Biomedical subjects

C Gennings

Publications and source records attributed to C Gennings.

At least 37 records · Page 2Linked to original sources

PubMed1995

An efficient experimental design for detecting departure from additivity in mixtures of many chemicals.

Berenbaum (J. Theor. Biol. 114 (1985) 413-431) described a procedure for detecting and characterizing departure from additivity in a combination of c (c > or = 2) chemicals. The attraction of this approach is that it is based on the concentration-response relationship of each of the individual components and, under the assumption of additivity, it is straight forward to predict the response of a given combination. Deviations between the observed and predicted responses for the combination are associated with departures from additivity. Berenbaum based his conclusions regarding synergism/antagonism on numerical differences which do not take into account inherent biological variability. We have developed a procedure which incorporates experimental variation is based on each individual component's concentration-response relationship, and leads to a conclusion regarding the statistical significance of any departure from additivity. The procedure is illustrated with an example.

Adenoma↗

PubMed1995

Analysis of anticonvulsant and neurotoxic responses to combination therapy with carbamazepine, felbamate and phenytoin by response-surface modeling.

Various combinations of carbamazepine (CAS 298-46-4), felbamate (CAS 25451-15-4), and phenytoin (CAS 57-41-0) were evaluated in mice (i.p.) for anticonvulsant activity (maximal electroshock seizure test) and minimal neurotoxicity (rotarod test). The results obtained from these studies were analyzed using response surface methodologies (RSM). The outcomes of these analyses in regard to anticonvulsant activity suggest that, under these experimental study conditions, at 0.5 h post treatment there is a significant carbamazepine/phenytoin synergism even though none of the drugs has a significant dose-response by that time when given alone, and that at 1.0 h post treatment, the combination dose-response is additive. Thus, there appears to be an important dose/time relationship. In regard to the neurotoxic response, the results suggest a significant carbamazepine/phenytoin synergism at 0.25 h post treatment and an additive neurotoxic effect due to the combination of felbamate/carbamazepine/phenytoin at 0.5, 1.0 and 2.0 h post exposure.

Animals↗

PubMed1994

Efficacy comparison of scopolamine and diazepam against soman-induced debilitation in guinea pigs.

The efficacy of diazepam (DZ) and scopolamine (SCP), in combination with atropine (ATR)+oxime therapy, against soman-induced seizure/convulsive activity and associated brain damage has been demonstrated, but the efficacy of each against the incapacitating effects of soman has not been addressed. Thus, the therapeutic efficacies of SCP (5 doses; 0-0.86 mg/kg) and DZ (5 doses; 0-5 mg/kg), when each was used in conjunction with ATR (3 doses; 0.5-8 mg/kg) + 2-PAM (25 mg/kg) therapy, were compared in groups of pyridostigmine pretreated guinea pigs exposed to 1.6, 2.0, 2.5, or 3.2 LD50s of soman. Response surface methodology was employed to describe the relationship between soman-induced incapacitation and the ATR/DZ or ATR/SCP dosages. Incapacitation was measured by toxicity scores assigned by three graders to test animals at 60 min postsoman. Results show that as the dosage of SCP increased, the mean toxicity scores decreased. Also, within the indicated dose ranges used, the efficacy of SCP was not dependent on the presence of ATR. In contrast, ATR alone was found to be more effective than when combined with DZ at any dose, and indicates that DZ might be temporarily contributing to soman-induced incapacitation. These findings suggest that in guinea pigs, SCP could replace ATR or DZ, or both, as therapy against soman-induced incapacitation.

Animals↗

PubMed1994

Efficacy comparison of scopolamine (SCP) and diazepam (DZ) against soman-induced lethality in guinea pigs.

