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Biomedical subjects

W H Carter

Publications and source records attributed to W H Carter.

At least 19 recordsLinked to original sources
PubMed1992

Relationships between various uses of antineoplastic drug-interaction terms.

In in vitro testing, no pharmacologic synergism has been found for the combination of cisplatin and etoposide in P388 leukemia in contrast to the demonstration of therapeutic synergism in the same model. No pharmacologic synergism has been found for the same combination in the treatment of four small-cell lung-cancer cell lines, although clinical results obtained using this combination in small-cell lung cancer and other cancers suggest a therapeutic advantage. The popular concept of synergy, implying a therapeutic advantage, is different from the pharmacologic meaning, which generally implies that less drug is required in a combination for an equal effect. Therapeutic advantage may be obtained regardless of whether drugs are synergistic in the pharmacologic sense in the treatment of a tumor. To gain a more comprehensive insight into concepts of drug interaction, it is important to recognize that the type of drug interaction seen is dependent on the drug doses used and may vary with the treatment of different cell lines. All of these factors complicate the use of the word synergism, or any associated term, in a categorical manner to describe the effects of combinations of antineoplastic drugs.

Animals↗
PubMed1992

Immunologic alterations in a murine model of hemorrhagic shock.

OBJECTIVE: To study multiple immune parameters in mice subjected to severe hemorrhage without fluid resuscitation. STUDY DESIGN: Controlled animal study. Anesthetized, female mice were hemorrhaged by tail bleeding. Immune parameters (spleen T-cell proliferation and activation, intracellular calcium flux, cytokine production, peritoneal neutrophil respiratory burst, and survival after intra-abdominal septic challenge) were measured at 24, 48, and 72 hrs after hemorrhage. MEASUREMENTS AND MAIN RESULTS: T-cell proliferation was decreased in animals after two 20% blood volume hemorrhages, 30 mins apart; single 30%, 40%, and 50% blood volume hemorrhages did not depress proliferation. "Helper/inducer" T cells from twice-hemorrhaged mice showed decreased expression of activation antigens (interleukin-2 receptor, Ia) after mitogen stimulation. In contrast, "suppressor/cytotoxic" T cells displayed increased activation, shown by augmented expression of interleukin-2 receptor and Ia antigens. Leukocyte production of prostaglandin E2, a mediator frequently implicated in immune down-regulation, was unaffected by hemorrhage. Secretion of tumor necrosis factor-alpha (TNF-alpha) in culture was increased when cells were harvested 48 hrs after injury. Intracellular calcium flux in stimulated lymphocytes was decreased 24 hrs after hemorrhage, suggesting deranged intracellular signal transduction. Respiratory burst activity of peritoneal neutrophils was unchanged following hemorrhage. When animals were subjected to septic challenge, the survival rate was markedly decreased after two hemorrhages (when sepsis was induced 24 hrs after hemorrhage). By 72 hrs posthemorrhage, most of the immunologic alterations, including resistance to septic challenge, had resolved. CONCLUSIONS: This uninstrumented hemorrhagic shock model allows quantification of multiple immune derangements. Immune suppression was identified after two smaller (20% blood volume) hemorrhages, but not after a single, larger hemorrhage. Immune derangements are maximal at 24 hrs posthemorrhage, and resolve in the subsequent 48 hrs.

Analysis of Variance↗
PubMed1991

A method for determining schedule dependency in tissue culture.

A dual-exposure drug treatment of cell lines in tissue culture provides a possible method for determining schedule dependency. This is suggested by results of treatment of human small cell lung carcinoma NIH H209 and murine L1210 leukemia cell lines with cisplatin, a non-schedule-dependent drug, and etoposide, a schedule-dependent drug. Nonlinear least squares was used to estimate the dose-response surface. The estimated regression coefficients for the effect of the first dose compared to that of the second dose support the premise that cisplatin is not schedule dependent. Unlike cisplatin, the second dose of etoposide was shown to be more effective than the first dose in the human small cell carcinoma line. This agrees with known clinical results where multiple etoposide dosing has been shown to be more effective and confirms schedule dependency. This methodology, or a refinement, may offer another tool for studying schedule dependency of drugs using tissue culture methods.

Animals↗
PubMed1991

An asymptomatic confidence interval for the response at the stationary point of a quadratic response surface.

The delta method is utilized to construct an asymptotic 100(1 - alpha)% confidence interval for the response at the stationary point of a quadratic response surface. The end-points of the interval can be found directly, compared to other more, computationally intense procedures that result in a conservative interval. The coverage probability associated with intervals constructed in this manner from studies with relatively small numbers of observations is investigated via a simulation study. Finally, the methodology is illustrated with an example involving the evaluation of a combination of cytotoxic agents in the treatment of murine L1210 leukemia.

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

Acute and chronic effects of cocaine on isolation-induced aggression in mice.

