Biomedical subjects
Publications and source records attributed to J D Henderson.
Concerns that chemical warfare (CW) agents themselves or in combination with other chemicals may cause long-term damage to nerve and muscle are reviewed and discussed. Experiments on mice and hens underway with agent GA and pyridostigmine bromide (PB) and their effects (either separately or together) are presented.
The regulatory aspects of generic drug substitution and the scientific concepts that serve as the basis for generic drug approval are discussed, with emphasis on the source of therapeutic equivalence information compiled by the Food and Drug Administration in Approved Drug Products with Therapeutic Equivalence Evaluations. The Food and Drug Administration's determination of bioequivalence for immediate-release and extended-release dosage forms is summarized, with a discussion of the underlying assumptions and current issues regarding bioequivalence testing. Medical practitioners must comply with the regulations stated in each state's Pharmacy Practice Act when allowing generic substitution and should ensure that the substituted product is therapeutically equivalent to the prescribed product.
We analyzed the effect of changing posture from supine to standing on the variability of R-R, P-R, and R-T intervals in 10 healthy volunteers using power spectral analysis. An electrocardiogram and respiratory trace were recorded before and after posture change. Variability in the P-R and R-T intervals was much less than in the R-R interval and demonstrated a lower-frequency (LF)-to-high-frequency (HF) ratio. Changing from a supine to a standing position showed no change in indexes of vagal influence on the P-R and R-T variability, in contrast to the well-documented decrease in the indexes of vagal influence on the R-R variability (HF power decreased from 2.33 to 0.41 ms2, P = 0.003; amplitude of the respiration-to-heart rate impulse response decreased from 31.6 to 14.4 ms.ml-1.s-1, P = 0.03; and LF/HF increased from 1.96 to 5.22, P = 0.005). We concluded from this study that the effects of standing were an observed reduction in vagal influence on the heart rate variability of the R-R interval and maintenance of lung volume-related vagal modulation of the P-R and R-T intervals.
The heart rate variability of 40 patients has been examined by spectral analysis following cardiac surgery. The heart rate variability was measured upon patient arrival in ICU in both a resting supine position, and following passive straight-leg raising. After 12 hours in ICU, the patients were classified as having been cardiovascularly stable or unstable according to a specially devised inventory. Their heart rate variability data was then examined to seek any predictor of instability. Passive straight-leg raising induced a decrease in spectral power across all of the component frequency bands. The LF/HF ratio rose with passive straight-leg raising, but failed to reach significance. None of these changes were sustained. There was no significant difference in heart rate variability patterns between the stable and unstable groups, and so no predictor was identified. Initial clinical assessment was also studied, and it too provided no reliable prediction of short-term cardiovascular instability.
A scientific panel assembled by the U.S. Environmental Protection Agency (EPA) determined that variability in cholinesterase (ChE) activities in the agency's pesticide/animal study database likely was due to a lack of accepted guidelines for ChE methodology. A series of trials was held in which participating laboratories measured ChE activity in blood and brain samples from untreated and pesticide-treated rats using a colorimetric assay method. The degree of inhibition of ChE activity in plasma and brain samples compared to controls was consistent among most of the laboratories. The ChE activity in erythrocyte samples differed more between laboratories due to a high blank, low erythrocyte AChE activity and hemoglobin absorption at the wavelength of the assay. Strategies are suggested for minimizing the variability of ChE activity in hemoglobin-rich samples.
PURPOSE: The purpose of this study were to evaluate the use of individual compartmental and population compartmental methods for bioequivalence determination, and to determine their utility as adjuncts to the current methods used for bioequivalence assessment. METHODS: Data from three bioequivalence studies of chlorthalidone were analyzed with PCNONLIN using individual compartmental modeling and NONMEM for population analyses. These results were compared with results obtained from the traditional noncompartmental or SHAM (slopes, heights, areas, and moments) approach for bioequivalence assessment and the 90% confidence interval procedure. RESULTS: Individual compartmental modeling and population compartmental modeling techniques performed well on this routine set of bioequivalence data which displayed simple pharmacokinetic properties. A direct assessment of the analysis methods was made by comparing the final estimates and 90% confidence intervals for the test to reference ratios (T/R) of AUC and CMAX. The final estimates and 90% confidence intervals for AUC T/R and CMAX T/R were similar and suggest consistency of results, independent of the method used. CONCLUSIONS: These results demonstrate the utility of modeling techniques as adjuncts to the traditional noncompartmental approach for bioequivalence determination.
