Spiramyin-loaded PLGA implants for the treatment of ocular toxoplasmosis: development, characterization, biocompatibility, and anti-toxoplasma activity.

Ocular toxoplasmosis is the major cause of infectious posterior uveitis worldwide, inducing visual field defect and/or blindness. Despite the severity of this disease, an effective treatment is still lacking. In this study, spiramycin-loaded PLGA implants were developed aiming at the treatment of ocular toxoplasmosis. Implants were manufactured by a hot-molding technique, characterized by Fourier Transform Infrared Spectroscopy, X-Ray Diffraction, Differential Scanning Calorimetry, Scanning Electron Microscopy; evaluated in terms of ocular biocompatibility by immunofluorescence, flow cytometry, cell migration, Hen's egg test-chorioallantoic membrane (HET-CAM) irritation test; and investigated in terms of in vitro efficacy against Toxoplasma gondii . Characterization techniques indicated that spiramycin was dispersed into the polymeric chains and both substances preserved their physical structures in implants. The HET-CAM test indicated that implants did not induce hemorrhage or coagulation, being non-irritant to the CAM. ARPE-19 cells showed viability by MTT assay, and normality in cell cycle kinetics and morphology, without stimulating cell death by apoptosis. Finally, they were highly effective against intracellular parasites without inducing human retinal pigment epithelial cell death. In conclusion, spiramycin-loaded PLGA implants represent a promising therapeutic alternative for the local treatment of ocular toxoplasmosis.

Successful treatment of acute experimental toxoplasmosis by spiramycin-loaded chitosan nanoparticles.

Spiramycin-metronidazole and spiramycin-loaded chitosan (CS) nanoparticles (NPs) were tested in comparison with the current spiramycin treatment of T.gondii concerning tissue penetration and blood brain barrier (BBB) passage. Swiss Albino mice were inoculated intraperitoneally with 2500 T. gondii tachyzoites RH strain and were divided into experimental and control groups. The experimental groups orally received CS NPs, spiramycin, spiramycin-metronidazole, spiramycin-loaded CS NPs 400 mg/kg and spiramycin-loaded CS NPs 100 mg/kg. Drug efficacy was assessed by mice survival time, mortality rate, parasite load in different organs and morphological study of the tachyzoites movement by light microscope and the ultra-structure by SEM. The results revealed that the maximum survival time of more than 200 days with no mortality on the sacrifice day (8th) was observed in mice receiving spiramycin-loaded NPs. Spiramycin-loaded NPs showed the highest significant percent reduction of tachyzoites (about 90% reduction) in liver, spleen and brain as compared to the other used drugs denoting successful bypass of BBB. Light microscopy of the treated peritoneal tachyzoites showed sluggish tachyzoites movement while the NPs caused loss of their movement. SEM of the treated tachyzoites were more mutilated and some of them appeared rupturing in those receiving CS NPs and spiramycin-loaded NPs. In conclusion, spiramycin-loaded NPs showed the highest efficiency in the treatment of acute toxoplasmosis. The non-toxic nature and the anti-parasitic effect of both CS and spiramycin make the use of spiramycin-loaded CS NPs a potential material for treatment of human toxoplasmosis.

Raro compromiso lingual de leishmaniasis mucocutánea por Leishmania perteneciente al subgénero Viannia / Rare Tongue Compromising of Mucocutaneous Leishmaniasis by Leishmania Subgenus Viannia

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The Impact of Short-Term, Intensive Antifolate Treatment (with Pyrimethamine and Sulfadoxine) and Antibiotics Followed by Long-Term, Secondary Antifolate Prophylaxis on the Rate of Toxoplasmic Retinochoroiditis Recurrence.

