Inhalation delivery dramatically improves the efficacy of topotecan for the treatment of local and distant lung cancer

Topotecan is potent anti-cancer drug approved for various malignancies but hematopoietic toxicities undermine its wider application and use of its most effective dose. This study aims to improve these limitations through inhalation-delivery. The pharmacokinetics, efficacy, and toxicity of 2–5 times lower inhalation doses of topotecan dry-powder were compared with the standard intravenous (IV) delivery once/twice-a-week. Human-derived EGFR-mutant (H1975), KRAS-mutant (A549), and EGFR/KRAS wild-type (H358) orthotopic and distant lung tumors were evaluated in murine models. Inhalation of 1 mg/kg topotecan significantly improved the half-life and drug exposure (area under the curve, AUC) compared to 5 mg/kg via IV-delivery. AUCs (h*ng/mL) for inhaled/IV topotecan in plasma, lung, liver, and brain were, 831/888, 60,000/1080, 8380/4000, and 297/15, respectively; while the half-life was also greatly increased in these tissues. The average lung tumor burden of H358-derived tumors was reduced from 15.0 g to 8.4 g (44%) in rats treated once-a-week with 2 mg/kg IV and 1.8 g (88%) with 1 mg/kg inhaled topotecan, corroborating previous findings using A549- and H1975-derived orthotopic lung tumors. Importantly, inhaled topotecan showed superior efficacy in suppressing lung tumors at distant sites. The growth of H1975- and H358-derived subcutaneous xenografts were completely arrested and A549-derived tumors were significantly reduced in mice treated twice-a-week with 1 mg/kg inhaled topotecan compared to a minor (H1975 and H358) or no reduction (A549) with twice-a-week 5 mg/kg IV topotecan.     

Detection of Equine Herpesvirus (EHV) ‐1, ‐2, ‐4 and ‐5 in Ethiopian Equids with and without Respiratory Problems and Genetic Characterization of EHV‐2 and EHV‐5 Strains

Infections with equine herpesviruses (EHVs) are widespread in equine populations worldwide. Whereas both EHV‐1 and EHV‐4 produce well‐documented respiratory syndromes in equids, the contribution of EHV‐2 and EHV‐5 to disease of the respiratory tract is still enigmatic. This study describes the detection and genetic characterization of EHVs from equids with and without clinical respiratory disease. Virus‐specific PCRs were used to detect EHV‐1, ‐2, ‐4 and ‐5. From the total of 160 equids with respiratory disease, EHV‐5 was detected at the highest prevalence (23.1%), followed by EHV‐2 (20.0%), EHV‐4 (8.1%) and EHV‐1 (7.5%). Concurrent infections with EHV‐2 and EHV‐5 were recorded from nine (5.2%) diseased horses. Of the total of 111 clinically healthy equids, EHV‐1 and EHV‐4 were never detected whereas EHV‐2 and EHV‐5 were found in 8 (7.2%) and 18 (16.2%) horses, respectively. A significantly higher proportion of EHV‐2‐infected equids was observed in the respiratory disease group (32/160, 20.0%; P = 0.005) compared to those without disease (8/111; 7.2%). EHV‐2‐positive equids were three times more likely to display clinical signs of respiratory disease than EHV‐2‐negative equids (OR 3.22, 95% CI: 1.42–7.28). For EHV‐5, the observed difference was not statistically significant (P = 0.166). The phylogenetic analysis of the gB gene revealed that the Ethiopian EHV‐2 and EHV‐5 strains had a remarkable genetic diversity, with a nucleotide sequence identity among each other that ranged from 94.0 to 99.4% and 95.1 to 100%, respectively. Moreover, the nucleotide sequence identity of EHV‐2 and EHV‐5 with isolates from other countries acquired from GenBank ranged from 92.9 to 99.1% and 95.1 to 99.5%, respectively. Our results suggest that besides EHV‐1 and EHV‐4, EHV‐2 is likely to be an important contributor either to induce or predispose equids to respiratory disease. However, more work is needed to better understand the contribution of EHV‐2 in the establishment of respiratory disease.     

Natalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing‐remitting multiple sclerosis

Background: Natalizumab (Tysabri) is a monoclonal antibody that was recently approved for the treatment of relapsing‐remitting multiple sclerosis (RRMS). Our primary objective was to analyse the efficacy of natalizumab on disability status and ambulation after switching patients with RRMS from other disease‐modifying treatments (DMTs). Methods: A retrospective, observational study was carried out. All patients (n = 45) initiated natalizumab after experiencing at least 1 relapse in the previous year under interferon‐beta (IFNB) or glatiramer acetate (GA) treatments. The patients also had at least 1 gadolinium‐enhancing (Gd+) lesion on their baseline brain MRI. Expanded Disability Status Scale (EDSS) scores, and performance on the Timed 25‐Foot Walk Test and on the Timed 100‐Metre Walk Test were prospectively collected every 4 weeks during 44 weeks of natalizumab treatment. Brain MRI scans were performed after 20 and 44 weeks of treatment. Results: Sixty‐two per cent of patients showed no clinical and no radiological signs of disease activity, and 29% showed a rapid and confirmed EDSS improvement over 44 weeks of natalizumab therapy. Patients with improvement on the EDSS showed similar levels of baseline EDSS and active T1 lesions, but had a significantly higher number of relapses, and 92% of them had experienced relapse‐mediated sustained EDSS worsening in the previous year. A clinically meaningful improvement in ambulation speed was observed in approximately 30% of patients. Conclusions: These results indicate that natalizumab silences disease activity and rapidly improves disability status and walking performance, possibly through delayed relapse recovery in patients with RRMS who had shown a high level of disease activity under other DMTs.     

Nonmarital sex and condom knowledge among Ethiopian young people: improved estimates using a nonverbal response card

The accurate assessment of risky sexual behaviors and barriers to condom use is essential to reduce the spread of HIV/AIDS. This study tests a new nonverbal response-card method for obtaining more accurate responses to sensitive questions in the context of face-to-face interviewer-administered questionnaires in a survey of 1,269 Ethiopian young people aged 13-24. Comparisons of responses between a control group that provided verbal responses and an experimental group that used the card indicate that the prevalence of nonmarital sexual intercourse may be two times higher and knowledge of condom access may be 22 percent lower in the study than typical population-survey methods suggest. These results suggest that our nonverbal response-card method yields less biased estimates of risky adolescent sexual behavior and perceived access to condoms than those derived from conventional face-to-face interviewer-administered surveys, and that this method provides an effective, easy-to-use, low-cost alternative.     

Gender bias in the food insecurity experience of Ethiopian adolescents

Food insecurity is a pressing public health concern in many developing countries. Despite widespread interest in the sociocultural determinants of food insecurity, little is known about whether youths living in food insecure households experience food insecurity. The buffering hypothesis reviewed here assumes that, to the extent possible, adult members of households will buffer younger household members from the ill effects of food insecurity. A variant of the buffering hypothesis argues that only certain members of the households will enjoy the benefits of buffering. We hypothesize that within the context of Ethiopia, where girls have historically experienced discrimination, buffering is preferentially aimed at boys, especially as the household experiences greater levels of food stress. These hypotheses are tested using data from a population-based study of 2084 adolescents living in southwestern Ethiopia. Results indicate that boys and girls were equally likely to be living in severely food insecure households. Despite no differences in their households' food insecurity status, girls were more likely than boys to report being food insecure themselves. This gender difference was the largest in severely food insecure households. This same pattern was observed when comparing male-female sibling pairs living in the same household. These results are among the first to show that household level measures of food insecurity predict adolescent experiences of food insecurity, and that in the Ethiopian socio-cultural context, the relationship between household level food insecurity and adolescent food insecurity varies by gender. We also show that adolescent food insecurity is strongly associated with measures of general health and well-being.     

Calcium,Magnesium, Iron,Zinc and Copper,Compositions of Human Milk from Populations with Cereal and ‘Enset’ Based Diets

Background

As breast milk is normally the only source of food in the early stages of life, the dietary levels of the essential elements in the milk of lactating mothers are significantly important. Ethiopia is a country of many nations and nationalities with distinct dietary habits. This variation in food habit may result in the variation of the nutritional quality of milk of lactating mothers who live in different part of the country, which in turn may affect the intake of nutrients by breast-fed infants. Therefore, a cross-sectional study of the levels of Ca, Mg, Fe, Zn and Cu in milk of mothers from societies with cereal and ‘enset’ based dietary habits was carried out to assess the influence of maternal diet on the levels of the elements in human milk.

Methods

Milk samples were collected from 27 voluntary mothers in Jimma and in 18 rural areas of Welkite. Breast milk samples were collected within four days postpartum and the concentrations of the elements were determined by using FAAS.

Results

Average concentrations (mg/L) of the elements determined in the milk of mothers from Jimma and rural Welkite respectively were: Ca (758 ± 107, 579 ± 168); Mg (22.6 ± 7.87, 30.5 ± 13.4); Fe (0.50 ± 0.08, 0.41 ± 0.17); Zn (2.3 ± 1.2, 2.49 ± 0.88) and Cu (0.28 ± 0.14, 0.16 ± 0.08).

Conclusions

Milk samples from Jimma were found to have significantly higher levels of Ca and Cu than those of rural Welkite (P < 0.05). Breast milk Ca and Cu levels were thus found to be influenced by dietary intake.