Targeted drug delivery to the skin and deeper tissues: Role of physiology, solute structure and disease

1. Drug delivery through the skin has been used to target the epidermis, dermis and deeper tissues and for systemic delivery, The major barrier for the transport of drugs through the skin is the stratum corneum, with most transport occurring through the intercellular region, The polarity of the intercellular region appears to be similar to butanol, with the diffusion of solutes being hindered by saturable hydrogen bonding to the polar head groups of the ceramides, fatty acids and other intercellular lipids, Accordingly, the permeability of the more lipophilic solutes is greatest from aqueous solutions, whereas polar solute permeability is favoured by hydrocarbon-based vehicles. 2. The skin is capable of metabolizing many substances and, through its microvasculature, limits the transport of most substances into regions below the dermis. 3. Although the flux of solutes through the skin should be identical for different vehicles when the solute exists as a saturated solution, the fluxes vary in accordance with the skin penetration enhancement properties of the vehicle. It is therefore desirable that the regulatory standards required for the bioequivalence of topical products include skin studies. 4. Deep tissue penetration can be related to solute protein binding, solute molecular size and dermal blood flow. 5. Iontophoresis is a promising area of skin drug delivery, especially for ionized solutes and when a rapid effect is required. 6. In general, psoriasis and other skin diseases facilitate drug delivery through the skin. 7. It is concluded that the variability in skin permeability remains an obstacle in optimizing drug delivery by this route.

The structure of versutoxin (delta-atracotoxin-Hv1) provides insights into the binding of site 3 neurotoxins to the voltage-gated sodium channel

Background: Versutoxin (delta-ACTX-Hv1) is the major component of the venom of the Australian Blue Mountains funnel web spider, Hadronyche versuta. delta-ACTX-Hv1 produces potentially fatal neurotoxic symptoms in primates by slowing the inactivation of voltage-gated sodium channels; delta-ACTX-Hv1 is therefore a useful tool for studying sodium channel function. We have determined the three-dimensional structure of delta ACTX-Hv1 as the first step towards understanding the molecular basis of its interaction with these channels. Results: The solution structure of delta-ACTX-Hv1, determined using NMR spectroscopy, comprises a core beta region containing a triple-stranded antiparallel beta sheet, a thumb-like extension protruding from the beta region and a C-terminal 3(10) helix that is appended to the beta domain by virtue of a disulphide bond. The beta region contains a cystine knot motif similar to that seen in other neurotoxic polypeptides. The structure shows homology with mu-agatoxin-l, a spider toxin that also modifies the inactivation kinetics of vertebrate voltage-gated sodium channels. More surprisingly, delta-ACTX-Hv1 shows both sequence and structural homology with gurmarin, a plant polypeptide. This similarity leads us to suggest that the sweet-taste suppression elicited by gurmarin may result from an interaction with one of the downstream ion channels involved in sweet-taste transduction. Conclusions: delta-ACTX-Hv1 shows no structural homology with either sea anemone or alpha-scorpion toxins, both of which also modify the inactivation kinetics of voltage-gated sodium channels by interacting with channel recognition site 3. However, we have shown that delta-ACTX-Hv1 contains charged residues that are topologically related to those implicated in the binding of sea anemone and alpha-scorpion toxins to mammalian voltage-gated sodium channels, suggesting similarities in their mode of interaction with these channels.

Evaluation of antibody response to the heptavalent pneumococcal conjugate vaccine in pediatric chronic kidney disease

Pneumococcal vaccination has been recommended for immunocompromised children, including patients with chronic kidney disease. We determined pneumococcal immunoglobulin (Ig) G antibodies to serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F before and after 48 pediatric patients with chronic renal failure were administered heptavalent conjugated pneumococcal vaccine. The patients were between 1 and 9 years of age and were separated into a conservative treatment group (Group 1) and a dialysis group Group 2). The antibody response to the vaccinal serotypes was evaluated by measuring antibody concentrations before the first dose and 60 days after the second one. Pre-vaccinal IgG concentrations >= 0.35 mu g/ml were detected for all serotypes in at least 50% of the patients in both groups. Patients from both groups showed a statistically indistinguishable behavior in terms of the medians of post-vaccination IgG levels. An ""adequate"" vaccine response was defined as a post-immunization level of specific pneumococcal serotype antibody >= 0.35 mu g/ml, based on the World Health Organization`s (WHO) protective antibody concentration definition for pneumococcal conjugate vaccines, or on a fourfold increase over baseline for at least five of the seven antigens of the vaccine. An ""adequate"" vaccinal response was obtained in 100% of the patients of both groups using WHO`s definition, or in 45.8% of Group 1 patients and 37.5% of Group 2 patients when the criterion was a fourfold antibody increase over baseline antibody concentrations.

