Long-acting forms of Sonic hedgehog with improved pharmacokinetic and pharmacodynamic properties are efficacious in a nerve injury model

The therapeutic effects of the Sonic hedgehog (Shh) have been difficult to evaluate because of its relatively short serum half-life. To address this issue polyethylene glycol modification (PEGylation) was investigated as an approach to improve systemic exposure. Shh was PEGylated by a targeted approach using cysteines that were engineered into the protein by site-directed mutagenesis as the sites of attachment. Sixteen different versions of the protein containing one, two, three, or four sites of attachment were characterized. Two forms were selected for extensive testing in animals, Shh A192C, which provided a single site for PEGylation, and Shh A192C/N91C, which provided two sites. The PEGylated proteins were evaluated for reaction specificity by SDS-PAGE and peptide mapping, in vitro potency, pharmacokinetic and pharmacodynamic properties, and efficacy in a sciatic nerve injury model. Targeted PEGylation was highly selective for the engineered cysteines and had no deleterious effect on Shh function in vitro. Systemic clearance values in rats decreased from 117.4 mL/h/kg for unmodified Shh to 29.4 mL/h/kg for mono-PEGylated Shh A192C that was modified with 20 kDa PEG-maleimide and to 2.5 mL/h/kg for di-PEGylated Shh A192C/N91C modified with 2, 20 kDa PEG vinylsulfone adducts. Serum half-life increased from 1 h for unmodified Shh to 7.0 and 12.6 h for the mono- and di-PEGylated products. These changes in clearance and half-life resulted in higher serum levels of Shh in the PEG-Shh-treated animals. In Ptc-LacZ knock-in mice expressing lacZ under regulation of the Shh receptor Patched, about a 10-fold lower dose of PEG-Shh was needed to induce beta-galactosidase than for the unmodified protein. Therapeutic treatment of mice with PEG-Shh enhanced the regeneration of injured sciatic nerves. These studies demonstrate that targeted PEGylation greatly alters the pharmacokinetic and pharmacodynamic properties of Shh, resulting in a form with improved pharmaceutical properties.     

Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent,selective, melanocortin subtype-4 receptor agonist

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.     

Personal and Social Factors Influencing Age at First Sexual Intercourse

Early initiation of sexual activity is aconcern, in part because of increased risk of sexuallytransmitted diseases, including HIV, and unwantedpregnancies among young people. In this study, 241 high schoolers were administered a questionnaire toestablish the relationships between age at first sexualintercourse and personal qualities (sexual style,attractiveness, physical maturity, restraint, autonomy expectations, and attitudes to gender roles),smoking and drug use, and aspects of the social context(social activities, media impact, peer norms). Therewere few effects of sex of respondent and none in which respondents' sex impacted on age ofinitiation. Overall (and among the male sample),perceptions of greater physical maturity, greater use ofuncommon (mostly illicit) drugs, and expectations of earlier autonomy significantly differentiatedbetween early and later initiators. This group offactors tends to confirm the view that early experienceof sexual intercourse is correlated with problembehaviors and a press toward adultbehaviors. For girls, this pattern was even clearer,with use of uncommon drugs being replaced as asignificant contributor to early sexual experience byrelative lack of restraint. We conclude that the desire to achieve thetransition to adulthood at an earlier age than theirpeers constitutes a powerful incentive for young peopleto become sexually active.     

Reproducibility of retinal vessel oxygen saturation measurements in healthy young subjects

