptibility data (FISH) was available for 38 patients. Cure rates for the 28 with clarithromycin-susceptible infection was 96% vs 50% for those with resistant or mixed infection, (p = .003). Good compliance was recorded in 48 patients. None of the patients discontinued therapy. CONCLUSIONS: Miocamycin appears to be a valid alternative for clarithromycin for H. pylori eradication. Head-to-head studies will be needed to ascertain whether it is superior.

Influence of chitosan glutamate on the in vivo intranasal absorption of rokitamycin from microspheres.

Intranasal delivery is an alternative method to target therapeutics to the central nervous system. In the present study, chitosan glutamate (CG)-based mucoadhesive microspheres containing rokitamycin (RK) were prepared by spray-drying and in vitro characterization. Moreover, the influence of CG on RK absorption in bloodstream and cerebrospinal fluid (CSF) was evaluated after nasal administration to rats. The in vivo results were compared with those obtained after nasal administration of chitosan (CH)-based microparticles containing RK and after intravenous (IV) administration of the free drug. The in vitro results indicate that the concentrations of feed solution or kind of CH influence the RK entrapment and size of microspheres. All formulations increase the solubility of this poorly water-soluble drug, but CG is more able to increase the in vitro dissolution rate of RK than CH. CG microspheres absorb water quickly and then dissolve, whereas CH particles need more volume of water for swelling and gelling. In vivo studies showed that, after IV administration, RK is not able to cross the blood-brain barrier and to reach the CSF from the bloodstream. On the contrary, drug goes to the CSF and the bloodstream only after nasal administration of CG microparticles.

New chitosan derivatives for the preparation of rokitamycin loaded microspheres designed for ocular or nasal administration.

Acanthamoeba spp. are the causative agents of granulomatous amoebic encephalitis (GAE) and amoebic keratitis. Recent studies performed by Rassu et al. showed that, compared with the free drug, the loading of rokitamycin in chitosan microspheres improves and prolongs the in vitro antiamoebic activity of rokitamycin. This could be useful in transporting the drug for either ocular application to treat amoebic keratitis or nasal administration as an alternative route for the administration of the drug to the brain in GAE therapy. Starting from the previous study, our goal was to optimize the technological parameters in order to obtain chitosan microparticles loaded with rokitamycin and to evaluate the use of new quaternary ammonium chitosan derivatives in the preparation of spray dried microspheres containing the macrolide; these derivatives showed better characteristics (solubility, penetration enhancement) compared with chitosan itself. Toxicity studies on new polymers were performed. Spray dried loaded microspheres based on chitosan or chitosan derivatives were obtained by using appropriate preparative parameters. Microparticles containing chitosan derivatives showed similar or often better properties than formulations made of chitosan with respect to size, in vitro release behaviour and mucoadhesiveness thus making them more suitable for ocular or nasal administration. New polymers did not demonstrate cytotoxicity.

Immune tolerance to drugs. I. Long-term tolerability of rokitamycin in patients with antibiotics hypersensitivity.

Macrolides are considered one of the safest anti-infective groups in clinical use and are well-tolerated as alternative antibiotics in patients with a previous adverse reaction to other classes of antibiotics. However there is scarce information in the literature about their long-term tolerability. The present study was performed to determine whether the results of a challenge test with rokitamycin could predict the response to ingestion of rokitamycin during illness. The study was carried out on 335 patients, who experienced adverse reactions to one or more antibiotics. All patients received peroral challenges with rokitamycin (granules or capsules). On the first day patients received a number of placebo doses equivalent to the rokitamycin doses. One week later, the test was administered by increasing doses of rokitamycin at 60 min intervals until the common daily therapeutic dose of 406.25mg was reached (31.25-93.75-125-156.25mg). A questionnaire was distributed to all subjects. In particular, subjects were asked to clarify any reactive symptom they had developed after ingestion of the drug. It was found that only 3.1% (4/129) of subjects, who used this drug, reported adverse reactions: three experienced urticaria/angioedema and one patient experienced erythema multiforme during treatment. This study, points out a low percentage of adverse reactions to rokitamycin after a negative challenge test, thus, emphasizing both safety and good predictive value as a challenge test.

