Efficacy of the topical skin protectant in advanced development

A topical skin protectant (TSP) (ICD 2289) is being developed to protect service members from exposure to chemical warfare agents (CWA). The TSP is designed for use on the skin at the overgarment closures and other vulnerable areas to enhance protection. The TSP, which is in phase II clinical studies, is a cream containing two chemically inert substances: perfluoroalkylpolyether and polytetrafluoroethylene. Animal data showed that the TSP was effective against percutaneous penetration of a blister agent, sulfur mustard (HD), by reducing the size of skin lesions and against T-2 mycotoxin by preventing the development of erythema and edema. The insect repellent N,N-diethyl-m-toluamide (DEET) reduced the TSP protection against HD regardless of the order of application on rabbit skin prior to dosing of HD. The protection was sustained when DEET was removed with a dry gauze prior to TSP application. The TSP was also effective against percutaneous exposure of nerve agents-thickened (with 5% methyl methacrylamide) soman (TGD) and VX (O-ethyl-S-[2-(diisopropylamino)ethyl]methylphosphonothioate )-by reducing the mortality rate and protecting the red blood cell acetylcholinesterase activity. The TSP was effective against VX when DEET was applied prior to TSP application. Because human efficacy studies using CWA cannot be conducted, the efficacy will be demonstrated by the level of protection against poison ivy (urushiol) contact dermatitis in humans.     

Reliability of labial closure force measurements in normal subjects and patients with CNS disorders.

This study determined the reliability of maximal upper and lower lip closing forces measured using a strain-gauged cantilever beam assembly. An intraclass correlation approach was used to explicitly partition the "error free" between-subject variance and measurement error variance across repeated days (2) and across repeated trials (5). Ten healthy adults served as controls and 30 patients with diagnoses of multiple sclerosis, cerebrovascular accident, or Parkinson's disease served as subjects. The intraclass correlation analyses revealed generally high reliability (R greater than .90) for upper and lower lip force measurements, for various combinations of control and/or patient groups, and within each individual patient group. There was moderate correspondence between the quantitative measures of lip force and the clinical assessment of combined upper (r = .67) and lower lip closure force (r = .62) but low correspondence between the quantitative measures of lip force and the presence of motor speech deficit. The lower lip force of patients with Parkinson's disease (M = 3.1 N) on Day 1 was markedly reduced from that of all other patient groups and controls (M = 10.1 N). These results yield helpful information for the design of investigations of oral-motor weakness and for the quantitative assessment of an individual's clinical status.     

Reliability of hand-held dynamometry and its relationship with manual muscle testing in patients with osteoarthritis in the knee

Support for this study was provided by the Arthritis Health Professions Association, Arthritis Foundation, National Office, and NIH (NIAMS) Multipurpose Arthritis Center Grant No. AM 30692. The reliability of data gathered with hand-held dynamometers (HHD) and the relationship between HHD measurements and manual muscle tests (MMT) have been assessed only with healthy subjects and patients with neuromuscular disorders, not with homogeneous groups of patients with orthopaedic problems. In this study, HHD and MMT were used to measure the strength of knee extensor muscles of 43 patients with osteoarthritis. Test-retest reliability of HHD was determined, and the two testing systems were compared. The HHD measurements indicated that the knee extensor muscles were weak; the MMT grades indicated good strength. The HHD intraclass correlation coefficient for knee extensor strength measurements was 0.92. The HHD measurements increased as the MMT grades increased. The Kendall tau correlation coefficient between HHD measurements and MMT grades for the knee extensor muscles was 0.24. Hand-held dynamometry is less subjective than MMT, especially at the stronger grades. For the purpose of documenting progress of patients, HHD provides a reliable, quantitative method. The use of HHD with weak examiners, weak patients, and inadequate trunk stabilization is questionable. Hand-held dynamometry is useful for clinical and research settings where isokinetic testing is either unfeasible (ie., home care) or cost-prohibitive. J Orthop Sports Phys Ther 1992;16(3):145-149.     

Applications of piezoelectric fluid jetting devices to neuroscience research.

Piezoelectric pumps or "jets" are used in industry for precise dispensing of small volumes of fluids. In the present work we have tested the feasibility of using these piezoelectric devices for dispensing fluids in neurobiological research. In one experiment, 70 picoliter (pl) droplets of histochemical reagent were jetted onto discrete targets of frozen tissue sections, and qualitative and quantitative histochemical studies were done on the small (170 microns diameter) circle of tissue wet by the droplets. In the second experiment, 70 pl droplets of neuroactive drugs were jetted onto brain tissue slices while recording single neurons extracellularly in vitro, and the effects of the drugs were found to vary systematically as a function of the number of drops and the distance between drop application and the recorded neuron. The results indicate that piezoelectric jets could have wide application for dispensing fluids in neurobiological research.     