PURPOSE: To assess the impact of intensive antifolate treatment, followed by secondary antifolate prophylaxis (A-SP) on the recurrence rate of toxoplasmic retinochoroiditis (TRC). To investigate whether there are any other factors potentially predisposing for recurrence. MATERIAL AND METHODS: A total of 637 medical records of TRC patients, who had been treated in the years 1994-2013 were reviewed. All patients were treated with pyrimethamine /sulfadoxine one 25mg/500mg tablet daily (P/S 25/500mg) for 21 days with a double loading dose for the first two days. From Day 2 the patients also received prednisone at a starting dose of 40mg and spiramycine 3 million IU three times daily, given for 10 days followed by azithromycin 500mg once daily for another 6 days. The analysis of the recurrence rate involved 352 patients who had completed 6-month secondary prophylaxis (P/S one 25 mg/500mg tablet twice a week). RESULTS: When secondary antifolate prophylaxis (A-SP) was instituted immediately after the treatment for TRC, the probability of 3-year recurrence-free survival after the first course of A-SP was 90.9%. A recurrence was most likely approximately 3.5 years after the first treatment. A univariate Cox regression model demonstrated that a risk for recurrence was 2.82 times higher (p = 0.02) in patients with retinal scars. In the multivariate analysis, the risk for recurrence was 2.41 higher (p = 0.06). In patients with haemorrhagic lesions the risk for recurrence was lower, aRR = 0.17 (approaching borderline statistical significance p = 0.08). CONCLUSIONS: With the institution of A-SP of immediately after the intensive treatment for TRC, i.e. when a reactivation was most likely, there was no recurrence during A-SP. Following A-SP the recurrence rates were low and recurrence-free periods tended to be longer. The treatment regimen employed had a beneficial effect on the recurrence interval as it reduced and delayed the highest probability of recurrence.

Effects of therapy with two combinations of antibiotics on the imbalance of MMP-2÷TIMP-2 in chronic periodontitis.

UNLABELLED: Periodontitis represents a chronic bacterial infection that induces immuno-inflammatory conditions affecting gingiva and tooth-supporting tissues. The role of some biological mediators in periodontal disease was widely investigated, especially that of MMP-8 and MMP-9. Recently, MMP-2 was also considered to be an appropriate therapeutic target for prevention of periodontal disease progression. However, effects of the combination of metronidazole with amoxicillin or spiramycin on the release and activation of MMP-2 and the balance MMP-2÷TIMP-2 were rarely studied. This study was designed to assess the influence of two combinations of antibiotics used for treatment of periodontitis on the balance MMP-2÷TIMP-2. Gingival samples obtained from patients with no pharmacological treated chronic periodontitis and those receiving either the association between amoxicillin-metronidazole and spyramicin-metronidazole were processed for paraffin embedding and then used to perform immunohistochemical reactions in order to detect MMP-2 and TIMP-2. All subjects were evaluated clinically and radiographic at the first visit and after treatment completed, the Loe & Silnees gingival index at six sites per tooth for the whole mouth being recorded. Statistical analysis was performed using non-parametrical techniques. Gingiva samples from untreated chronic periodontitis patients revealed a diffuse positive reaction for MMP-2 in the epithelium and also in fibroblasts and macrophages from the lamina propria. For gingiva samples from patients treated with antibiotics, MMP-2 positive reaction was restricted to deep epithelial layers and few cells of the connective tissue. No significant difference was observed for TIMP-2 expression. The clinical indexes were in accordance with immunohistochemical results. After treatment, gingival index values were significantly lower then before (p<0.001) in both groups treated with antibiotics. CONCLUSIONS: The two combinations of antibiotics tested in our study seem to have a dual ability to reduce inflammation as well as to inhibit MMP-2 activity.

Spiramycin/cotrimoxazole versus pyrimethamine/sulfonamide and spiramycin alone for the treatment of toxoplasmosis in pregnancy.