Quantitative comparison of the cytocidal effect of seven macrolide antibiotics on human periodontal ligament fibroblasts.

The cytocidal effect of seven macrolide antibiotics on human periodontal ligament fibroblasts (Pel cells) was studied. Pel cells were exposed for 48 h to erythromycin (EM), clarithromycin (CAM), roxithromycin (RXM), azithromycin (AZM), josamycin (JM), midecamycin (MDM), and rokitamycin (RKM), and allowed to form colonies. The cytocidal effect of the macrolides was measured as a decrease in colony-forming efficiency and was found to increase with the concentration. To obtain a quantitative measure of the cytocidal effect, the LD50, i.e. the concentration that decreases colony-forming efficiency 50% relative to control cells, was extrapolated from the concentration-response curves. The rank of the macrolides according to their cytocidal effect (LD50) was RKM > RXM > CAM > AZM > JM > MDM approximately EM. RKM, RXM, CAM, AZM, and JM were at least 1.7-12.2 times more cytocidal than MDM or EM. When extrapolated from the concentration-response curves, the relative survival of the Pel cells exposed to each of the macrolides at the MIC90 concentrations for periodontopathic bacteria was estimated to be: > or = 53.8% for RKM, > or = 92.7% for RXM, > or = 94.6% for CAM, > or = 97.1% for AZM, and > or = 86.2% for EM. The effect of the antibiotics on the mRNA expression of alkaline phosphatase (ALP) and type I procollagen (COL) was examined in Pel cells exposed for 48 h to RXM, CAM, AZM, and EM, which exhibited strong, moderate, and weak cytocidal activity. The constitutive levels of both ALP and COL mRNA were retained in cells exposed to RXM at < or = 3 microM, CAM at < or = 10 microM, and AZM or EM at < or = 3 microM. The MIC90 against periodontopathic bacteria is < or = 4.8 microM for RXM, 5.3 microM for CAM, 2.7 microM for AZM, and 21.8 microM for EM. These results suggest that topical administration of CAM or AZM to the gingival crevice at their MIC90 concentration for periodontopathic bacteria would have little adverse effect on the growth and differentiation of the periodontal ligament. It is important to note, however, that these findings have yet to be extrapolated to in vivo conditions.

Pharmacokinetics of miocamycin following intravenous administration to cattle.

The plasma pharmacokinetics for a single intravenous dose (10 mg/kg body weight) of miocamycin (a 16-membered macrolide drug) was investigated in Holando Argentino cattle (n = 5). Blood drug concentrations were determined by a microbiological method and data were best-fitted to a two-compartment open model. The pharmacokinetic profile consisted of a short distribution phase (t1/2 alpha = 7.41 +/- 0.53 min), followed by an extended terminal elimination phase (t1/2 beta = 2.49 +/- 0.23 h). The volume of distribution at steady-state was large (2.13 +/- 0.17 l/kg), suggesting extensive tissue distribution, the clearance value was 0.60 +/- 0.03 l/h.

[Rokitamycin in odontostomatology. Controlled study of doses]. / Rokitamicina in odontostomatologia. Studio controllato tra dosi.

BACKGROUND: Rokitamycin is a semisynthetic macrolide with a lactonic ring with 16 atoms, showing anti-bacterial action at concentrations near to MIC. A controlled clinical study is carried out, in parallel groups, whose aim was to assess the therapeutic action and safety of two dosage schemes of rokitamycin, in the short term treatment (5 days) of acute infective processes of odontostomatological origin. METHODS: Twenty patients (14 males, 6 females) were recruited for the trial, suffering from alveolitis, abscess, phlegmon, sialadenitis and suppurating cysts. The patients were divided in a randomized fashion into two groups: 10 patients were treated orally with 800 mg/day and 10 with 1200 mg/day. Rokitamycin was supplied in 400 mg tablets. RESULTS: The 5 days of treatment with rokitamycin determined the complete resolution of the infective process, with eradication of the germs originally isolated, all belonging to the Streptococcus genus. Clinical efficacy was evident by the third day of treatment, with a prompt improvement of symptoms (functional limitation, pain, tumefaction) and the return of body temperature to within normal limits, in a totally superimposable fashion between the two groups. Safety was excellent with both doses, with no side effects observed. CONCLUSIONS: The results of the study show that treatment with rokitamycin in the short term, at the usual dosage of 800 mg/day, is a valid therapeutic scheme in infective processes in odontostomatology.