Purpose: An adequate oxygenation and perfusion is essential for the function of the inner retina. Recently, several techniques for the measurement of retinal oxygen saturation became available. We set out to evaluate reproducibility of the measurements using a modified Retinal Vessel Analyzer. Methods: A total of 20 healthy female and male subjects aged between 18 and 35 years (22.9 ± 3.9; mean ± SD) were included. The measurement of retinal oxygen saturation with the retinal oximeter employed in this study is based on optical reflectometry using the different absorption characteristics of oxygenated and deoxygenated haemoglobin. The intraclass correlation coefficients and the coefficients of variation (CV) for test–retest, short‐term as well as day‐to‐day measurements were calculated. Results: The intraclass correlation coefficients were between 0.91 and 0.94 for retinal branch arteries and between 0.84 and 0.88 for retinal branch veins. In retinal arteries, we calculated a test–retest CV of 3.24 ± 3.18% for oxygen saturation measurements. In retinal veins, data were slightly less reproducible with a CV of 4.92 ± 3.57%. Short‐term reproducibility of both measurement cycles on each study day was in the same range (CV in retinal arteries: 2.91 ± 2.42% and CV in retinal veins: 4.76 ± 3.14%). The day‐to‐day coefficient of variation was slightly higher (CV in retinal arteries: 3.97 ± 2.87% and CV in retinal veins: 6.18 ± 3.36%). Conclusion: The reproducibility of haemoglobin oxygen saturation measurements using the retinal oximeter is acceptable. Further studies on the validity of the obtained results are, however, required.     

Therapeutic drug monitoring in pregnancy

ABSTRACT:: Therapeutic drug monitoring (TDM) is commonly recommended to optimize drug dosing regimens of various medications. It has been proposed to guide therapy in pregnant women, in whom physiological changes may lead to altered pharmacokinetics resulting in difficulty in predicting the appropriate drug dosage. Ideally, TDM may play a role in enhancing the effectiveness of treatment while minimizing toxicity of both the mother and fetus. Monitoring of drug levels may also be helpful in assessing adherence to prescribed therapy in selected cases. Limitations exist as therapeutic ranges have only been defined for a limited number of drugs and are based on data obtained in nonpregnant patients. TDM has been suggested for anticonvulsants, antidepressants, and antiretroviral drugs, based on pharmacokinetic studies that have shown reduced drug concentrations. However, there is only relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Further studies are required to determine whether implementation of TDM during pregnancy improves outcome and is associated with any benefit beyond that achieved by clinical judgment alone. The cost effectiveness of TDM programs during pregnancy also remains to be examined.     

Medication-focused approach to total pain: poor symptom control,polypharmacy, and adverse reactions

Neuropathic pain, known to have poor opioid response, can be difficult to control. Although several classes of adjuvant medications are believed to be of benefit in managing neuropathic pain, they have potential side effects that occasionally outweigh their benefits. The psychospiritual suffering of patients with advanced cancer may heighten the distress associated with physical symptoms. If undiagnosed, this may lead to increases in dose and the number of medications administered in the hope of better symptom control. This case report describes the successful interdisciplinary management of an advanced cancer patient whose multiple drug therapy had added to rather than alleviated his distress by causing more side effects than symptom relief.     

Improved glucose metabolism in mice lacking α-tocopherol transfer protein

Background Conflicting evidence suggests a possible role for vitamin E in mammalian glucose metabolism and the protection from type 2 diabetes. The alpha-tocopherol transfer protein (α-TTP) mediates the transfer of α-tocopherol (α-TOH) from hepatocytes to very-low-density lipoproteins, thereby controlling plasma levels of α-TOH. Aim of the study The aim of this study was to investigate the putative impact of α-TTP knock-out on glucose metabolism in mice. Methods Mice deficient for α-TTP and wild-type control littermates were fed a diet containing 200 mg α-tocopheryl acetate per kg to ameliorate α-TOH deficiency in knock-out mice. We investigated fasting and postprandial plasma glucose, insulin and triglyceride levels of both groups of mice at different ages. All genotypes and age groups were further subjected to glucose and insulin tolerance tests, and number of insulin-producing islets of Langerhans were determined. Results Plasma α-TOH levels of knock-out mice were 34% the levels of wild-type controls: Any signs of α-TOH deficiency were absent at any age. Unexpectedly, serum glucose levels both in the fasted and in the fed state were lower in α-TTP-deficient mice at any age. Removal rates for intraperitoneally injected glucose were found to be significantly increased in young α-TTP-deficient mice. This improved glucose tolerance was caused by increased insulin secretion in response to an intraperitoneal glucose challenge due to an increased number of pancreatic islets, as well as by increased sensitivity to intraperitoneally injected insulin, both significantly promoting glucose metabolism in α-TTP-deficient mice. Conclusions Our findings suggest that α-TTP-deficiency in states of α-TOH supplementation unexpectedly promotes glucose tolerance in mice due to both increased insulin secretion and insulin action, suggesting differential roles of α-TTP and α-TOH in the pathogenesis of type 2 diabetes mellitus. Marc Birringer and Doreen Kuhlow have contributed equally to this publication.     

