A possible pH-controlled drug delivery system based on a derivative of the polysaccharide scleroglucan

Four carboxylated derivatives of scleroglucan have been obtained by oxidation, to different extents, of the glucopyranose side chains of the natural polysaccharide. The diffusion of model molecules through aqueous solutions of these new products was measured at various pH values. The reversible pH induced sol-gel transition of some of the polyelectrolyte solutions tested effects a remarkable variation in the diffusion rate of the permeating species; in this sense the most interesting polysaccharide appears to be the product with 70% oxidized glucopyranose moieties. The behaviour of scleroglucan and its derivatives has been compared with that of carboxymethylcellulose and the mechanism involved in drug permeation and release discussed. The possible application of one of the new products in controlled release formulations for oral use is also reported.     

Phase I North Central Cancer Treatment Group Trial-N9923 of escalating doses of twice-daily thoracic radiation therapy with amifostine and with alternating chemotherapy in limited stage small-cell lung cancer

PURPOSE: The primary goal was to identify the maximum tolerable dose (MTD) of thoracic radiation therapy (TRT) that can be given with chemotherapy and amifostine for patients with limited-stage small-cell lung cancer (LSCLC). METHODS AND MATERIALS: Treatment began with two cycles of topotecan (1 mg/m(2)) Days 1 to 5 and paclitaxel (175 mg/m(2)) Day 5 (every 3 weeks) given before and after TRT. The TRT began at 6 weeks. The TRT was given in 120 cGy fractions b.i.d. and the dose escalation (from 4,800 cGy, dose level 1, to 6,600 cGy, dose level 4) followed the standard "cohorts of 3" design. The etoposide (E) (50 mg/day) and cisplatin (C) (3 mg/m(2)) were given i.v. before the morning TRT and amifostine (500 mg/day) was given before the afternoon RT. This was followed by prophylactic cranial irradiation (PCI). The dose-limiting toxicities (DLTs) were defined as Grade > or =4 hematologic, febrile neutropenia, esophagitis, or other nonhematologic toxicity, Grade > or =3 dyspnea, or Grade > or =2 pneumonitis. RESULTS: Fifteen patients were evaluable for the Phase I portion of the trial. No DLTs were seen at dose levels 1 and 2. Two patients on dose level 4 experienced DLTs: 1 patient had a Grade 4 pneumonitis, dyspnea, fatigue, hypokalemia, and anorexia, and 1 patient had a Grade 5 hypoxia attributable to TRT. One of 6 patients on dose level 3 had a DLT, Grade 3 esophagitis. The Grade > or =3 toxicities seen in at least 10% of patients during TRT were esophagitis (53%), leukopenia (33%), dehydration (20%), neutropenia (13%), and fatigue (13%). The median survival was 14.5 months. CONCLUSION: The MTD of b.i.d. TRT was 6000 cGy (120 cGy b.i.d.) with EP and amifostine.     

Toxocara seropositivity in Sri Lankan children with asthma

Background:  Toxocariasis occurs in humans due to infection with Toxocara canis or T. cati, the nematode parasites of dogs and cats, respectively. The relationship between toxocariasis and asthma is complex, with some studies demonstrating that children with asthma were more likely to be Toxocara seropositive as compared to non-asthmatic children, and other studies indicating no such significant relationship. The aim of the present study was to investigate Toxocara seropositivity and its association with asthma in a selected group of Sri Lankan children.
Methods:  Two groups of children were studied: group 1 included 100 children with confirmed bronchial asthma who were on regular inhaler steroid treatment for asthma; group 2 included 96 children who did not have physician-diagnosed asthma or upper respiratory tract infections, attending the same hospital. Diagnosis of Toxocara seropositivity was based on IgG Toxocara Microwell Serum Elisa Kits. Enzyme-linked immunosorbent assay was regarded as positive for a reading of 0.3 optical density units. Stool samples were examined for helminth ova.
Results:  Toxocara seropositivity in children with asthma was 29% and this was significantly more than Toxocara seropositivity among non-asthmatic children ( P  < 0.001). Toxocara seropositivity was identified as a significant risk factor of asthma in a univariate model. Eosinophilia was seen in a significantly higher proportion of non-asthmatic and asthmatic children who were Toxocara seropositive. Toxocara seropositivity, however, was not identified as a significant risk factor in a multivariate model.
Conclusions:  The analysis confirmed previously identified risk factors for asthma but there was no association between the helminth parasitic infection, toxocariasis and bronchial asthma in children.     