The purpose of the present study was to investigate the effects of acute and chronic cocaine administration on aggressive behaviour in mice. The animals were made more aggressive by individual housing for a period of 6 weeks. Group-housed anosmic conspecifics which were not aggressive were used as intruder controls. In acute studies, cocaine induced no significant change in aggressive behaviour at low doses (0.5-5 mg/kg) but significantly decreased aggressive behaviour after doses of 10 and 20 mg/kg. Cocaine increased the isolation-induced aggressive behaviour in mice when they were injected twice daily for a week with low doses of 0.5 or 1 mg/kg. In particular, the latency to first attack was significantly decreased by the drug and the frequency of attack towards the non-aggressive intruder was dramatically increased. Higher cocaine doses (10 or 20 mg/kg) under the described treatment regimen decreased these agonistic repertories. Tolerance did not develop to the anti-aggressive effects of high doses of cocaine on continued treatment.

Aggression↗
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

Effect of somatostatin analogs on gastric acid secretion in dogs and rats.

The effects of several superactive analogs of somatostatin on gastric acid response to various exogenous and endogenous stimulants were investigated in conscious dogs and rats with gastric fistulae (GF). The inhibition was compared to that induced by somatostatin-14 (S-S-14) at two dose levels. Several octapeptide analogs of somatostatin including D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), which were superactive in tests on suppression of GH levels, were 4-5 times more potent than S-S-14 in inhibiting desglugastrin-stimulated gastric acid secretion in GF dogs. The analog RC-160 also reduced the rise in serum gastrin levels and gastric acid secretion induced by sham feeding (SF) in dogs with gastric and esophageal fistulae (EF), but did not decrease food consumption. Gastric acid secretion induced by histamine (80 micrograms/kg/h) in dogs was not affected by 1-5 micrograms/kg/h of analog RC-121 or by 5 micrograms/kg/h of S-S-14. Analogs RC-160, RC-121, and RC-98-I (D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2) and others also powerfully inhibited desglugastrin-induced potent as S-S-14 in dogs but its activity was higher in rats. The results indicate that octapeptide analogs which are superactive in GH-inhibition tests are also more potent than S-S-14 in suppressing gastric acid secretion. These findings may be of clinical value.

Amino Acid Sequence↗
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↗
PubMed1987

The evaluation of biological interactions using response surface methodology.

Response surface methodology was employed in the statistical analysis of the combination exposures of genotoxic agents, bischloroethylnitrosourea with cis-diamminedichloroplatinum (II) and cis-diamminedichloroplatinum (II) with X rays. The measured endpoint in each case was sister chromatid exchanges in V79 Chinese hamster cells. The combination experiments employed a factorial design in which cells were treated, in various concentration combinations, with two agents simultaneously. Bis-chloroethylnitrosourea and cis-diamminedichloroplatinum (II) each exhibited curvilinear concentration-related increases in sister chromatid exchanges. X rays exhibited a dose-dependent increase in sister chromatid exchanges. For the cis-diamminedichloroplatinum (II)/X ray combinations, response surface methodology indicates a less-than-additive interaction, suggested by the non-parallel concentration-response curves of one agent at varying concentrations of the other, and a slight dose-dependent increase in sister chromatid exchanges due to X rays alone. Both cis-diamminedichloroplatinum and bis-chloroethylnitrosourea exhibited concentration-related increases in sister chromatid exchanges, cis-diamminedichloroplatinum (II) being 8-10 times (dependent on what level of effect was compared) more potent than bis-chloroethylnitrosourea. For the cis-diamminedichloroplatinum (II)/bis-chloroethylnitrosourea combinations, an increasingly less-than-additive interaction was detected. The analysis of these combinations demonstrates the strength of response surface methodology, a collection of mathematical and statistical techniques for detecting, analyzing and describing the biological effects resulting from exposures to multiple cytotoxic agents. The descriptive ability of these procedures is shown to be useful in that it leads to the suggestion of hypotheses regarding mechanisms of action.

Animals↗
PubMed1987

Evaluation of the interaction of three genotoxic agents in eliciting sister-chromatid exchanges using response surface methodology.

Chinese hamster cells (V79) were treated with ethylnitrosourea (ENU), bischloroethylnitrosourea (BCNU), and cis-diamminedichloroplatinum(II) (DDP) alone and in combination. Sister chromatid exchanges (SCEs) were quantitated as measures of genotoxicity of the three agents. The combination experiment employed a factorial design in which cells were treated, in various concentration combinations, with all agents simultaneously. Response surface methodology using a polynomial model in treatment variables to approximate the mean the distribution of SCE events was employed for analysis of the interactions of the three genotoxic agents. Due to unequal variances of the number of SCEs in the various treatment groups, a weighted least-squares analysis was used to estimate the parameters of the dose-response relationship. The single-agent results suggest that the DDP concentration-response curve has a much steeper slope than the ENU and BCNU curves, and is concave downward as compared to the relatively linear concentration-response curves of ENU and BCNU. The combination results suggest that ENU and DDP are involved in a negative interaction. The BCNU/DDP interaction, the ENU/BCNU interaction, and the three-factor interaction are not statistically significant. The analysis of these data demonstrates the usefulness of a statistical procedure for evaluating the biological effects resulting from exposure to multiple cytotoxic agents. The methodology can be used with many other types of endpoints and is not limited by the number of treatment agents.