Time- and Fluid-Sensitive Resuscitation for Hemodynamic Support of Children in Septic Shock Barriers to the Implementation of the American College of Critical Care Medicine/Pediatric Advanced Life Support Guidelines in a Pediatric Intensive Care Unit in a Developing World

Objectives: To analyze mortality rates of children with severe sepsis and septic shock in relation to time-sensitive fluid resuscitation and treatments received and to define barriers to the implementation of the American College of Critical Care Medicine/Pediatric Advanced Life Support guidelines in a pediatric intensive care unit in a developing country. Methods: Retrospective chart review and prospective analysis of septic shock treatment in a pediatric intensive care unit of a tertiary care teaching hospital. Ninety patients with severe sepsis or septic shock admitted between July 2002 and June 2003 were included in this study. Results: Of the 90 patients, 83% had septic shock and 17% had severe sepsis; 80 patients had preexisting severe chronic diseases. Patients with septic shock who received less than a 20-mL/kg dose of resuscitation fluid in the first hour of treatment had a mortality rate of 73%, whereas patients who received more than a 40-mL/kg dose in the first hour of treatment had a mortality rate of 33% (P < 0.05.) Patients treated less than 30 minutes after diagnosis of severe sepsis and septic shock had a significantly lower mortality rate (40%) than patients treated more than 60 Minutes after diagnosis (P < 0.05). Controlling for the risk of mortality, early fluid resuscitation was associated with a 3-fold reduction in the odds of death (odds ratio, 0.33; 95% confidence interval, 0.13-0.85). The most important barriers to achieve adequate severe sepsis and septic shock treatment were lack of adequate vascular access, lack of recognition of early shock, shortage of health care providers, and nonuse of goals and treatment protocols. Conclusions: The mortality rate was higher for children older than years, for those who received less than 40 mL/kg in the first hour, and for those whose treatment was not initiated in the first 30 Minutes after the diagnosis of septic shock. The acknowledgment of existing barriers to a timely fluid administration and the establishment of objectives to overcome these barriers may lead to a more successful implementation of the American College of Critical Care Medicine guidelines and reduced mortality rates for children with septic shock in the developing world.

Child psychiatry takes to the streets: A developmental partnership between a university institute and children and adolescents from the streets of Sao Paulo, Brazil

Objective: High levels of domestic violence, mental illness, and alienation from authorities are associated with high incidence of children/adolescents living on the streets in low and middle income countries. The Equilibrium Project (Programa Equilibrio) was created to facilitate social reintegration through a virtual partnership between an academic psychiatric institute and highly vulnerable children and adolescents living on the streets, in group shelter with supervision, and in other high risk situations. Methods: Descriptive presentation of qualitative data and analysis of preliminary empirical data collected over a 24-month period. Results: Dialogue between academic professionals, street children, and city officials shaped The Equilibrium Project over the last 2 years. The program has progressively moved from a professional clinic setting to a community-based but protected activity center with recreational and professional services and an emphasis on linkage with social service agencies, city government and law enforcement officials in an academic research context. A total of 351 patients have been served of whom virtually all were neglected by their parents, 58.4% report physical or sexual abuse, 88.89% have been diagnosed with a psychiatric disorder, 40.4% drug use. After 2 years of operation, 63.5% (n = 223) successfully completed or continue in treatment and 34.8% (n = 122) were reunited with their families. Conclusions and Practice implications: Program development guided by consumer input led to a successful program offering professional services in a protected community setting that facilitates social reintegration by providing ""go between"" services integrating relationships between alienated consumers and formal psychiatric, pediatric, social service, and criminal justice systems. (C) 2011 Elsevier Ltd. All rights reserved.

ADHD in a representative sample of the Brazilian population: estimated prevalence and comparative adequacy of criteria between adolescents and adults according to the item response theory

Background: Attention deficit hyperactivity disorder (ADHD) is a clinically significant disorder in adulthood, but current diagnostic criteria and instruments do not seem to adequately capture the complexity of the disorder in this developmental phase. Accordingly, there are limited data on the proportion of adults affected by the disorder, specially in developing countries. Method: We assessed a representative household sample of the Brazilian population for ADHD with the Adult ADHD Self-report Scale (ASRS) Screener, and evaluated the instrument according to the Rasch model of item response theory. Results: The sample was comprised by 3007 individuals, and the overal prevalence of positive screeners for ADHD was 5.8% [95% confidence interval (CI), 4.8-7.0]. Rasch analyses revealed the misfitt of the overall sample to expectations of the model. The evaluation of the sample stratified by age revealed that data for adolescents showed a signficant fittnes to the model expectations, while items completed by adults were not adequated. Conclusions: The lack of fitness to the model for adult respondents challenges the possibility of a linear transformation of the ordinal data into interval measures and the utilization of parametric analyses of data. This result suggests that diagnostic criteria and instruments for adult ADHD must take into account a developmental perspective. Moreover, it calls for further evaluation of currently employed research methods in light of modern theories of psychometrics. Copyright (C) 2010 John Wiley & Sons, Ltd.