High Rate of Reduced Susceptibility to Ciprofloxacin and Ceftriaxone among Nontyphoid Salmonella Clinical Isolates in Asia

This multinational study from Asia revealed that reduced susceptibility to ciprofloxacin (MIC, 0.125 to 1 μg/ml) in nontyphoid Salmonella isolates was common in Taiwan (48.1%) and Thailand (46.2%) and in S. enterica serotype Choleraesuis (68.8%) and S. Virchow (75.0%) from all countries. Reduced susceptibility to ceftriaxone (MIC, 2 to 8 μg/ml) remained uncommon in Asia, except in Taiwan (38.0%) or in S. Typhimurium (25.0%) from all countries.Nontyphoid Salmonella bacteria, with more than 2,500 serotypes, usually cause diarrheal diseases in humans that may be complicated by extraintestinal infections, such as bacteremia, meningitis, and osteomyelitis (11). Resistance to antimicrobial agents, including fluoroquinolones and expanded-spectrum cephalosporins, has been a serious problem worldwide. Nontyphoid salmonellosis has been rampant in Asia (7); however, data on the antimicrobial susceptibilities, as well as the prevalence, of various serotypes in many Asian countries after 2000 have been lacking.During 2003 to 2005, 400 clinical isolates of nontyphoid Salmonella bacteria were randomly collected from 11 medical centers in seven Asian countries (Table ​(Table1)1) and transported to the central laboratory in Samsung Medical Center, Seoul, Korea, for serogrouping and serotyping using O and H antisera, respectively (Difco Laboratories, Detroit, MI). Susceptibilities to ciprofloxacin, tetracycline, ceftriaxone, ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole were determined by a broth microdilution method, and the results were interpreted according to the breakpoints for MICs suggested by the NCCLS (10). For statistical analysis, isolates in the “intermediate” category were deemed “resistant” in this study. Concomitant resistance to at least three of the six antibiotics tested was defined as multidrug resistance (MDR). Isolates with ciprofloxacin MICs of 0.125 to 1 μg/ml were defined as having “reduced susceptibility” to ciprofloxacin (9). Similarly, “reduced susceptibility” to ceftriaxone was defined as isolates showing ceftriaxone MICs of 2 to 8 μg/ml (14). These definitions were proposed in previous reports to reflect the clinical therapeutic responses (9, 14). The χ² test and Student''s t test were used to determine the significance of differences, and a P value of <0.05 was considered statistically significant.

TABLE 1.

Serotype distribution of the 400 nontyphoid Salmonella isolates among the countries

Phase III randomized, double-blind study of maintenance CAI or placebo in patients with advanced non-small cell lung cancer (NSCLC) after completion of initial therapy (NCCTG 97-24-51)

PURPOSE: This study assessed whether maintenance therapy with carboxyaminoimidazole (CAI), compared to placebo, prolonged overall survival in stage IIIB/IV NSCLC patients who had tumour regression or stable disease after treatment with one chemotherapy regimen. METHODS: After completion of chemotherapy, patients were randomized to receive daily oral CAI at 250mg or placebo. Treatment continued until patient refusal, disease progression or unacceptable adverse event (AE). Quality of life (QOL) was assessed by UNISCALE and Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L). RESULTS: Registration was halted early for slow accrual (targeted 360, randomized 186: 94 CAI, 92 placebo). All patients were off active treatment at time of analyses. Non-haematologic AEs (primarily grade 1, 2) observed significantly more often in the CAI group included fatigue (54.5% versus 29.3%), anorexia (31.1% versus 13.0%), nausea (62.2% versus 30.4%), vomiting (32.2% versus 14.1%), neurosensory (60.0% versus 44.6%) and ataxia (33.3% versus 16.3%). Patients discontinued treatment for AEs, death on study or refusal more often in the CAI group (36.0% versus 8.7%, p<0.0001). No significant differences in survival or time to progression were observed (median: CAI versus placebo: 11.4 months versus 10.5 months, log rank p=0.54; 2.8 months versus 2.4 months, log rank p=0.50). More patients receiving CAI reported a clinically significant (10-point) decline in QOL particularly on the functional (58% versus 37%, p=0.05) construct of FACT-L and UNISCALE (72% versus 51%, p=0.04). CONCLUSION: The addition of CAI following chemotherapy does not provide clinical benefit or improvement in QOL over placebo in advanced NSCLC.     

Proteolysis of the barley receptor-like protein kinase RPG1 by a proteasome pathway is correlated with Rpg1-mediated stem rust resistance

In plants, disease resistance mediated by the gene-for-gene mechanism involves the recognition of specific effector molecules produced by the pathogen either directly or indirectly by the resistance-gene products. This recognition triggers a series of signals, thereby serving as a molecular switch in regulating defense mechanisms by the plants. To understand the mechanism of action of the barley stem rust resistance gene Rpg1, we investigated the fate of the RPG1 protein in response to infection with the stem rust fungus, Puccinia graminis f. sp. tritici. The investigations revealed that RPG1 disappears to undetectable limits only in the infected tissues in response to avirulent, but not virulent pathotypes. The RPG1 protein disappearance is rapid and appears to be due to specific protein degradation via the proteasome-mediated pathway as indicated by inhibition with the proteasomal inhibitor MG132, but not by other protease inhibitors.     