Intermolecular phosphorylation of insulin receptor as possible mechanism for amplification of binding signal

Clustering of cell-surface insulin receptors has led to the speculation that intermolecular phosphorylation of unoccupied receptors catalyzed by ligand-occupied receptors within the cluster could be a mechanism by which the insulin-binding signal is amplified. We examined whether insulin receptors can be phosphorylated by an intermolecular mechanism. In this study, we used highly purified insulin receptors isolated from rat liver plasma membranes and human placental membranes. Rat liver insulin receptors were "activated" by incubation with 10 nM insulin in the presence of ATP. Subsequent to removal of insulin by immunodepletion, these receptors were used as an enzyme source to study phosphorylation of unphosphorylated "substrate" human receptors. Initially, we found no evidence that the addition of activated rat receptors increased phosphorylation of human receptors, when assessed by immunoprecipitation with a human-specific monoclonal antibody. To examine the possibility that these negative results were due to insufficient receptor concentration, activated human receptors were mixed with unphosphorylated substrate receptors at concentrations up to 60 micrograms/ml. In this study, we found that addition of activated receptors resulted in increased phosphorylation of the substrate receptors at the highest concentrations employed. These are the first data indicating that insulin receptors per se are capable of intermolecular phosphorylation. In vivo, this could be the initial step in amplifying the insulin-binding signal.     

Cisplatin disposition in children and adolescents with cancer

Summary The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m² (11) or 90 mg/m² (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (±SE) elimination half-life of free cisplatin in serum was 1.3 (±0.4) h. Serial serum concentrations of total platinum following 90 mg/m² dosages were adequately described by a biexponential equation. The mean (±SE) serum T_1/2 of total platinum was 0.42 (±0.10) h and the mean (±SE) T_1/2 was 44.43 (±8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K₁₂) that is about six times the rate of transport out of tissues (K₂₁). The mean (±SE) renal clearance of total platinum from 0–3 h was 37.36 (±11.96) ml/min/m² and 35.8 (±13.6) ml/min/m² for the 30 mg/m² and 90 mg/m² groups, respectively. This value decreased to 3.25 (±0.94) and 2.16 (±0.4) ml/min/m² for the two groups by the 6–12 h interval, and remained between 1 and 3 ml/min/m² for the duration of the observation period. The ratio of total plantinum clearance to creatinine clearance decreased significantly(P<0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.     

Altered behavioral response to dopamine D3 receptor agonists 7-OH-DPAT and PD 128907 following repetitive amphetamine administration.

Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, is mediated in part by dopaminergic pathways. Increased locomotor response to drug treatment, a sensitizable behavior, is modulated by an opposing balance of dopamine receptor subtypes, with D1/D2 dopamine receptor stimulation increasing and D3 dopamine receptor activation inhibiting amphetamine-induced locomotion. We hypothesize that tolerance of D3 receptor locomotor inhibition contributes to behavioral sensitization. In order to test the hypothesis that expression of behavioral sensitization results in part from release of D3 receptor-mediated inhibition, thereby resulting in decreased response to D3 receptor agonists, we examined the effect of repetitive amphetamine administration on the behavioral response to the D3 receptor preferring agonists 7-OH-DPAT and PD 128907. D3-selective effects have recently been described for both drugs at a low dose. At 1 week following completion of a repetitive treatment regimen, amphetamine-pretreated rats displayed a decreased response to D3-selective doses of both 7-OH-DPAT and PD 128907, when compared to animals receiving saline pretreatment. Moreover, in addition to the quantitative alteration in response, there was a change in the inter-relation between response to amphetamine and D3 agonist. A highly significant inverse relation between locomotor inhibitory response to PD 128907 and the locomotor-stimulant response to amphetamine was observed prior to amphetamine treatment. In contrast, 10 days following repetitive amphetamine treatment, the relation between response to PD 128907 and amphetamine was not detected. The observed behavioral alteration could not be accounted for by changes in D3 receptor binding in ventral striatum. These findings suggest a persistent release of D3 receptor-mediated inhibitory influence contributes to the expression of behavioral sensitization to amphetamine.