Nonclinical aspects of biopharmaceutical development: discussion of case studies at a PhRMA-FDA workshop

Robust assessments of the nonclinical safety profile of biopharmaceuticals are best developed on a scientifically justified, case-by-case basis, with consideration of the therapeutic molecule, molecular target, and differences/similarities between nonclinical species and humans (ICH S6). Significant experience has been gained in the 10 years ensuing since publication of the ICH S6 guidance. In a PhRMA-FDA-sponsored workshop, "Nonclinical Aspects of Biopharmaceutical Development," industry and US regulatory representatives engaged in exploration of current scientific and regulatory issues relating to the nonclinical development of biopharmaceuticals in order to share scientific learning and experience and to work towards establishing consistency in application of general principles and approaches. The proceedings and discussions of this workshop confirm general alignment of strategy and tactics in development of biopharmaceuticals with regard to such areas as species selection, selection of high doses in toxicology studies, selection of clinical doses, the conduct of developmental and reproductive toxicity (DART) studies, and assessment of carcinogenic potential. However, several important aspects, including, for example, appropriate use of homologues, nonhuman primates, and/or in vitro models in the assessment of risk for potential developmental and carcinogenic effects, were identified as requiring further scientific exploration and discussion.     

Residential care centers for persons with intellectual disability in Israel. Trends in the number of children 1999-2008

In 1998, a questionnaire was developed by the Health Services, Office of the Medical Director at the Ministry of Social Affairs and Social Services. This questionnaire was aimed to assess, on a yearly basis, the health of the residents with intellectual disability and the services provided to them by specific residential care centers within Israel. The present study was conducted to examine trends in the number of children with intellectual disability in residential care centers in Israel during 1999-2008. We demonstrated a clear downward trend with regard to the percent of children living in residential care facilities, from 18.1% of the total population in 1999 to 12.8% in 2008.     

Outcome assessment of the Ministry of Health Malaysia dialysis programme

We describe the outcomes on haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) provided by the Ministry of Health (MOH). The assessment was based on data from the Malaysian Dialysis Registry on 2480 HD and 732 CAPD patients who commenced dialysis between 1980 and 1996. Young patients (age < 40) have remarkable long term survival (life expectancies of 16 years on HD, 18 years on CAPD). Adjusting for background mortality, relative survival of older patients was as good as younger ones. Diabetics did poorly. 52% of HD and 26% of CAPD patients were employed in 1996. 71% of HD patients scored 10(normal) on QL index (a measure of quality of life) while 60% of CAPD patients have similar score. Differences in rehabilitation and QL index scores by age, gender and diabetes were also observed. Outcomes of dialysis in the MOH programme are reassuring.     

Tumor necrosis factor is not required for particle-induced genotoxicity and pulmonary inflammation

Particle-induced carcinogenicity is not well understood, but might involve inflammation. The proinflammatory cytokine tumor necrosis factor (TNF) is considered to be an important mediator in inflammation. We investigated its role in particle-induced inflammation and DNA damage in mice with and without TNF signaling. TNF–/– mice and TNF+/+ mice were exposed by inhalation to 20 mg m^–3 carbon black (CB), 20 mg m^–3 diesel exhaust particles (DEP), or filtered air for 90 min on each of four consecutive days. DEP, but not CB particles, induced infiltration of neutrophilic granulocutes into the lung lining fluid (by the cellular fraction in the bronchoalveolar lavage fluid), and both particle types induced interleukin-6 mRNA in the lung tissue. Surprisingly, TNF–/– mice were intact in these inflammatory responses. There were more DNA strand breaks in the BAL cells of DEP-exposed TNF–/– mice and CB-exposed mice compared with the air-exposed mice. Thus, the CB-induced DNA damage in BAL-cells was independent of neutrophil infiltration. The data indicate that an inflammatory response was not a prerequisite for DNA damage, and TNF was not required for the induction of inflammation by DEP and CB particles.An erratum to this article can be found at     

Evaluation of nutritional value,characteristics, functional properties of <Emphasis Type="Italic">Cymodocea nodosa</Emphasis> and its benefits on health diseases

Background

Nutritional fact study has prime importance to make the species edible and commercially viable to the food consumers. This is the first report that indicates the chemical characterization, functional, antioxidant and antihypertensive properties of Cymodocea nodosa to evaluate its nutritional status.

Methods

Physico-chemical determination was determined by colorimetric and spectroscopic analysis. The functional and texture properties were evaluated since a desirable texture should be retained. Bioactive substances were determined by liquid chromatography-high resolution electrospray ionization mass spectrometry HPLC-DAD-ESI/MS2 analysis. Health benefit of this plant was highlighting by the antioxidant and antihypertensive potentials.