[Rokitamycin tolerance in patients with adverse reactions to chemotherapeutic agents]. / Tolleranza alla rokitamicina in pazienti con reazioni avverse a chemioterapici.

The main task in the drug intolerance reactions is the choice of "alternative" drug by oral challenge. The tolerance of rokitamycine (RKM), a new macrolide with a wide activity spectrum in 133 antibiotic-intolerant patients has been studied by open oral challenge with incremental dosage until a cumulative dose of 406 mg. The RKM in 96.2% of cases has been well tolerated. Only 5 patients (3.8%) have had reactions, mainly "atypical" and of minor clinical importance, at cumulative doses ranging from 31.25 to 250 mg. The RKM has been well tolerated also by 6 patients who have had reactions to macrolides belonging to the same group (16 membered). Finally, the use of RKM as alternative drug in chemotherapeutics-intolerant patients has been proposed.

Evaluación del antibiótico miocamicina en niños con infecciones bacterianas cutáneas / Evaluation of the miocarmycin antibiotic in children with bacterial skin infecctions

Se llevó a cabo un ensayo clínico prospectivo abierto con 42 niños que sufrían de enfermedades de la piel, para verificar la eficacia y tolerancia de la Miocamicina, un nuevo antibiótico-macrólido. Se incluyeron 31 casos con impétigo, 5 forunculosis y 6 foliculitis con edades comprendidas entre 1 mes hasta 12 años de edad. De éstos, 27 fueron niñas y 15 niños, promedio de edad 3,3 años. La duración del tratamiento fue de 10 días, a una dosis oral de 30-50 mg/Kg/día. la suspensión de Miocamicina contenía 200 mg/5 ml. Se encontraron 30 aislados bacterianos con alta sensibilidad a la Miocamicina, 2 casos de sensibilidad intermedia y 10 casos con mediana resistencia, la mayoría de los cuales fueron Staphylococcus aureus. Los resultados clínicos mostraron porcentaje de éxito terapéutico equivalente a 90,32 por ciento dentro del grupo de 31 pacientes con impétigo. Asi mismo curaron completamente 3 forunculosis de un grupo de 6 casos, en tanto que 2 mejoraron parcialmente. Por su parte, se logró exito terapéutico total en 50 por ciento de los casos de foliculitis. Del grupo total de 42 pacientes, en 2 no se modificó la patología y 4 empeoraron. Estos datos totalizan un promedio de curación completa, para las 3 piodermias indicadas, equivalente a 85,71 por ciento. Los efectos secundarios se presentaron sólo en 2 casos y consistieron en diarrea ligera y pérdida de apetito, hecho que nos da una tolerancia del 95,23 por ciento

Uso y eficacia de la miocamicina en infecciones de piel y tejido blando en niños / Use and efficacy of miocamycin in skin and soft tissue infections in children

