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Biomedical subjects

J D Henderson

Publications and source records attributed to J D Henderson.

At least 19 recordsLinked to original sources
PubMed1992

Neurotoxicity of acute and repeated treatments of tabun, paraoxon, diisopropyl fluorophosphate and isofenphos to the hen.

The neuropathic potential of acute and repeated exposures of the phosphoramidates tabun (GA) and isofenphos (IFP), of diisopropyl fluorophosphate (DFP) and paraoxon (PO) were examined in the hen with treatments for up to 90 days via intramuscular injections of the highest tolerated doses with atropine protection. Plasma acetylcholinesterase (AChE), non-specific butyrylcholinesterase (BChE) and creatine kinase (CK) activities were measured in order to monitor whether the compounds were present at biologically active concentrations. Locomotor behavior was observed and tissues from the peripheral and central nervous systems were examined for signs of organophosphate-induced delayed neuropathy (OPIDN). No behavioral or histological evidence of OPIDN was observed after treatments with GA, IFP, PO, saline or atropine sulfate. DFP-treated birds displayed locomotor and neuropathological signs of OPIDN with a no effect level (NOEL) between 25 and 50 micrograms/kg.

Acetylcholinesterase↗
PubMed1992

Blood esterase determinations as markers of exposure.

The bases of using blood enzyme activity measurements [e.g. AChE, non-specific cholinesterase (BChE), carboxylesterase] as markers of organophosphate ester (OP) exposure are inhibition of activity by the binding of OPs to serine active sites in the enzymes, and the accessibility of the enzymes in RBCs and serum. The methods used to determine esterases in the blood of humans, experimental animals, and wildlife are outlined with emphasis on the acetylcholinesterase (AChE) of the red blood cell. Adaptations of an acetylthiocholine ester assay of Ellman et al. (1961) are common, but other colorimetric procedures, radiometric assays, and pH methods are also in use. Optimized, standardized methods are needed to assess exposures and provide a solid basis for risk assessment analyses. Useful adjuncts to ChE measurements are oxime reactivation tests and assay of neuropathy target esterase, an enzyme associated with organophosphate-induced delayed neuropathy. Determination of urinary metabolites compliments, but does not substitute for, the information obtained from blood ChE studies. Future assays are likely to involve antibodies to OP-protein complexes. Improvements in techniques permit the detection of small decreases in ChE activities. Whether or not such small decreases in ChE activities can, by themselves, constitute an adverse effect for input into risk assessment analyses is a controversial matter.

Biomarkers↗
PubMed1990

Acetylcholinesterase and neuropathy target esterase in chickens treated with acephate.

Reports that near-lethal doses of the pesticide methamidophos (O,S-dimethyl phosphoramidothioate) caused a delayed neurotoxicity (OPIDN) in humans and that another phosphoramidate, isofenphos, caused OPIDN in the hen at high doses, prompted a study of the abilities of acephate (O,S-dimethyl acetylphosphoramidothioate) to inhibit brain acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in vivo. Hens were treated orally with 5-700 mg/kg of acephate, or im with 50-200 micrograms/kg of diisopropyl-fluorophosphate (DFP, positive control) and sacrificed 24 hr later. Brain homogenates were assayed for AChE as an estimate of acute toxicity, for NTE to indicate acephate's potential to cause OPIDN, and for residues of acephate and its metabolite methamidophos. A range finding study confirmed the LD50 level for acephate was approximately 800 mg/kg. Regression analyses indicated an ID50 (a dose that inhibits 50% of activity) for acephate inhibition of AChE of 10 mg/kg and an extrapolated ID50 for inhibition of NTE of 1300 mg/kg, almost twice the LD50. In contrast, ID50 values for DFP were similar for AChE (146 micrograms/kg) and NTE (132 micrograms/kg). Brain methamidophos levels were 10 to 16 percent of the total acephate plus methamidophos brain concentration. The lower the dose of acephate, the higher was the relative percentage of methamidophos. The results show acephate is a more potent inhibitor of AChE than it is of NTE in hens and suggest it would be difficult to administer a single dose of acephate sufficient to cause OPIDN without killing the animal.