Diazepam (DZ) and scopolamine (SCP) are known to be beneficial when each is used in combination with atropine (AT) + oxime therapy against intoxication by soman, but the efficacy of each might be expected to vary with the dosage of AT. Thus the therapeutic efficacy of SCP (5 doses; 0-0.86 mg/kg) versus DZ (5 doses; 0-5 mg/kg), when used in conjunction with AT (3 doses; 0.5-8 mg/kg) + 2-PAM (25 mg/kg) therapy, was tested in groups of pyridostigmine pretreated guinea pigs exposed to 1.6, 2.0, 2.5 or 3.2 LD50s of soman. Response surface methodology was employed to describe the relationship between lethality and the AT/DZ or AT/SCP dosages. Results show that within the indicated dose ranges used, the efficacy of SCP is not dependent on the presence of AT, whereas AT is needed for DZ to maintain the lowest probability of death. These findings suggest that in guinea pigs SCP could supplement AT or replace DZ as therapy against nerve agent intoxication.

Animals↗

PubMed1992

Risk assessment in immunotoxicology. I. Sensitivity and predictability of immune tests.

We have previously reported on the design and content of a screening battery involving a "tier" approach for detecting potential immunotoxic compounds in mice (Luster et al., 1988, Fundam. Appl. Toxicol. 10, 2-19). This battery has now been utilized to examine a variety of compounds by the NIEHS Immunotoxicology Laboratory, the National Toxicology Program-sponsored laboratories, and by the Cell Biology Department at the Chemical Industry Institute of Toxicology. The database generated from these studies, which consists of over 50 selected compounds, has been collected and analyzed in an attempt to improve future testing strategies and provide information to aid in quantitative risk assessment for immunotoxicity. Studies presented here have established the ability of each of the tests or test combinations in the screening battery to detect immunotoxic compounds. Efforts are currently underway using this database to determine the relationships between these immune tests and susceptibility to challenge with infectious agents or transplantable tumor cells. The present analyses indicated that the performance of only two or three immune tests are sufficient to predict immunotoxic compounds in rodents (greater than 90% concordance). The tests that showed the highest association with immunotoxicity were the splenic antibody plaque forming cell response (78%) and cell surface marker analysis (83%). The relationship between immunotoxicity and carcinogenicity, as well as genotoxicity, was also determined. These analyses suggested that potential immunotoxic compounds are likely to be rodent carcinogens (p = 0.019) although for compounds that are not immunotoxic the carcinogenic status is unclear. There was no relationship observed between immunotoxicity and mutagenicity as determined using in vitro genotoxicity tests. The significance of these observations is discussed in terms of the relationship between immunotoxicity tests and biological/toxicological processes concerned with human health (e.g., infectious disease).

Animals↗

PubMed1991

A CCl4/CHCl3 interaction study in isolated hepatocytes: non-induced and phenobarbital-pretreated cells.

The purpose of this study was to evaluate an isolated hepatocyte model for predicting the in vivo hepatotoxicity of carbon tetrachloride (CCl4) and chloroform (CHCl3), alone and in combination. Response surface methodology (RSM) was used to analyze and describe the data. The interaction was evaluated for % initial K+ (cell injury) and % LDH leakage (cell death) in non-induced (untreated) and phenobarbital-pretreated suspended hepatocytes. CCl4 and CHCl3 were delivered alone and in combination in dimethyl sulfoxide (DMSO) to suspended hepatocytes. The maximum observed no-effect level (MONEL) for CCl4 in non-induced cells was 1.0 mM (LDH and K+). In induced cells, the MONEL was 0.25 mM (K+) and 0.5 mM (LDH). The MONEL for CHCl3 in non-induced cells was 5.0 mM (LDH and K+) and in induced cells was 0.5 mM (K+) and 1.0 mM (LDH). Phenobarbital pretreatment enhanced the toxicity of both CCl4 and CHCl3, alone and in combination. RSM analysis of the % initial K+ and % LDH for CCl4 and CHCl3 in combination in noninduced and induced cells showed a greater than additive interaction. The isolated hepatocyte model appears to be a promising system for evaluating the toxicity of chemical mixtures and predicting their in vivo effects.

Animals↗

PubMed1990

Evaluation of a two-drug combination pretreatment against organophosphorus exposure.