We studied heart rate variability (HRV) using spectral analysis techniques in 58 adult patients recovering from general anaesthesia. The aim was to discover how HRV was affected by a variety of common preoperative, intraoperative and postoperative factors. ECG, respiration, level of consciousness, nausea, pain and arterial pressure were recorded during the first hour of recovery from general anaesthesia. HRV was found to decrease with increased weight, age, complexity of operation, use of reversal agents for neuromuscular block and preoperative beta-block. These effects were not mediated by changes in respiration. HRV was unaffected by administration of morphine. The level of nausea or pain had no effect on HRV except that pain decreased the relative ratio of high frequency to low frequency power within the power spectrum. In the group of patients that did not receive reversal agents, there was an abrupt increase in HRV when patients became responsive to verbal command.
Power spectral analysis of heart rate variability has been used to gain some understanding of the activity of the autonomic nervous system. In this study various indices of heart rate variability were related to the degree of preoperative anxiety experienced by 32 patients presenting for day case surgery. It was found that there was no correlation between anxiety and mean heart rate, or between anxiety and the spectral power in the mid frequency band (0.05-0.15 Hz). However, there was an increase in the relative power of the higher frequency band (0.15-0.5 Hz) with increasing anxiety levels (Spearman correlation r = 0.4034). This suggests that preoperative anxiety may often be associated with a relative vagal predominance in the sympathovagal balance.
Infiltration of specific immunocytes and stimulation of abnormal gastrointestinal motor activity during ileal inflammation induced by mucosal exposure to ethanol and acetic acid were investigated in 17 dogs. Ileal inflammation significantly increased the frequency of giant migrating contractions (GMCs) and decreased the frequency of migrating motor complexes (MMCs). The frequency of retrograde giant contractions (RGCs) increased only on the day of ethanol and acetic acid treatment. Diarrhea, urgency of defecation, and apparent abdominal discomfort were related to the increased frequency of GMCs. Ileal inflammation also prolonged the duration of postprandial MMC disruption. Histological and immunohistochemical findings indicated transmural inflammation with marked increase in polymorphonuclear cells in the lamina propria and muscularis externa layers. Myeloperoxidase activity increased severalfold in both layers. Cells containing interleukin-2 receptor (IL-2R) increased in the lamina propria. Other immunocytes, such as B and T lymphocytes, dendritic cells, and human leukocyte antigen DR-1 (HLADR)-positive cells, did not exhibit a significant increase in the inflamed ileum compared with the normal proximal jejunum. We conclude that stimulation of GMCs may be the major motility marker of intestinal inflammation.
Five mutagenicity tests were performed on Agent GA (Tabun, phosphoramidocyanidic acid, dimethyl-, ethyl ester) as part of a program to demilitarize chemical warfare agents. GA was mutagenic in Salmonella spp. assays with S-9 and it was a direct-acting mutagen to mouse lymphoma cells. GA did not promote unscheduled DNA synthesis in rat hepatocytes; it induced sister chromatid exchanges in mouse cells in vitro but in vivo. The conclusion that GA is a weakly acting mutagen is supported by the fact that it was mutagenic in only three of the five assays, and that increases in mutagenicity were often less than 2-fold the controls and occurred near toxic levels.
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To examine the phenomenon of apparent age resistance of young chicks to organophosphate-induced delayed neuropathy (OPIDN), groups of either 2- or 10-week-old chicks were exposed subcutaneously daily for 4 days to the neuropathic organophosphate (OP), di-isopropylfluorophosphate (DFP, 1 mg/kg), the non-neuropathic OP, paraoxon (PO, 0.25 mg/kg) or atropine (20 mg/kg). Subsequently, all birds were examined at post-exposure intervals (calculated from the last day of exposure) for up to 56 days for neurological deficits and morphological lesions in the central and peripheral nervous systems (CNS, PNS). Clinically, none of the birds in the 2-week-old groups, or in the 10-week-old PO or atropine exposed groups had neurological deficits. However, all birds in the 10-week-old DFP exposed group developed ataxia by 7 days post-exposure (DPE) and then progressive paralysis. Therefore, all birds in the 10-week-old groups were killed at 14 DPE. Pathologically, the 2-week-old DFP exposed chicks had increasingly severe lesions of Wallerian-like degeneration predominantly in the spinal cord from 7 DPE and subsequently. In the 10-week-old DFP exposed chicks, the degenerative lesions of OPIDN were first detected in the CNS at 3 DPE and then with equally increasing severity in the CNS and PNS up to 14 DPE. A higher incidence of neuronal necrosis and chromatolysis in ventral motor horn neurons of spinal cord grey matter and in dorsal root ganglia occurred in both the DFP exposed age groups compared with those lesions in other groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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.
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.
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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.
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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.