Animals↗
PubMed1989

Fibrillation induced at powerline current levels.

Electrical fibrillation of the human heart results in many unfortunate deaths. Because little information is available on short duration high current fibrillation, current levels below 1 and 50 A were used to induce ventricular fibrillation in hogs. Application times ranged between 16 ms and 3 s. Fibrillation was only produced when currents were applied during the T-wave period of the cardiac cycle. However, only 50 percent of the current application during the T-wave caused fibrillation. The total body resistance of the hogs was also measured at the high voltages and currents. The average resistance for 90 current applications was 284 omega. Trends in the data show that the total resistance decreases for increasing voltage, for increasing electrode size, and for current applications following the first current application.

Animals↗
PubMed1989

Chloramine-T solutions: effect on wound healing in guinea pigs.

An evaluation of the wound-healing and disinfectant activities of chloramine-T (Chlorazene) used in hydrotherapy whirlpools was studied in a guinea pig cutaneous wound model. Standard microbiologic methods were used to determine the bacteriocidal activity of Chlorazene in cultures containing up to 2.03 x 10(6) colony-forming units per milliliter of Pseudomonas aeruginosa. Full-thickness skin wounds in 40 guinea pigs were inoculated with Pseudomonas aeruginosa and all animals allowed to recover from anesthesia. Twenty-four hours later, animals were placed in water only or water containing Chlorazene (300ppm) for 20 minutes. This procedure was repeated daily for up to seven days after inoculation of wounded skin. Rate of wound epithelialization and number of infected wounds were determined. Large reductions in numbers of cultured organisms were observed after treatment with Chlorazene. No differences in rate of wound healing could be determined in water- or Chlorazene-treated animals. Chlorazene-treated wounds contained fewer pseudomonas organisms than water-treated controls on postinoculation days five and six. These results confirm that Chlorazene is an effective water disinfectant. Data also indicate that in the concentration used, Chlorazene does not affect the rate of wound healing.

Animals↗
PubMed1988

Toxicity of an acute dose of agent VX and other organophosphorus esters in the chicken.

The neurotoxicities of single doses of a chemical warfare agent VX [phosphonothioic acid, methyl-S-(2-[bis(1-methylethyl)amino/ethyl) O-ethyl ester], a metabolite of the agricultural chemical parathion, paraoxon, PO (phosphonothioic acid, diethyl paranitrophenyl ester), and the known neuropathic agents DFP] phosphorofluoridic acid, bis(1-methylethyl) ester] and TOCP (phosphoric acid, tri-o-tolyl ester) were compared in the chicken. Single injections (subcutaneous, sc) of VX as high as 150 micrograms/kg (5 times the LD50, intramuscular, im) were tolerated by laying tens if atropine and 2-pralidoxime were used as antidotes before and immediately after injection. The 150 of VX for inhibition of chicken brain acetylcholinesterase was approximately 5 X 10(-10). Plasma acetylcholinesterase, but not butyrylcholinesterase, was depressed 2 h after injections of 2-20 micrograms VX/kg im without antidotes. Levels of plasma enzymes such as creatine kinase, indicative of tissue damage, were increased after exposure to both VX and PO. Injections of up to 150 micrograms/kg of VX with antidotes did not cause locomotor or histological signs of organophosphorus-induced delayed neuropathy, but single injections of 400 mg TOCP/kg did.

Acetylcholinesterase↗
PubMed1988

Toxicity of repeated doses of organophosphorus esters in the chicken.