A pretreatment combination of physostigmine and azaprophen (6-methyl-6-azabicyclo[3.2.1]octan-3-ol-2,2-diphenylpropionate), a novel cholinolytic, was evaluated for its ability to minimize soman-induced incapacitation and lethality in guinea pigs. This was accomplished by using response surface methodology to model and analyze the combination, varying physostigmine from 0 to 194 micrograms/kg, azaprophen from 0 to 5 mg/kg, and soman from 30 to 150 micrograms/kg. One hundred percent survival was achieved against 5 LD50 of soman using as little as 100 micrograms/kg of physostigmine in the presence of 5 mg/kg azaprophen. Both survival and soman-induced incapacitation were similarly affected by this pretreatment combination. For both endpoints, greater efficacy was achieved with the combination than could be achieved with either component alone (therapeutic synergism). This suggests that such a pretreatment combination may prove very efficacious against soman-induced lethality and incapacitation in higher species.

Animals↗

PubMed1990

Evaluation of the efficacy of two carbamates, physostigmine and pyridostigmine, when used in conjunction for protection against organophosphate exposure.

Recent studies have shown that pretreatment with either pyridostigmine (PYR) or physostigmine (PHY) followed by atropine-oxime therapy is very effective in reducing the lethality of nerve agents. The therapeutic efficacy of a PHY and PYR combination pretreatment was evaluated in guinea pigs challenged with two LD50s of soman. Endpoints measured were percentage of acetylcholinesterase inhibition induced by the pretreatment and survival up to 24 hr postchallenge. Response surface methodology was employed to describe the relationship between each endpoint and the pretreatment combination. Although both carbamates contributed to blood acetylcholinesterase inhibition, PHY alone protected as well as the optimal dose of the combination.

Acetylcholinesterase↗

PubMed1990

Assessing the efficacy of azaprophen and physostigmine as a pretreatment for soman-induced incapacitation in guinea pigs by response-surface modeling.

Physostigmine (PHY) has the advantage over pyridostigmine of minimizing OP-induced incapacitation because it penetrates into the CNS. However, physostigmine is behaviorally toxic at relatively low concentrations. It is anticipated that this could be offset by a cholinolytic to prevent behavioral deficit due to the carbamate pretreatment alone. The therapeutic efficacy of physostigmine/azaprophen pretreatment therapy was evaluated in soman-challenged guinea pigs. Response surface methodology was employed to describe the relationship of the pretreatment combination with duration of incapacitation. The significance of the combination relative to PHY alone was evaluated in addition to dose combinations that yield optimal time to recovery. Analysis of the fitted response surface indicated that combination pretreatment with these compounds significantly reduces the time to recovery after soman challenge versus pretreatment with PHY alone.

Animals↗

PubMed1990

Interactions of water contaminants. I. Plasma enzyme activity and response surface methodology following gavage administration of CCl4 and CHCl3 or TCE singly and in combination in the rat.

The joint hepatotoxicity of CCl4 and CHCl3 or TCE in male CD rats following simultaneous oral administration has been investigated. Rats with chronic indwelling arterial cannulas were administered a single oral dose of CCl4 and CHCl3 or CCl4 and TCE in 5% Emulphor at doses of 0 to 700 mg/kg. Hepatotoxicity was evaluated by measuring the activity of AST, ALT, and SDH in plasma at 0, 3, 6, 12, 24, 36, 48, and 72 hr postgavage. Response data were analyzed for interaction using response surface methodology. CCl4 alone displayed dose-dependent toxicity. TCE demonstrated little evidence of hepatotoxicity. In combination, both CCl4/CHCl3 and CCl4/TCE displayed a synergistic (supraadditive) response for peak plasma enzyme activity.

Alanine Transaminase↗

PubMed1990

Antagonism between intracerebroventricularly administered N-methyl-D-aspartate and bicuculline methiodide in induction of clonic seizures in mice.

N-Methyl-D-aspartate and bicuculline were administered alone or as a combination by intracerebroventricular injection to mice, and their convulsant activity was monitored. Both of these compounds elicited clonic seizures, though by different mechanisms. However, their simultaneous administration resulted in less than additive induction of clonic activity.

Animals↗

PubMed1990

Synergistic inhibition of platelet aggregation by fibrinogen-related peptides.