The role of alcoholic beverage preference in the severity of alcohol dependence and adherence to the treatment

The severity of dependence on alcohol and the efficacy of diverse types of treatments for alcoholism have been the subject of various researches. This study focused on the types of beverages preferentially consumed by alcohol-dependent outpatients and their effects on the severity of dependence and therapeutic outcomes. Our sample comprised 153 patients, 18-60 years of age, with an International Classification of Diseases (ICD-10) diagnosis of alcohol dependence, who were randomly divided into three different groups to receive topiramate (up to 300 mg/day), naltrexone (50 mg/day), or placebo during 12 weeks of follow-up. Spirits and beer were the main beverages consumed. At the start of this research, the group of spirits drinkers showed higher severity of alcohol dependence, higher craving for alcohol, more frequent history of treatments for alcoholism, and lower income than the group of beer preference drinkers. During the study, beer preference drinkers demonstrated higher adherence to the treatment, independently of the types of medications prescribed (P = .02, odds ratio, 2.46, 95% confidence interval, 1.17-5.19). This study suggests that the severity of dependence and the adherence to the treatment can be factors that set apart beer drinkers from spirits drinkers. As the compliance with the treatment for alcoholism was lower among spirits preference drinkers, a more intensive model of treatment would be necessary. (C) 2009 Elsevier Inc. All rights reserved.

Hippocampus lipid peroxidation induced by residual oil fly ash intranasal instillation versus habituation to the open field

Epidemiological studies have demonstrated the adverse effects of particulate matter (PM) inhalation on the respiratory and cardiovascular systems. It has been reported that air pollution may affect the central nervous system and decrease cognitive function. In rats, residual oil fly ash (ROFA) instillation causes decreased motor activity and increased lipid peroxidation in the striatum and the cerebellum. Our objective was to determine whether chronic instillation of particles induces changes in learning and memory in rats and whether oxidants in the hippocampus may contribute to these adverse effects. Forty-five-day-old male Wistar rats were exposed to ROFA by intranasal instillation and were treated with N-acetylcysteine (NAC) at 150 mg/kg i.p. for 30 days. Control groups were exposed to ROFA, NAC, or neither. On days 1, 8, and 30 of the protocol, rats were submitted to the open field test to evaluate habituation. After the last open field session, the rats were killed by decapitation. The hippocampus was used to determine lipid peroxidation (LP) by the thiobarbituric acid-reactive substances test. ROFA instillation induced an increase in LP in the hippocampus compared to all treatment groups (p = .012). NAC treatment blocked these changes. All of the treatment groups presented a decrease in the frequency of peripheral walking (p = .001), rearing (p = .001), and exploration (p = .001) over time. Our study demonstrates that exposure to particles for 30 days and/or NAC treatment do not modify habituation to an open field, a simple form of learning and memory in rats, and that oxidative damage induced by ROFA does not modulate these processes.

POISSON DISTRIBUTION TO ANALYZE NEAR-THRESHOLD MOTOR EVOKED POTENTIALS

Motor unit action potentials (MUAPs) evoked by repetitive, low-intensity transcranial magnetic stimulation can be modeled as a Poisson process. A mathematical consequence of such a model is that the ratio of the variance to the mean of the amplitudes of motor evoked potentials (MEPs) should provide an estimate of the mean size of the individual MUAPs that summate to generate each MEP. We found that this is, in fact, the case. Our finding thus supports the use of the Poisson distribution to model MEP generation and indicates that this model enables characterization of the motor unit population that contributes to near-threshold MEPs. Muscle Nerve 42: 825-828, 2010

The relation of triceps surae surgical lengthening and crouch gait in patients with cerebral palsy

To investigate the effect of earlier triceps surae (TS) surgical lengthening at knee kinematics in the stance phase in patients with cerebral palsy (CP). One thousand and thirty-nine participants from an eligible total of 1750 children with CP were referred to gait analysis laboratory from January 2000 to April 2007. Inclusion criteria were the diagnosis of diparetic spastic CP levels I to III (GMFCS) and complete kinematics documentation. Patients with an asymmetrical knee pattern at kinematics and with different types of TS management among sides were excluded. The patients were divided into two groups according to the mean minimum knee flexion (MMKF) in stance phase: group A (n = 253) MMKF >= 30 degrees and group B (n = 786) MMKF less than 30 degrees. For each group, the occurrence of following procedures for TS in the past: (i) earlier surgery, (ii) gastrocnemius lengthening (zone I), (iii) gastrocnemius and soleus lengthening (zone II), and (iv) calcaneous tendon lengthening (zone III), was investigated. A chi(2) test was applied to check if the number of procedures performed was different between groups. The level of significance was defined as P value of less than 0.05. The number of patients with no earlier surgeries at TS was higher in group B (51.8%) than in group A (39.1%), and this difference was significant (P<0.01). In addition, the number of procedures at the calcaneous tendon was more elevated in group A (36.8%) than in group B (27%), and this finding was statistically significant as well (P<0.02). The percentage of surgical lengthening at zones I and II was very similar between the groups A and B. This study has shown that patients without earlier surgical procedures at TS are more susceptible to reach better extension of the knees in the stance phase. Patients in a crouch gait had a higher number of calcaneous tendon lengthening performed in the past than patients with a more normal knee extension in the stance phase. J Pediatr Orthop B 19:226-230 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.