Hens were repeatedly exposed to paraoxon (PO, phosphonothioic acid, diethyl paranitrophenyl ester), the chemical warfare agent VX/phosphorofluoridic acid, methyl-S-(2-[bis(1-methylethyl)amino/ethyl)O-ethyl ester], or the neuropathic DFP [phosphorofluoridic acid, bis(1-methylethyl)ester] as evidence was sought for nerve or other tissue damage following long-term treatments at high dose levels. Thirty-day and 90-d trials were performed in which each bird was injected 3 or 5 times per week with atropine as protection, weighed, their eggs collected, and their blood enzymes (cholinesterases creatine kinase, and lactic dehydrogenase) and locomotion periodically examined. Muscle and brain enzymes were assayed at the end of the experiments. Doses of PO and VX were at or above LD50 levels. DFP doses were lowered with each run to estimate a no-observable-effect level for organophosphate-induced delayed-neuropathy (OPIDN). No abnormalities attributable to repeated exposures to either PO or VX were found, even though acute, short-term symptoms of toxicity appeared after each injection. No evidence for OPIDN was obtained with repeated exposures to PO and VX under conditions where OPIDN was caused by DFP. Histological signs of OPIDN appeared in the spinal cord without gross symptoms of ataxia following repeated treatments of 25 mg/kg of DFP. The results of one experiment suggested that exposure to protective injections of atropine delays the appearance of the locomotor symptoms of the DFP-induced neuropathy.

Animals↗
PubMed1988

The effect of crystal structure on mouse lung inflammation and fibrosis.

In order to identify the physical and structural parameters that relate best to the membranolytic, inflammatory, and fibrotic potentials of different silicon dioxide (SiO2) and titanium dioxide (TiO2) crystals, we have studied the potential of four different SiO2 and two different TiO2 crystal structures to lyse human red blood cells and to induce pulmonary inflammation and fibrosis in mice. The crystals studied were quartz, tridymite, cristobalite, coesite, anatase, and rutile. Mice were injected intratracheally with each crystal at constant surface area. Inflammation and fibrosis were assessed 6 wk after crystal instillation by wet lung weight (lung index), protein concentration of lung lavage fluid, the level of hydroxyproline in the lung, and histologic examination. In vitro red blood cell (RBC) lysis was evaluated by incubating the crystals with 51Cr-labeled RBC and measuring the release of 51Cr into the medium. Known crystallographic data for each of the minerals were used to calculate the percent occupied volume. Biologic activity seemed to correlate with percent occupied volume, suggesting that surface molecular topology may be important in crystal-cell interactions. The crystals with more irregular surfaces and protruding oxygen atoms, which form surface pockets (quartz, tridymite, and cristobalite), showed a dramatic increase over saline controls for lung index (greater than 2 x), cell number and lavage protein concentration (greater than 4 x), and hydroxyproline level (greater than 2 x). The other more boxlike crystals (coesite, anatase, and rutile) displayed little change in these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Atropine and DFP-induced delayed neurotoxicity.

Atropine is often given as an antidote for acute cholinergic effects in studies of a delayed neuropathy (OPIDN) caused by some organophosphorus esters. These experiments examined if atropine would also affect the onset and/or severity of signs of OPIDN. Chickens were given one to six 200 micrograms/kg doses of diisopropyl phosphorofluoridate (DFP) with or without 20 mg/kg atropine (IM). Locomotion, brain neurotoxic esterase (NTE) activity, and histology of the nervous system were examined. The results demonstrated that atropine treatments delayed onset of the signs of OPIDN and may have slightly increased brain NTE activity in vivo. Relatively high levels (Ki: approximately 3.0 mM) of atropine inhibited NTE activity in vitro.

Animals↗
PubMed1988

DFP-induced elevation of strength-duration threshold in hen peripheral nerve.