OBJECTIVE: To compare the effectiviness of spiramycin/cotrimoxazole (Sp/C) versus pyrimethamine/sulfonamide (Pyr/Sul) and spiramycin alone (Spy) on mother-to-child transmission of toxoplasmosis infection in pregnancy. STUDY DESIGN: Retrospective study of pregnant women evaluated for suspected toxoplasmosis between 1992 and 2011. RESULT: A total of 120 mothers and their 123 newborns were included. Prenatal treatment consisted of spiramycin in 43 mothers (35%), spiramycin/cotrimoxazole in 70 (56.9%) and pyrimethamine/sulfonamide in 10 (8.1%). A trend toward reduction in toxoplasmosis transmission was found when Sp/C was compared with Pyr/Sul and particularly with Spy alone (P=0.014). In particular, Spy increased the risk of congenital infection when compared with Sp/C (odds ratio (OR) 4.368; 95% CI: 1.253 to 15.219), but there was no significant reduction when Sp/C was compared with Pyr/Sul (OR 1.83; 95% CI: 0.184 to 18.274). CONCLUSION: The treatment based on Sp/C has significant efficacy in reducing maternal-fetal transmission of Toxoplasma gondii when compared with Pyr/Sul and particularly to Spy. Randomized controlled trials would be required.

Assessment of laboratory methods used in the diagnosis of congenital toxoplasmosis after maternal treatment with spiramycin in pregnancy.

BACKGROUND: The different laboratory methods used in the diagnosis of congenital toxoplasmosis have variable sensitivity and specificity. There is no evidence to prove that maternal treatment reduces the risk of fetal infection. The purpose of this study was to assess methods for the confirmation of congenital toxoplasmosis after maternal treatment with spiramycin during pregnancy, and to evaluate the effect of this treatment on clinical manifestations of the disease in newborns (NB). METHODS: This was a community-based, cross-sectional study of acute toxoplasmosis in newborns at risk of acquiring congenital infection. Participating newborns were born in the Clinical Hospital Maternity Ward of the Federal University of Goiás. Eligible participants were divided into 2 groups: group 1 consisted of 44 newborns born to mothers treated with spiramycin during pregnancy and group 2 consisted of 24 newborns born to mothers not treated with spiramycin during pregnancy because the diagnosis of toxoplasmosis was not performed. The sensitivity and specifity of PCR for T. gondii DNA in peripheral blood and serological testing for specific anti-T. gondii IgM and IgA, and the effects of maternal spiramycin treatment on these parameters, were determined by associating test results with clinical manifestations of disease. RESULTS: The sensitivity of the markers (T. gondii DNA detected by PCR, and the presence of specific anti-T. gondii IgM and IgA) for congenital toxoplasmosis was higher in group 2 than in group 1 (31.6, 68.4, 36.8% and 3.7, 25.9, 11.1% respectively). Even with a low PCR sensitivity, the group 2 results indicate the importance of developing new techniques for the diagnosis of congenital toxoplasmosis in newborns. Within group 1, 70.4% of the infected newborns were asymptomatic and, in group 2, 68.4% showed clinical manifestations of congenital toxoplasmosis. CONCLUSIONS: The higher proportion of infants without clinical symptoms in group 1 (70.4%) suggests the maternal treatment with spiramycin delays fetal infection, reducing the clinical sequelae of the disease in newborns. Given the low sensitivity of the tests used, when there is suspicion of congenital transmission several serological and parasitological tests are required in order to confirm or exclude congenital toxoplasmosis in newborns.

Effect of spiramycin and tulathromycin on abomasal emptying rate in milk-fed calves.