We have evaluated the ability of the fibrinogen-related peptides Gly-Arg-Gly-Asp-Ser (GRGDS), Gly-Gln-Gln-His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val (gamma-chain peptide), and Gly-Pro-Arg-Pro (GPRP) to inhibit platelet aggregation in platelet-rich plasma individually and in combination. When used alone, GRGDS totally inhibited ADP-induced aggregation of human platelets in platelet-rich plasma; however, the maximum inhibitory effect of the other peptides was less than 80%. The concentrations necessary to inhibit platelet aggregation in plasma by 50% were 100 mumols/l and 1 and 3.2 mmol/l for GRGDS, gamma-chain peptide, and GPRP, respectively. When evaluating the effect of peptide mixtures, we discovered that the combination GPRP + GRGDS worked together synergistically (p less than 0.001, analysis by surface response methodology), whereas GPRP + gamma-chain peptide did not. For example, our analysis indicated that a mixture of 50 mumols/l GRGDS plus 180 mumols/l GPRP would produce 50% inhibition of platelet aggregation. This is an effect twofold greater than that produced by 50 mumols/l GRGDS alone, and one that would require an 18-fold greater concentration of GPRP if used alone. These data indicate that the combination GPRP + GRGDS inhibited platelet aggregation in plasma in a synergistic fashion and suggest the potential value of their combined use in antithrombotic therapy.

Adenosine Diphosphate↗

PubMed1990

Interpreting plots of a multidimensional dose-response surface in a parallel coordinate system.

The dose-response surface for a combination of drugs is a multidimensional figure. Consequently, it is not possible to view such a surface using orthogonal axes when the number of dimensions exceeds 3. Parallel axes have been used to represent hyperdimensional figures. This paper reports on the use of parallel coordinate axes to plot the dose-response surface and its contours of constant response (isobols) for a combination of drugs. It is shown that patterns formed by intersecting line segments in the parallel system can aid in the interpretation of the fitted dose-response surface. More generally, analytic results are developed that permit the ready visualization and characterization of interaction effects of a polynomial model.

Biometry↗

PubMed1990

Isobolographic characterization of drug interactions incorporating biological variability.

Isobolograms have been widely used to characterize the nature of the interaction between combinations of drugs or chemicals. Some authors have applied this technique without accounting for the variability in the data or without adjusting for multiple comparisons to the line of additivity. This paper develops a graphical procedure which takes into account the variability of the data and which maintains favorable statistical properties. The isobolographic procedure utilized is illustrated by using three classical pharmacological drug combinations in female ICR mice. An additive relationship is illustrated with the loss of righting reflex after combinations of doses of sodium hexobarbital with itself. An antagonistic relationship is illustrated with the protection by mecamylamine of nicotine-induced lethality. A synergistic relationship is illustrated with the loss of righting reflex after combinations of ethanol and chloral hydrate. The procedure's statistical properties (level of significance and power) were determined using a simulation study. The isobolographic procedures developed here are applicable for quantal, continuous and count data. These procedures are applicable for identifying beneficial drug combinations, or conversely, identifying hazards resulting from exposure to multiple toxicants.

Animals↗

PubMed1989

Toxic interactions between carbon tetrachloride and chloroform in cultured rat hepatocytes.

Primary cultures of adult rat hepatocytes were incubated (1.5-16 hr) with various concentrations of CCl4 (less than or equal to 0.5 mM) and/or CHCl3 (less than or equal to 2.5 mM). Agent-dependent alterations in hepatocyte functions were assessed by measuring (1) [3H]choline incorporation into phosphatidylcholine (endoplasmic reticulum), (2) MTT (tetrazolium salt) reduction (mitochondria), and (3) AST release into medium (plasma membrane). Cultured hepatocytes incubated with 0.5 mM CCl4 displayed a significant (p less than or equal to 0.001) and rapid (1.5 hr) reduction (40%) in endoplasmic reticulum function that preceded significant (p less than or equal to 0.001) alterations in mitochondria (6-16 hr) and plasma membrane (6-16 hr) functions. CCl4-dependent alterations in liver cell functions are a result of CCl4 bioactivation since metyrapone inhibits the CCl4-mediated changes in cell functions. Response surface methods (RSM) were used to determine the influence of combinations of CCl4 and CHCl3 on liver cell MTT reduction and [3H]choline incorporation. Regression coefficients were determined for CCl4, CHCl3, and CCl4-CHCl3. All results were significant (p less than 0.0001) and implied that CCl4 was a more potent hepatotoxin in vitro than CHCl3. The RSM analysis also suggested that combinations of CHCl3 and CCl4 have greater than additive effects on MTT reduction and [3H]choline incorporation. These effects of CCl4 and/or CHCl3 on liver cell functions in vitro are consistent with liver alterations observed in vivo. Therefore, primary cultures of adult rat hepatocytes may be an appropriate model in vitro to assess the hepatotoxic potential of agents alone or in combination.