Se realizó un estudio clínico, abierto, no comparativo para evaluar la eficacia y seguridad de miocamicina, en infecciones de piel y tejido blando. Para este propósito se evaluaron treinta y dos (32) pacientes, entre 2 y 14 años con relación clínica y bacteriológica de afecciones de piel y tejido blando, que podían ser manejadas ambulatoriamente. La dosis utilizada fue de 30 mg/kg/día V.O. mediante dos tomas al día por 10 días; con evaluaciones clínicas a los tres, siete y/o diez días posteriores al comienzo del tratamiento. En veintisiete (27) pacientes se aisló el germen causal, los gérmenees aislados con mayor frecuencia fueron estafilococo coagulasa positivo en 14 casos (43 por ciento) y luego 3 Streptococus piógenes en 7 casos (21,8 por ciento). El porcentaje de curación fue del 94 por ciento y la tolerancia Streptococcus pyogenes considererada como excelente o buena en el 98 por ciento de los casos. Se presentaron efectos adversos gastrointestinales transitorios en cinco casos, siendo los más frecuentes: dolor abdominal, náuseas y vómitos. Ninguno de los casos requirió la interrupción del tratamiento

[Benzathine penicillin G and miocamycin in the treatment of children with streptococcal pharyngitis: a controlled therapeutic trial]. / Penicilina G benzatina y miocamicina en el tratamiento de niños con faringitis estreptococica: ensayo terapeutico controlado.

The aim of this study was to compare the clinical and bacteriologic effectiveness of miocamycin (Miocamin, Merck) as compared to benzathine penicillin G in the treatment of streptococcal pharyngitis. One hundred forty nine patients (aged 2 to 15 years) with culture proven Group A streptococcal pharyngitis were randomly assigned to receive miocamycin (15 mg/kg/day bid per os) or one injection of 600,000 or 1,200,000 units of benzathine penicillin G. The clinical response was similar in both groups, in terms of fever duration (16 +/- 14 hours with miocamycin vs 13 +/- 13 hours with penicillin) and normalization of appetite (87.7% of children with miocamycin vs 95.8% of children with penicillin after three days). Bacteriologic eradication of streptococcus was achieved in 66% of children treated with penicillin and 32% of those treated with miocamycin (p < 0.001). We conclude that a single benzathine penicillin is more effective eradicating streptococcus pyogenes than miocamycin in children with streptococcal pharyngitis.

Determinaçäo dos níveis amigdalianos de miocamicina até 12 horas após a administraçäo / Determination of miocamycin levels up to 12 hours after administration

Foram determinados os níveis amigdalianos de miocamicina em cinco pacientes após administraçäo de dose única de 10mg/kg e em 10 pacientes após dois dias de administraçäo de 10 mg/kg de 8/8 horas. No grupo de doses múltiplas, foram detectados níveis tissulares até 12 horas apús a administraçäo. Neste grupo, os valores observados (Cmax, AUC) foram superiores aos do grupo de dose única, apontando para um acúmulo tecidual do antibiótico com a repetiçäo das doses. Estas observaçöes reforçam a validade de um esquema de administraçäo da miocamicina de 12 em 12 horas

Pharmacokinetics of rokitamycin after single administration to healthy volunteers.

The pharmacokinetics of rokitamycin tablets were studied in 12 healthy volunteers in a randomized cross-over design. The doses tested were 200 mg, 300 mg, 400 mg and 600 mg, as single oral administration. Rokitamycin was absorbed quickly with Tmax for all doses around 30 min after drug intake. Total AUC and Cmax values were linearly related to the administered dose. The buffer formulation determined a low interindividual variation. The overall findings show a good similarity with the data obtained in Japanese subjects. Tolerability was very good.

Miocamycin distribution in tonsillar and pulmonary tissues after repeated administration.