Impaired abomasal motility is common in cattle with abomasal disorders. The macrolide erythromycin has been demonstrated to be an effective prokinetic agent in healthy calves and in adult cattle with abomasal volvulus or left displaced abomasum. We hypothesized that 2 structurally related macrolides, spiramycin and tulathromycin, would also be effective prokinetic agents in cattle. Six milk-fed, male, Holstein-Friesian calves were administered each of the following 4 treatments: spiramycin, 75 000 IU/kg BW, IM, this dose approximates 25 mg/kg BW, IM; tulathromycin, 2.5 mg/kg BW, SC; 2 mL of 0.9% NaCl (negative control); and erythromycin, 8.8 mg/kg BW, IM (positive control). Calves were fed 2 L of cow's milk containing acetaminophen (50 mg/kg body weight) 30 min after each treatment was administered and jugular venous blood samples were obtained periodically after the start of sucking. Abomasal emptying rate was assessed by the time to maximal plasma acetaminophen concentration. Spiramycin, tulathromycin, and the positive control erythromycin increased abomasal emptying rate compared to the negative control. We conclude that the labeled antimicrobial dose of spiramycin and tulathromycin increases the abomasal emptying rate in healthy milk-fed calves. Additional studies investigating whether spiramycin and tulathromycin exert a prokinetic effect in adult cattle with abomasal hypomotility appear indicated.

Un dérèglement de la motilité de l'abomasum est fréquent chez les bovins avec des troubles de l'abomasum. L'érythromycine, un antibiotique de la famille des macrolides, a été reconnu comme un agent procinétique efficace chez les veaux en santé et chez les bovins adultes avec un volvulus de l'abomasum ou un déplacement à gauche de la caillette. Nous avons émis l'hypothèse que deux autres macrolides apparentés structurellement, la spiramycine et la tulathromycine, seraient également des agents procinétiques efficaces chez les bovins. Six veaux mâles de race Holstein-Friesian nourris au lait ont reçu chacun des quatre traitements suivants : spiramycine, 75 000 IU/kg de poids corporel (BW), par voie intramusculaire (IM), cette dose équivaut approximativement à 25 mg/kg BW, IM; tulathromycine, 2,5 mg/kg BW, par voie sous-cutanée (SC); 2 mL d'une solution de NaCl 0,9 % (témoin négatif); et érythromycine 8,8 mg/kg BW, IM (témoin positif). Les veaux ont reçu 2 L de lait de vache contenant de l'acétaminophène (50 mg/kg de poids corporel) 30 min après l'administration de chaque traitement et des échantillons de sang veineux ont été obtenus périodiquement après le début de la tétée. Le rythme de vidange de l'abomasum a été évalué par le temps requis pour atteindre la concentration plasmatique maximale d'acétominophène. La spiramycine, la tulathromycine, et le témoin positif érythromycine ont fait augmenter le rythme de vidange de l'abomasum comparativement au témoin négatif. Nous concluons que la dose antimicrobienne de spiramycine et de tulathromycine mentionnée sur l'étiquette augmente le rythme de vidange de l'abomasum chez des veaux en santé nourris au lait. Des études supplémentaires semblent indiquées pour évaluer si la spiramycine et la tulathromycine ont un effet procinétique chez les bovins adultes avec hypomotilité de l'abomasum.(Traduit par Docteur Serge Messier).

[Clinical experience on treating Toxoplasma gondii infection during pregnancy by using acetyl spiramycin combined with azithromycin].

OBJECTIVE: To explore an effective therapy for pregnant Toxoplasma gondii infection by using acetyl spiramycin combined with azithromycin. METHODS: ELISA and PCR were used to diagnose and evaluate the therapy efficiency to toxoplasmosis in pregnant women. RESULTS: The serological test showed that the positive rates of specific antibodies IgM and IgG to Toxoplasma gondii in 285 pregnant women were 1.05% (3/285) and 5.97% (17/285), respectively. All the 3 cases of serum IgM positive pregnant women received the amniotic fluid PCR tests for Toxoplasma gondii DNA and 2 were positive, and they received spiramycin combined with azithromycin. After the therapy, their serum IgM antibody specific to Toxoplasma gondii and positive amniotic fluid PCR test for Toxoplasma gondii DNA turned to be negative. CONCLUSION: Acetyl spiramycin in combination with azithromycin is effective in the treatment of pregnant toxoplasmosis.

Unresolved questions about the most successful known parasite.