Animals↗
PubMed1987

Combination of 5-fluorouracil and cyclophosphamide in L1210 and P388 leukemias with changes in optimum treatments as a function of the age of the L1210 tumor at first treatment.

The interaction of 5-fluorouracil and cyclophosphamide in the treatment of L1210 and P388 leukemias was studied using response surface methodology. Single dose treatment of each drug was administered simultaneously or with a 24-hr interval between 5-fluorouracil and cyclophosphamide to the advanced tumors or at various times after L1210 inoculation. While at low doses the action of the combination of the two drugs was greater than expected, there was no therapeutic synergism if the drugs were given together (optimum doses cyclophosphamide 366 mg/kg and 364 mg/kg, respectively, in advanced L1210 and P388 leukemias) or in the early tumor when cyclophosphamide was given 24 hours after 5-fluorouracil. In the advanced tumor, using the regimen employing a 24-hr interval between drugs, therapeutic synergism could be demonstrated (optimum doses 5-fluorouracil 130 mg/kg followed by cyclophosphamide 248 mg/kg in advanced L1210 leukemia and 5-fluorouracil 110 mg/kg followed by cyclophosphamide 263 mg/kg in advanced P388 leukemia). The evidence generated suggested that improved therapy could be found in two separate regions of the treatment space, raising the possibility of more than one mechanism of drug interaction. The location of the optimal treatment depended on the tumor burden at the time treatment was initiated. A shift from one region to the other occurred after 4-6 days of tumor growth when the original inoculum was 10(5) i.p. L1210 cells. Another more obvious conclusion that can be drawn is that treatment was less effective as the tumor became more advanced. The notion that different tumor stages may require different ratios of drugs in a clinically useful combination should receive attention.

Animals↗
PubMed1987

Demonstration of a schedule-dependent therapeutic synergism utilizing the interacting drugs methotrexate and teniposide in L1210 leukemia.

When three variables require simultaneous adjustment for treatment optimization, the experimental determination of the optimum treatment becomes more complicated than generally appreciated, especially when one variable is the interval between drug administrations. Molecular pharmacological studies at this institution suggest that teniposide, in doses that are achievable in vivo, blocks methotrexate efflux from cells, enhancing formation of methotrexate polyglutamates which are active retentive forms of the drug. Hence, the combination might show a synergistic effect if teniposide is given at an appropriate time in relation to administration of methotrexate. This paper considers the problem of estimating the optimal dose levels and timing of administration of these drugs in B6D2F1 mice bearing L1210 leukemia in vivo as a model for the analysis of multidrug regimens when time and dose are variables. Because of the complexity of these experiments, an adaptive approach was applied. Three cycles of treatment were given using methotrexate at 0-400 mg/kg, teniposide at 0-60 mg/kg, and an interval of 0-54 hours between the two drugs. The single drugs prolonged median survival up to 24 days under the conditions of these experiments. The combination given simultaneously resulted in median survival of up to 33.5 days, while use of an appropriate interval between drugs prolonged median survival to greater than 50 days. An analysis of the underlying dose-time response gives a much better appreciation of the relationships among the variables. The concept that optimal doses included less methotrexate and more teniposide as the interval between drugs is increased was developed only through modeling. This finding is critical in demonstrating the importance of including all nonnegligible variables in the experimental design if the results are to be considered valid. Confidence regions about the optimum dose and about the response at the optimum provide a sound basis for a claim of therapeutic synergism as demonstrated by use of a scheduling variable in the experiment design. A nonproportional hazards analysis permits the conclusion of nonproportionality and emphasizes the contribution of methotrexate to optimal short-term survival (15-24 days) and teniposide to long-term survival (24-39 days).

Animals↗
PubMed1986

Estimation and analysis of the concentration-response surfaces associated with multiple-agent combinations.

Chinese hamster cells (V79) were treated with ethylnitrosourea (ENU) and cis-diamminedichloroplatinum(II) (DDP) alone and in combination. Sister chromatid exchanges (SCEs) were quantified as measures of genotoxicity of the two agents. The combination experiment employed a factorial design in which cells were treated, in various concentration combinations, with both agents simultaneously. Response surface methodology, using a polynomial model based on a negative binomial distribution of SCE events, was employed for analysis of the interactions of the two genotoxic agents. The negative binomial distribution, a generalization of the Poisson distribution, is required since SCEs are discrete variables which, under the conditions of these experiments, have a distribution which exhibits extra-Poisson variability. The model of the ENU/DDP combinations indicated an increasingly less-than-additive effect resulting from increasing concentrations of each agent in the combination. The analysis of these experiments demonstrates the usefulness of a powerful statistical procedure for evaluating the biological effects resulting from exposure to multiple cytotoxic agents. The methodology can be used with many other types of endpoints and is not limited by the number of treatment agents.

Cells, Cultured↗