Role of clinical judgment in the application of a nucleic acid amplification test for the rapid diagnosis of pulmonary tuberculosis

BACKGROUND: Several nucleic acid amplification (NAA) tests for Mycobacterium tuberculosis (MTB) have been licensed for the rapid diagnosis of active pulmonary tuberculosis (PTB) in respiratory secretions. There is uncertainty however regarding the practical application of these tests in clinical decision making. OBJECTIVE: To evaluate the utility of the COBAS AMPLICOR assay (Roche Diagnostics; Singapore) for MTB as applied by specialists for the rapid diagnosis of PTB in the routine clinical setting. DESIGN: A prospective study of consecutive patients suspected of PTB and tested with the AMPLICOR assay under the care of respiratory physicians. The final diagnosis was based on all relevant clinical information after at least 3 months of follow-up. Accuracy of the NAA test was compared with that of the initial expectant treatment. Expectant treatment was based on an integrated approach that incorporated clinical evaluation with results of direct smear and NAA tests. RESULTS: The incidence of PTB in 168 patients was 32%. The basis for expectant treatment of PTB was positive smear result in 47%, clinical suspicion in 26%, and positive AMPLICOR result in 23%. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the AMPLICOR test were 77%, 100%, 99%, 90%, and 93%, respectively. In comparison, they were 96%, 97%, 94%, 98%, and 97%, respectively, for the integrated clinical approach. CONCLUSIONS: In the rapid diagnosis of PTB, the clinical judgment of specialists augmented the utility of the NAA test: (1) specialists selected patients with high-to-moderate pretest probabilities, (2) they commenced treatment promptly on a positive NAA test result, and (3) they were willing to start treatment in some patients on the basis of high clinical suspicion despite negative smear and negative NAA test results.     

Topotecan is an active agent in the first-line treatment of metastatic or recurrent endometrial carcinoma: Eastern Cooperative Oncology Group Study E3E93.

PURPOSE: To determine the clinical activity and the toxicity profile of the topoisomerase-I inhibitor, topotecan, in women with recurrent or advanced endometrial carcinoma. PATIENTS AND METHODS: A prospective, phase II clinical trial was initiated by the Eastern Cooperative Oncology Group (ECOG). Patients had histologically confirmed advanced or recurrent endometrial carcinoma, measurable disease, no prior cytotoxic therapy, an ECOG performance status of 0 to 2, and evidence of disease progression while on progestins or after radiation therapy. Topotecan was administered at 1.5 mg/m(2) (or 1.2 mg/m(2) for patients with prior pelvic radiation) intravenously daily for 5 days every 3 weeks. RESULTS: A total of 44 patients were enrolled; 42 were eligible. The study was suspended because of unexpected toxicities, primarily sepsis and bleeding. After toxicity review, the study was reopened using lower doses of topotecan (1.0 mg/m(2) or 0.8 mg/m(2) for patients with prior radiation therapy). In addition, prophylactic use of growth factors was allowed after the first cycle, and patients with performance status of 2 were excluded. The major toxicities were hematologic and gastrointestinal. Among the 40 assessable patients, there were three (7.5%) complete responders and five partial responders (12.5%), for an overall response rate of 20%. The median duration of response was 8.0 months and of overall survival was 6.5 months. CONCLUSION: Topotecan is an active agent for the treatment of advanced endometrial carcinoma. At the doses and schedules initially used, toxicities were unacceptable; however, at the modified doses, toxicities were acceptable and clinical activity was preserved.     

Macrolide resistance and genotypic characterization of Streptococcus pneumoniae in Asian countries: a study of the Asian Network for Surveillance of Resistant Pathogens (ANSORP)

OBJECTIVES: To characterize mechanisms of macrolide resistance among Streptococcus pneumoniae from 10 Asian countries during 1998-2001. METHODS: Phenotypic and genotypic characterization of the isolates and their resistance mechanisms. RESULTS: Of 555 isolates studied, 216 (38.9%) were susceptible, 10 (1.8%) were intermediate and 329 (59.3%) were resistant to erythromycin. Vietnam had the highest prevalence of erythromycin resistance (88.3%), followed by Taiwan (87.2%), Korea (85.1%), Hong Kong (76.5%) and China (75.6%). Ribosomal methylation encoded by erm(B) was the most common mechanism of erythromycin resistance in China, Taiwan, Sri Lanka and Korea. In Hong Kong, Singapore, Thailand and Malaysia, efflux encoded by mef(A) was the more common in erythromycin-resistant isolates. In most Asian countries except Hong Kong, Malaysia and Singapore, erm(B) was found in >50% of pneumococcal isolates either alone or in combination with mef(A). The level of erythromycin resistance among pneumococcal isolates in most Asian countries except Thailand and India was very high with MIC(90)s of >128 mg/L. Molecular epidemiological studies suggest the horizontal transfer of the erm(B) gene and clonal dissemination of resistant strains in the Asian region. CONCLUSION: Data confirm that macrolide resistance in pneumococci is a serious problem in many Asian countries.