Every 3 years, the International Congress on Congenital Toxoplasmosis meeting gathers experts with different backgrounds who are involved in congenital toxoplasmosis: gynecologists, pediatricians, ophthalmologists, microbiologists, epidemiologists and research scientists. Most attendees come from the Americas and Europe, where substantial work has been performed to better understand this disease. Two presentations that stressed major current issues in the field of toxoplasmosis are summarized here.

[Management of cervical cellulitis with and without mediastinal extension: report of 17 cases]. / Prise en charge des cellulites cervicales avec on sans extension médiastinale: à propos de 17 cas.

OBJECTIVES: Cervical cellulitis is infrequent but serious. The aim of our study was to describe the way we care and to identify certain factors that promote the development of such a condition. PATIENTS AND METHODS: We conducted a retrospective study covering the period 2004 to 2009 and included patients with cervical cellulitis with or without mediastinal extension surgically supported by ENT department of the University Hospital of Dijon. Data were collected clinical, radiological, treatment, type of surgery and complications. RESULTS: Seventeen patients met our inclusion criteria, four of which had a form associated with mediastinitis. Eight patients had taken NSAIDs and/or corticosteroids and fifteen patients antibiotics before their hospitalization. All have benefited from surgery with an average of 1.35 interventions (range 1 to 3) and support postoperative resuscitation. In both cases the outcome was unfavourable. CONCLUSION: The use of NSAIDs and/or corticosteroids was a factor in promoting this type of infection. In the context of surgical treatment, it does not seem necessary to surgically reoperate systematically.

[Hemophagocytic syndrome and toxoplasmic primo-infection]. / Syndrome d'activation macrophagique et primo-infection toxoplasmique.

Hemophagocytic syndrome (HPS) is a clinical entity that combines the clinical, biological and histological symptoms. The physiopathological mechanism involves the interaction between T lymphocytes/NK cells and macrophages, at the origin of an uncontrolled activation of the macrophages. The consequence is a hemophagocytosis extending to numerous organs, preferentially bone marrow. Clinical symptoms include cytopenia, fever unresponsive to antibiotics and multiple organ dysfunctions. Infections, lymphoproliferative disorders, cancers, systemic diseases are the most prevalent triggers or etiologies of HPS. Because of its high risk of mortality, HPS constitutes a diagnostic and therapeutic urgency. The search for an aetiology, in particular by serological testing, is essential because it conditions the treatment and thus the evolution of the disease. We report here the case of a 12 years-old boy presenting a HPS secondary to a toxoplasmic primo-infection. The objective of this work is to present the step of the biological diagnosis of HPS. Moreover, this observation allows the study of a very rare clinical presentation of toxoplasmic primo-infection, in an immunocompetant patient.

[Oral spiramycin for prevention of restenosis in coronary arteries].

Restenosis is the main problem of percutaneous coronary intervention (PCI). We investigated influence of oral Spiramycin (oral 16- cyclic macrolide antibiotic) on restenosis rate after uncovered metal stents implantation. 73 patients with acute myocardial infarction (1month) and one vessel lesion were divided into two groups. The first group composed of 42 patients, were treated with 100 mg aspirin +75 mg clopidogrel per day. The second group composed of 31 patients (12 patients were diabetic and 14 had long stenosis) received aspirin+clopidogrel+ spiramycin (one tablet - 3.000.000 IU per day during 6 weeks). Mean vessel diameter in first group patients was 3,2+0,4 millimeters; in second group patients was 3,1+0,3 millimeters. Angiography was performed twice: after six months of stent implantation and after an year of stent implantation. At 12-month follow up there were no major adverse cardiac events in both groups. Restenosis rate was significantly higher in the first group of patients (14,3% vs 6,4%; p<0,001; 4,8% vs 3,2% p<0,01). Oral administration of spiramycin for prevention of restenosis is safe and cost-effective in case of uncovered metal stents.