Animals↗

PubMed1988

Lingual epithelium of spontaneously hypertensive rats has decreased short-circuit current in response to NaCl.

Alterations in ion transport associated with hypertension have been found in a variety of organs. We used a modified Ussing chamber to compare the NaCl dependence of the short-circuit current across the dorsal lingual epithelium in vitro from spontaneously hypertensive rats (SHR) with that from Wistar-Kyoto rats (WKY). The short-circuit current in response to mucosal NaCl was less in SHR than in WKY at hyperosmotic concentrations (above 0.15 M and up to 2.0 M). Since ion transport in the lingual epithelium has been found to play a role in early events of salt taste transduction, the attenuation in the short-circuit current in hypertensive animals may be a factor in the enhanced salt preference of SHR compared with WKY.

Analysis of Variance↗

PubMed1987

Efficacy of a combination of acetylcholinesterase reactivators, HI-6 and obidoxime, against tabun and soman poisoning of mice.

The bispyridinium oxime HI-6, 1-((((4-amino-carbonyl)pyridinio)methoxy) methyl)-2-(hydroxyimino)methyl)pyridinium dichloride monohydrate, combined with atropine is an effective treatment for soman (pinacolyl methylphosphonofluoridate) poisoning but is relatively ineffective against tabun (ethyl N-dimethyl phosphoroamidocyanidate) poisoning in mice. This contrasts with those results obtained using the bispyridinium oxime obidoxime[1,1'-(oxy bis(methylene)) bis(4-(hydroxyimino)methyl) pyridinium dibromide]. The purpose of this study was to investigate the efficacy of the combination of HI-6 and obidoxime plus atropine against poisoning by tabun and soman in mice. The combination of ineffective single doses of obidoxime (5 or 10 mg/kg) and HI-6 (25 or 50 mg/kg) improved the treatment of tabun poisoning over either oxime alone. Combinations employing higher concentrations of obidoxime (25 or 50 mg/kg) and HI-6 (100 or 200 mg/kg) resulted in significant toxicity in the absence of organophosphate poisoning. Against soman poisoning the addition of obidoxime to HI-6 did not attenuate the efficacy of HI-6. The half-life of elimination and peak serum concentrations of HI-6 and obidoxime were not altered following administration of the combined injection. Reactivation of tabun-inhibited acetylcholinesterase was found consistently in the diaphragm but not in the brain. Using response surface methods it was possible to estimate the optimal therapy against soman and tabun poisoning (74.5 mg/kg HI-6 + 31.9 mg obidoxime against 1052 microns/kg obidoxime against 390 microns/kg challenge of soman).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗

PubMed1986

Prospective study of catheter replacement and other risk factors for infection of hyperalimentation catheters.

To determine risk factors for infection of hyperalimentation catheters, we prospectively studied 169 catheter systems (88 patients) by using a semiquantitative culture technique. Infection occurred in 24 (14%) catheters (16 patients), was inversely proportional to the number of previous catheters inserted by the operator (P less than .02), and was proportional to the interval between admission and catheter insertion (P less than .0005). Catheter replacement over a guidewire was no more likely to be associated with infection than was a de novo percutaneous insertion at another site (P = .6). Using a proportional hazards model, we estimated the risk of infection per day to be 1.3 times greater for a catheter if the patient had been hospitalized 50 days instead of seven days, and 3.8 times greater if the patient had a Swan-Ganz catheter at the time of insertion.

Adult↗