Previous research has indicated that organophosphorus agents which induce a delayed neuropathy also elevate the strength-duration threshold during the progression of the neuropathy. To establish further the correlation between strength-duration changes and delayed neuropathy, the purpose of the present study was to investigate the biochemical and electrophysiological effects of two additional agents: diisopropylflourophosphate (DFP) and phosphonothioc acid, methyl-[2-(dimethylamino)-ethyl]O-ethyl ester (VX). DFP-treated hens exhibited clinical signs of toxicity at the time of electrophysiologic recording and biochemical analysis. DFP treatment also resulted in significantly elevated thresholds of the strength-duration curves of both the sciatic and tibial nerves. The VX-treated animals exhibited no clinical signs, despite aggressive dosing, and there were no significant changes in the electrophysiologic characteristics (conduction velocity, relative refractory period, strength-duration threshold) of either peripheral nerve. Acetylcholinesterase activities of the brain and skeletal muscle were significantly reduced in the VX- and DFP-treated hens, whereas creatine phosphokinase activities in these tissues were unaffected. These results are consistent with the view that elevation of the strength-duration threshold in peripheral nerves is among the earliest indicators of organophosphorus-induced delayed neuropathy.

Acetylcholinesterase↗
PubMed1987

Tissue biocompatibility of kevlar aramid fibers and polymethylmethacrylate, composites in rabbits.

Two groups of female NZW rabbits were implanted in the paravertebral muscles with aramid (du Pont Kevlar aramid 49) fibers and aramid-polymethylmethacrylate (PMMA) composites for 14 and 28 days. Rabbits were killed at these times periods, necropsies performed, sites scored for gross tissue response, and tissue specimens containing the implants removed for histopathological evaluation. A mild fibrous tissue reaction was observed around all implants containing aramid fiber similar to that observed around the silicone control implant. Some foreign body giant cells were also present adjacent to the fibers. An intense necrotic inflammatory reaction was present around the positive control material (PVC Y-78). The tissue response to implantation of aramid fiber and fiber-PMMA composites indicates that aramid is a biocompatible material.

Acrylic Resins↗
PubMed1987

Renal hemodynamic effects of ketanserin therapy in essential hypertension.

Ketanserin is a novel agent that has been shown to be a specific 5-HT2-serotonergic antagonist. It has useful antihypertensive properties. Owing to its unique mechanism of action, it has been suggested that ketanserin may have a favorable effect on tissue blood flow during chronic therapy for hypertension. This double-blind study was designed to evaluate the acute (1 week) and chronic (8 weeks) effects of ketanserin on renal hemodynamic parameters and renin-aldosterone axis in patients with uncomplicated hypertension. Compared to placebo, ketanserin caused a significant blood pressure reduction at the end of the 8-week study period. Despite the reduction in systematic arterial pressure, glomerular filtration rate and renal plasma flow were preserved. Ketanserin therapy induced a slight reduction in plasma renin activity and a marginal increase in the sodium excretion. Although the results of this study are limited by the small number of patients, it appears that ketanserin may have favorable renal hemodynamic effects in uncomplicated essential hypertension.

Aged↗
PubMed1985

Pharmacokinetic calculator program for generation of initial parameter estimates from a three-compartment infusion model.

A polyexponential curve-stripping program, KIN, is described for use on the HP-41CV programmable calculator. The program may be used in the analysis of plasma-concentration-time curves for a three-compartment intravenous bolus or infusion model with linear elimination processes. The coefficients and hybrid rate constants of the exponential function are then used to compute pharmacokinetic parameters (volume of the central compartment, intercompartmental rate transfer constants), which may be used as initial estimates of model parameters in non-linear regression curve-fitting procedures.

Computers↗
PubMed1985

DATALIN--an interactive data entry program for use with NONLIN.

A package of FORTRAN programs for data entry into NONLIN (version II) is described which may be used in the analysis of plasma-concentration time curves after single or multiple doses for fourteen pharmacokinetic models described in terms of the model's microconstants (volume of compartments, rate constants). In all cases, infusion rates must be zero-order and absorption rates first-order. The program contains an edit subroutine allowing for changes in initial parameter estimates and their lower and upper limits, weighting factors, number of iterations in the NONLIN analysis, and plot option. Individual X and Y values may be changed and listed and X-Y data pairs may be inserted or deleted. Factors pertaining to each of the data entries in relation to NONLIN are discussed.

Animals↗