Exploratory investigation of obesity risk and prevention in Chinese Americans

ObjectiveTo examine the beliefs and attitudes related to obesity risk and its prevention in Chinese Americans via in-depth, qualitative interviews using the guiding tenets of Health Belief Model, Theory of Planned Behavior, and social ecological models.DesignA qualitative study using tenets of the Health Belief Model, the Theory of Planned Behavior, and social ecological models.SettingThe New York City metropolitan area.ParticipantsForty young Chinese American adults (24 females; 16 males) were interviewed.Main Outcome MeasuresObesity risk and prevention.AnalysisCommon themes were identified, coded, and compared using NVivo computer software.ResultsPoor dietary habits and sedentary lifestyles were seen as major weight gain contributors. Obesity was seen predominately as a non-Asian phenomenon, although 60% of the participants felt susceptible to obesity. Physical and social environmental factors were the overriding themes generated as to the causes of weight gain among young adult Chinese Americans. Physical factors included the powerful effect of media-generated advertisements and a plethora of inexpensive fast and convenience foods emphasizing large portion sizes of low nutrient density. The social environment encourages the consumption of large quantities of these foods. Traditional Chinese cuisine was seen as providing more healthful alternatives, but increasing acculturation to American lifestyle results in less traditional food consumption. Some traditional Chinese beliefs regarding the desirability of a slightly heavy physique can encourage overeating.Conclusion and ImplicationsNutrition educators need to be public policy advocates for environments providing tasty, low cost, healthful foods. Young adult Chinese Americans seek knowledge and skills for making convenient healthful food selections in the midst of a culture that advocates and provides an abundance of unhealthful choices.     

Enhancing measurement of primary health care indicators using an equity lens: An ethnographic study

Introduction  

One important goal of strengthening and renewal in primary healthcare (PHC) is achieving health equity, particularly for vulnerable populations. There has been a flurry of international activity toward the establishment of indicators relevant to measuring and monitoring PHC. Yet, little attention has been paid to whether current indicators: 1) are sensitive enough to detect inequities in processes or outcomes of care, particularly in relation to the health needs of vulnerable groups or 2) adequately capture the complexity of delivering PHC services across diverse groups. The purpose of this paper is to contribute to the discourse regarding what ought to be considered a PHC indicator and to provide some concrete examples illustrating the need for modification and development of new indicators given the goal of PHC achieving health equity.     

The Validity of Performance Assessments Using Simulation

Background: The authors wished to determine whether a simulator-based evaluation technique assessing clinical performance could demonstrate construct validity and determine the subjects' perception of realism of the evaluation process.

Methods: Research ethics board approval and informed consent were obtained. Subjects were 33 university-based anesthesiologists, 46 community-based anesthesiologists, 23 final-year anesthesiology residents, and 37 final-year medical students. The simulation involved patient evaluation, induction, and maintenance of anesthesia. Each problem was scored as follows: no response to the problem, score = 0; compensating intervention, score = 1; and corrective treatment, score = 2. Examples of problems included atelectasis, coronary ischemia, and hypothermia. After the simulation, participants rated the realism of their experience on a 10-point visual analog scale (VAS).

Results: After testing for internal consistency, a seven-item scenario remained. The mean proportion scoring correct answers (out of 7) for each group was as follows: university-based anesthesiologists = 0.53, community-based anesthesiologists = 0.38, residents = 0.54, and medical students = 0.15. The overall group differences were significant (P < 0.0001). The overall realism VAS score was 7.8. There was no relation between the simulator score and the realism VAS (R = -0.07, P = 0.41).