Hypersensitivity reactions to metronidazole.

BACKGROUND: Hypersensitivity reactions to metronidazole are infrequently described. However, we believe that such reactions are increasing due to growing use of the drug for the treatment of amebiasis and anaerobe infections combined with other antibiotics. The present study assesses the need for oral provocation in patients with probable hypersensitivity reactions to metronidazole. METHODS: We performed cutaneous prick tests with spiramycin and metronidazole as well as epicutaneous tests with metronidazole at different concentrations in four patients with cutaneous reactions to Rhodogil (metronidazole plus spiramicyn). Controlled oral challenges were then carried out with placebo using erythromycin, spiramycin and metronidazole except in the last patient due to a positive prick test. RESULTS: Only one patient showed a positive metronidazole prick test. The epicutaneous tests were negative. All patients tolerated erythromycin and spiramycin up to therapeutic doses. Oral provocation with metronidazole proved positive, the first patient presenting a delayed exanthema and the other two early erythema and itching. CONCLUSIONS: We present four cases of cutaneous exanthemas caused by metronidazole (two early and two delayed) and probably mediated by an immune mechanism which we have only been able to demonstrate in one case. Taking into account the low sensitivity of the cutaneous tests (prick tests and epicutaneous tests), oral provocation must be considered the "gold standard" for establishing the diagnosis in many cases of hypersensitivity reactions to metronidazole.

Structural identification of bitespiramycin metabolites in rat: a single oral dose study.

Bitespiramycin is a macrolide antibiotic consisting of a mixture of some nine spiramycin ester derivatives. It has a similar spectrum of antibiotic activity to that of spiramycin but has superior pharmacokinetic properties. In this study, a rapid and facile LC/ESI-MSn method was applied to study the metabolism of bitespiramycin in rat following a single oral dose (80 mg kg-1). Concentrations of parent drug constituents and metabolites were determined in plasma, urine, feces and bile. Concentrations of parent drug constituents and metabolites in plasma were very low. In urine, feces and bile, parent drug constituents and 38 metabolites were identified on the basis of their chromatographic and mass spectrometric properties. The identity of 17 metabolites was confirmed by comparison with reference substances. The principal metabolites were the corresponding spiramycins formed by hydrolysis of the 4''-(3-methylbutanoate) groups. Other important metabolic pathways were: hydrolytic loss of the forosamine and mycarose sugars; aldehyde reduction; cysteine conjugation of the aldehyde group; and hydrolysis of the lactone ring. Products formed by lactone ring opening were found only in urine, and those formed by aldehyde reduction were found only in feces. Aldehyde reduction and hydrolytic loss of forosamine represent novel biotransformation pathways for spiramycin derivatives.

Effectiveness of spiramycin in murine models of acute and chronic toxoplasmosis.

The antitoxoplasmic activity of spiramycin (SPI) was evaluated in murine models of infection using a type-1 (RH) or type-2 (Me49) strain of Toxoplasma gondii. In mice infected with 10(2) tachyzoites of the RH strain, treatment with 100 and 200 mg SPI/kg/day had only a limited effect; despite some dose-dependent prolongation of survival, it was unable to protect mice against death. In contrast, in acute infection induced by peroral inoculation of 10, but not 20, cysts of the Me49 strain, a 3-week course of 100 mg SPI/kg/day and a 4-week course of 200 mg/kg/day significantly enhanced protection and markedly reduced brain cyst burdens at 6 months post infection (p.i.). In chronic infection established by inoculation of 10 cysts 3 months previously, a 3-week course of 200 mg SPI/kg/day resulted in significantly decreased brain cyst burdens compared with controls, both 2 weeks after treatment cessation and by 6 months p.i. Although a favourable effect on chronic infection may be specific for mice, these data merit investigation, since they may have clinical ramifications.

Concentrations and in vivo antibacterial activity of spiramycin and metronidazole in patients with periodontitis treated with high-dose metronidazole and the spiramycin/metronidazole combination.