Twenty patients undergoing tonsillectomy were treated with a peroral administration of 600 mg of miocamycin every 12 hours for 4 days. On the 5th day, after a last administration of a dose of 600 mg the ablation of the tonsils was carried out on groups of 4 subjects, each one at the following times after oral intake of the drug: 2, 4, 6, 8, 12 h. Twenty-nine patients, admitted to hospital to undergo lung resection were treated with peroral administration of miocamycin in accordance with the above mentioned dose scheme. The operation was carried out on groups of 5 subjects, each on the fifth day at the following times after the last administration: 2, 3, 4, 6, 8 and 12 h (4 subjects). Simultaneously blood was withdrawn for the determination of miocamycin in serum. Miocamycin was measured by a microbiological procedure using Sarcina lutea ATCC 9341. The highest levels of miocamycin were observed after 2h in tonsils (3.2 +/- 0.82 mg/kg) and serum (1.3 +/- 0.33 mg/l). After 12h miocamycin proved to be still measurable in the tissue (0.12 +/- 0.05 mg/kg), whereas it was not detected in serum. In pulmonary tissue, the highest levels of miocamycin were likewise identified at the 2nd hour (2.82 +/- 0.59 mg/kg), simultaneously with the highest serum levels (2.3 +/- 0.61 mg/l). At the 12th hour miocamycin could still be dosed in 3 tissue samples, with values between 0.1 and 0.2 mg/kg and was found just at dosing limits in only one serum sample.

[Evaluation of in vitro activity of rokitamycin against Chlamydia trachomatis].

Evaluation of the in vitro activity of rokitamycin (RKM) against Chlamydia trachomatis in cycloheximide treated HeLa 229 cells and McCoy cells by comparing with five drugs including doxycycline (DOXY), minocycline (MINO), ofloxacin (OFLX), ampicillin (ABPC) and erythromycin (EM) with regard to assaying minimal inhibitory concentrations (MICs), minimal lethal concentrations (MLCs), and by yield reduction assays: 1) direct treatment of Chlamydial organisms with various concentrations of antibiotics before inoculation, 2) pre-treatment of host cell (HeLa 229) with the antibiotics before they are infected and 3) treatment of already infected cultures (48 hrs after infection) with antibiotics. The yield of Chlamydia was determined by both assaying the infectivity of Chlamydia and/or Chlamydiazyme value (from Abott Co Ltd USA). It was found that similar MIC was obtained among the drugs tested (except EM) in both HeLa 229 cell and McCoy cell assay system. The MLC of RKM (0.3 micrograms/ml) was the same as that of OFLX and was significantly lower than that of other drugs tested. When Chlamydial organisms and the host cells were treated with various concentrations (25-0.1 micrograms/ml) of the drug, the infectivity and the growth of Chlamydia was noteworthily decreased with RKM treatment. Infectivity of Chlamydia in an already infected cultures also decreased with RKM treatment within 24 hours when comparing the value of the control. In other drugs treatment, 96 hours or more hours were required for obtaining the same infectivity as RKM.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacokinetics of ponsinomycine with repeated ingestion in healthy volunteers]. / Pharmacocinétique de la ponsinomycine administrée en prises répétées chez le volontaire sain.

Ponsinomycin or miocamycin (MOM) is a new macrolide which is totally metabolized in vivo. The disposition of its 3 major metabolites (Mb12, Mb6 and Mb9a), was investigated following multiple dosing with ponsinomycin at a dose of 800 mg every 12 h, for 8 days, in healthy volunteers. Drug measurements were conducted by high performance liquid chromatography. In agreement with the low values of their apparent elimination half-lives, respectively less than 1.5 h and 3.0 h, metabolites Mb12 and Mb9a did not accumulate with time. Their pharmacokinetics was apparently stable with time. Conversely Mb6 did accumulate, by approximatively a factor 2, although its apparent elimination half-life was only close to 2 h. This value must therefore be considered with caution. A dose dependency effect was previously observed, Mb6 pharmacokinetics could be non linear with time as well. The relative importance of this metabolite is therefore greater at steady-state, following multiple administration than after single dosing with ponsinomycin.

[Effect of rokitamycin on bacterial flora in human feces].