Results

Results showed that the seagrass powder was characterized by a high content of fibers (56.4%), the fatty acids profile was dominated by the oleic acid, which represents about 62.0% of the total fatty acids and the functional properties proved important values of swelling capacity (6.71?±?0.2) and water holding capacity (12.26?±?0.25), that were comparable to those of some foodstuffs. Finally, the physico-chemical analysis shows the wealth in phenolic compounds, that could be explained by the high antioxidant and antihypertensive ability which was concentration dependent.

Conclusion

The results from this study suggested that this marine plant could be utilized as a healthy food item for human consumption.

     

Effect of exposure to occupational noise and shift working on blood pressure in rubber manufacturing company workers

This study aimed to assess the relationship between shift working and occupational exposure to noise with blood pressure (BP). The study was carried out in a rubber manufacturing company in 2010. Demographic, medical and occupational information for carrying out the study were collected through direct interview. All 331 under study workers were divided into four groups according to work shift and noise exposure severity, from non-noise exposed day time workers (Group 1) to noise exposed shift workers (Group 4). Finally, systolic and diastolic blood pressure levels were compared among these four groups. The results of this study showed that there was a significant difference between average systolic and diastolic BP and hypertension (HTN) frequency in the four groups (p<0.05). The highest rate of HTN and mean systolic and diastolic BP were observed among shift workers who were exposed to noise higher than permissible limit (Group 4). Also the results of logistic regression analysis showed that there was a significant relationship between simultaneous exposures to noise more than the permitted limit and shift work with HTN (p<0.05). The results of our study showed that shift working and simultaneous exposure to noise have an additive effect on occurrence of HTN. It is recommended that during periodic physical examinations of noise exposed shift workers, assessment of the cardiovascular system and BP should be done as well as the auditory system.     

Effects of exposure to mixed organic solvents on blood pressure in non-smoking women working in a pharmaceutical company

Some studies suggest that exposure to industrial solvents can affect blood pressure. The objective of this study was to investigate the effect of a mixture of organic solvents on blood pressure in women working in a pharmaceutical company in Iran. Four hundred and thirty-three women were included in the study. Women working in packing units (group 1) were not exposed to the mixture of organic solvents, women in new laboratory units (group 2) were exposed to the mixture within the permitted range and women working in old laboratory units (group 3) were exposed to the mixture above the permitted limit. We compared systolic and diastolic blood pressures (SBP & DBP) and prevalence of hypertension and pre-hypertension among groups. The results revealed a significant difference in SBP and pre-hypertension (p<0.001) and hypertension (p<0.05) prevalence between the exposed and the control group, but DBP did not differ significantly. Logistic regression analysis showed a significant association between hypertension and exposure to mixed solvents. Odds ratio for hypertension in the group 2 and group 3 (exposed) workers was 2.36 and 3, respectively, compared to controls. Our results suggest that exposure to a mixture of organic solvents may increase SBP and hypertension and pre-hypertension prevalence in drug manufacture workers. Therefore, more attention should be paid to workers that work in such settings by periodically measuring blood pressure and implementing accurate and comprehensive programs to reduce exposure to organic solvents.     

Reproductive performance following conservative microsurgical management of tubal pregnancy

Between 1981 and 1986, 58 women underwent conservative surgery for ectopic pregnancy; 30 had both tubes present, and 28 had the operation on their single tube. Twenty-five of the 30 women with both tubes present desired pregnancy; 17 (68%) conceived again, 14 (56%) had at least one intrauterine pregnancy and 3 (12%) had a repeat extrauterine pregnancy. Twenty-six of the women with a solitary tube desired pregnancy, 12 (46%) of them had at least one intrauterine pregnancy, and 10 (38.5%) had a repeat extrauterine pregnancy. It was concluded that the incidence of intrauterine pregnancy after conservative surgery in patients with both tubes present is not lower than after radical surgery, and that the incidence of extrauterine pregnancy is not higher. The intrauterine pregnancy rate in patients with a solitary tube is high and still higher than the best results available with in-vitro fertilization and embryo transfer. Therefore conservative surgery is indicated in these patients despite the high incidence of repeat extrauterine pregnancy. Since most of the patients who conceived did so during the first year following the operation, we recommend that patients try to conceive immediately.     

Emergency head & neck imaging: infections and inflammatory processes

Neck infections are fairly common in the emergency setting, affecting a broad spectrum of the patient population. Care should be taken not only to distinguish these conditions from other noninfectious origin such as malignancy but also to guide acute clinical management. A familiarity with neck anatomy, the imaging modalities used for investigation of such conditions, as well as common findings on imaging are critical to the care of affected patients. Cross-sectional imaging is a mainstay in this setting. This article presents the most common neck infections, and details some of their most prominent findings on cross-sectional imaging.