OBJECTIVES: Previous studies have shown that metronidazole, alone or in combination with spiramycin (250 mg/1 500 000 units, three times/day), is an effective treatment for active periodontitis, although the dose of metronidazole currently used (750 mg/day) could provide concentrations in gingival crevice fluid that are too low for the MICs of the involved pathogens. This study tested the in vivo antibacterial efficacy of the currently used metronidazole dose (as contained in the fixed spiramycin/metronidazole combination) in patients with an active periodontitis, and of a high dose (1500 mg/day) of metronidazole alone. METHODS: We measured the MICs of spiramycin and metronidazole for the recovered pathogens and the gingival crevice fluid antibiotic concentrations of both antibiotics, and attempted to correlate them with bacterial eradication. RESULTS: The concentrations of metronidazole consistently exceeded the MICs for the pathogens isolated in the corresponding sites, even at the usual metronidazole (250 mg three times/day) dose. All the bacterial species were eradicated during treatment and at follow-up, although Fusobacterium spp. eradicated during treatment reappeared in a majority of the cases at follow-up, 30 days after treatment, in both groups. CONCLUSIONS: The results of antibiotic therapy with metronidazole or the spiramycin/metronidazole combination are consistent with their in vitro antibacterial activity and with the local antibiotic concentrations; they suggest that the currently used metronidazole dose (250 mg, three times/day) alone or as part of the spiramycin/metronidazole combination, could be sufficient for the treatment of active periodontitis.

[Parallel catalytic hydrogen wave of acetylspiramycin caused by dissolved oxygen and its application].

AIM: To propose a novel polarographic method for the determination of acetylspiramycin (ASPM) is proposed. METHODS: In 0.1 mol x L(-1) NH4Cl-NH3 x H2O (pH 8.9) buffer containing dissolved oxygen, ASPM yielded a sensitive parallel catalytic hydrogen wave with the peak potential of -1.63 V (vs SCE) by single sweep polarography. RESULTS: The 2nd order derivative peak currents (i(p)") of the parallel catalytic hydrogen waves of ASPM showed a linear relationship with its concentrations in the range from 1.74 x 10(-3) microg x mL(-1) to 3.84 microg x mL(-1) (r = 0.9979, n=13). Its detection limit was 5.80 x l0(-4) microg x mL(-1) (3sigma) and RSD (n=13) was 1.24% at the concentration level of 0.871 microg x mL(-1). CONCLUSION: The proposed method could be applied to the determination of ASPM in ASPM tablets.

Tissue distribution of bitespiramycin and spiramycin in rats.

AIM: To investigate the tissue distribution of bitespiramycin (BSPM) and spiramycin (SPM) in rats. METHODS: Liquid chromatographic-mass spectrometric assay was applied for the determination of three major components (isovalerylspiramycins, ISV-SPMs) of BSPM and their major active metabolites (SPMs) in rat tissues and plasma after an oral dose of bitespiramycin, as well as SPMs. RESULTS: High levels of drug concentrations were observed in most tissues, especially in the liver, stomach, intestine, spleen, lung, womb, and pancreas. BSPM persisted long time in many rat tissues such that the drug concentration in spleen was 69.4 nmol/g at 60 h post-dose and it was still above the minimum inhibitory concentration of many susceptible pathogens. At 2.5 h post-dose, the total concentrations of ISV-SPMs and SPMs achieved in tissues were from 6 to 215 times higher than the corresponding concentrations in plasma. At 2.5 h post-dose, the mean C(t)/C(p) of BSPM appeared to be 2- or 3-fold those of SPM in most tissues. The tissue to plasma concentration ratios following oral dose of BSPM were higher than those of SPM in most tissues. The drug was not detected in brain and testis after a single dose of BSPM and SPM. CONCLUSION: Both BSPM and SPM penetrate into rat tissues well and BSPM has higher tissue affinity than SPM.