Rokitamycin, a newly developed macrolide antibiotic was orally administered to 7 healthy male volunteers (22-25 years) for 7 consecutive days to study changes in bacterial flora and concentrations of the drug in feces, and to observe adverse reactions and laboratory test parameters. A dose of 200 mg (2 tablets: 100 mg/tablet) was given 3 times daily before meals and the fecal studies were done on the 5 days before administration (adm.) [b.a.], at the time of administration (0), and the 3rd, 5th, 7th (the final day of treatment) days during adm. [u.a.] and the 3rd, 5th, 10th, 20th, 30th days after adm. [a.a.]. The results obtained are summarized as follows. 1. Obvious changes in mean populations of total aerobes and enterobacteriaceae were not found. In changes of each bacteria of enterobacteriaceae, Escherichia coli was not observed in cases from initial day of treatment to the 3rd day a.a. Cases from which Citrobacter sp. was isolated tended to increase after 3 days u.a. and gradually decrease after 3 days a.a. Among Gram-negative bacilli, cases where isolation of Pseudomonas sp. was observed increased temporarily on the 3rd u.a., Gram-positive cocci did not show particular patterns of changes. No changes in mean count of total anaerobes were observed during the course of the experiment. Among individual anaerobes, numbers of Lactobacillus and Peptococcaceae decreased slightly from the 3rd day u.a. and returned on the 5th day a.a. 2. Clostridium difficile D-1 toxin was detected in feces at amounts approximately 500 ng/g in 2 cases each on 20th and 30th day a.a., with 1 incidence occurring in the same person on the 2 separate days. 3. The drug was detected in all 7 cases on the 3rd, 5th and 7th days u.a., and in 1 cases each on the 5th and the 30th day a.a. The mean peak level was 315.5 micrograms/g on the 7th day u.a. The reason for the detection of the drug in feces in 1 case on the 30th day a.a. at a value of 5.90 micrograms/g was not clear. 4. Adverse reactions and abnormal laboratory test results due to this drug were not observed in any cases.

[Evaluation of effectiveness of rokitamycin dry syrup in acute enteritis in pediatrics. A comparative study on rokitamycin and fosfomycin dry syrups].

Because Campylobacter jejuni is most frequently identified as a causative organism of bacterial enteritis in pediatrics, a study was done to evaluate the clinical efficacy against Campylobacter enteritis and the safety of a macrolide antibiotic, rokitamycin (RKM). In case of acute enteritis, RKM was used in a form of dry syrup at a dose level of approximately 30 mg (in potency)/kg body weight and its efficacy and safety were compared to those of fosfomycin (FOM) dry syrup which is currently in use at a dose level of 60 mg (in potency)/kg. Both drugs were administered, as a rule, in 3 divided daily dose (RKM before meal and FOM after meal) for 5 consecutive days. Comparisons of the drugs were made using a well-controlled method. Obtained results are summarized as follows. 1. No significant differences in background factors of the 2 drug groups were apparent, hence it was deemed that no obstacles existed in making comparative studies of the 2 groups with regard to their efficacies and safeties. 2. Overall efficacy rate against Campylobacter enteritis was 100% in the RKM group with a rate of excellent efficacy of 91.3% and the former was 94.4% in the FOM group with the latter of 72.2%. Though the RKM group apparently showed higher rates by 5.6% and 19.1%, respectively, for overall and excellent efficacies, they were not statistically significant as both drugs showed good efficacies. When acute cases of enteritis other than those caused by Campylobacter were included in the analysis, overall efficacy rates and rates of excellent efficacy were, respectively, 97.6% and 85.7% for the RKM group and 88.6% and 68.2% for the FOM group, thus RKM showed higher efficacy rates by 9.0% and 17.5%, respectively. These differences were deemed statistically significant using the U-test. 3. Numbers of days required for most of the major symptoms to subside were 3 days or less for the group for which RKM was used against Campylobacter enteritis. Similar results were observed for the FOM group also. In cases of acute enteritis due to other causes than Campylobacter, slower recoveries were observed for both the RKM and the FOM groups than in Campylobacter enteritis cases, with the latter group slower than the former. In cases of puruloid stool, the recovery in the RKM group was significantly faster by U-test than the FOM group, and a similar trend was observed overall. 4. Bacteriologically, the eradication rate of Campylobacter in the RKM group was very good at 91.3% with the FOM group showing a rate of 78.9%.(ABSTRACT TRUNCATED AT 400 WORDS)