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Biomedical subjects

W H Carter

Publications and source records attributed to W H Carter.

At least 73 records · Page 4Linked to original sources
PubMed1984

Pentazocine-tripelennamine ("T's and Blues") substitution studies in morphine-dependent rodents.

Tripelennamine, pentazocine and various pentazocine-tripelennamine combinations were tested for their ability to substitute for morphine in morphine-dependent rodents. Rats and mice were rendered physically dependent on morphine by the Drug-Admixed Food Method. Pentazocine produced a dose-related partial suppression of morphine withdrawal signs in mice, as well as in both mildly and severely dependent rats. Tripelennamine did not suppress morphine withdrawal signs, but rather aggravated them. Furthermore, tripelennamine did not potentiate the ability of pentazocine to suppress morphine withdrawal signs. It is concluded that the primary reason for the reported "street" abuse of the tripelennamine-pentazocine combinations is not related to any remarkable ability of the combination to effectively suppress the discomfort of heroin withdrawal.

Animals↗
PubMed1984

Potentiation of narcotic-induced antinociception by tripelennamine in morphine-tolerant and drug-naive mice.

The ability of tripelennamine and chlorpheniramine to potentiate morphine- and pentazocine-induced antinociception in drug-naive and morphine-tolerant mice was tested utilizing the hot-plate method. Both tripelennamine and chlorpheniramine alone produced dose-dependent increases in hot plate latency which were naloxone reversible. Cross-tolerance developed between tripelennamine and morphine, whereas no cross-tolerance developed between chlorpheniramine and morphine. Neither tripelennamine nor chlorpheniramine significantly potentiated morphine-induced antinociception in drug-naive mice. The effects of tripelennamine and morphine were additive. Tripelennamine but not chlorpheniramine, however, significantly potentiated antinociception produced by low but not high doses of pentazocine in drug-naive mice. Furthermore, in morphine-tolerant mice, tripelennamine, but not chlorpheniramine, potentiated both morphine- and pentazocine-induced antinociception. It is concluded that the abuse of various narcotic-tripelennamine combinations can be attributed, at least in part, to a specific property of tripelennamine to potentiate narcotic effects in the drug-naive and morphine-tolerant state.

Analgesia↗
PubMed1984

A likelihood ratio test for a patterned covariance matrix in a multivariate growth-curve model.

In a multivariate growth-curve model, the estimator of the parameter matrix is a function of the matrix of the sums of squares and of the cross-products due to error. However, if the assumption of a patterned covariance matrix is valid, then the parameter estimator does not depend on the error matrix. A likelihood ratio test of this patterned covariance matrix is constructed and its distribution is discussed. A numerical example is provided in which the design consists of two treatment groups, with three repeated measures being taken of the three response variables.

Growth↗
PubMed1983

Solid tumor models for the assessment of different treatment modalities. XXI. Comparison of different radiation dose schedules alone or in combination with cyclophosphamide.

Total radiation (4500 rad) and cyclophosphamide doses (450 mg/kg or 2.7 g/m2) were held constant over a 24-day period in rat hepatoma 3924A using radiation schedules in which 1500 rad were given over a 1- to 2-day period in 1-8 fractions, repeated at 11-day intervals, with or without cyclophosphamide. Reducing the rad per fraction resulted in a reduced incidence of complete tumor response and tumor cures, and a reduction in the magnitude of skin response. Cure rates were 40, 10, 0, and 0%, respectively, for the 1500, 750, 500, and 250 rad per fraction groups without cyclophosphamide. When the 1500, 750, 500, 375, 250, and 188 rad per fraction groups were given 150 mg/kg cyclophosphamide day 1 after radiation, major increases occurred in tumor cures, with the cure rates being 80, 80, 80, 70, 60, and 50%, respectively. The addition of cyclophosphamide did not significantly alter skin reaction to radiation. The higher rad per fraction schedules were more effective in controlling metastatic dissemination when radiation was used alone. The addition of cyclophosphamide markedly reduced metastatic dissemination in both high and low-dose per fraction schedules. Optimal treatment levels were estimated from analysis of fitted response surfaces, and the quantitative interrelationship between normal tissue reaction, probability of tumor cure, and associated relative hazard to the host estimated from the results of these analytical methods. Hyperfractionated radiation dose schedules with dose/fraction in the clinical range combined with cyclophosphamide can significantly increase the therapeutic ratio and prevent metastatic dissemination compared with radiation alone as a result of the increased effectiveness of combined modality therapy on the tumor, without a concomitant increase in normal tissue reaction.

Animals↗
PubMed1983

Radioimmunoassay of CRF-like material in rat plasma: validation of the method.

The availability of antibodies against the ovine corticotropin releasing factor (CRF), which cross-react with a CRF-like immunoreactivity (CRF-LI) in the rat, has enabled us to develop a radioimmunoassay (RIA) for rat CRF-LI in plasma and crude hypothalamic extracts. 125I-Tyr CRF 1-41 was used as the tracer, and synthetic ovine CRF as the reference hormone. The precision profile of the assay indicates a high degree of reproducibility except for the lower dose range. The minimum detectable dose was 20 pg/tube. This assay can detect differences in plasma CRF-LI levels after various manipulations that simultaneously alter the ACTH levels in plasma. A wide range of CRF concentrations has been found in plasma of normal rats. Caution should be exercised in the interpretation of the values obtained since an ovine RIA system was used.

Adrenocorticotropic Hormone↗
PubMed1983

Sensitized (T6 X RFM)F1 donor B cells are engrafted and synthesize antibodies without further antigenic stimulation in RFM recipients with allogenic host-vs-graft disease.

Host-vs-graft (HVG) syndrome is the fatal disease of altered immunity that may be induced in susceptible strains of inbred mice by the perinatal inoculation of semiallogenic spleen cells. The allogenic HVG reaction causes severe depletion of both the donor F1 and host T lymphocytes, but the B cell system is hyperplastic and serum immunoglobulins (Ig) are markedly elevated. Death is caused by glomerulonephropathy and coagulopathy, both thought to be due to immune complexes. Previous work indicated that RFM host B cells are poor antibody producers, and therefore are an unlikely source of the high levels of serum Ig. The present studies were undertaken to determine if (T6 X RFM)F1 donor B cells could survive the allogenic HVG reaction and then contribute to the hyperglobulinemia. Spleen cells from (T6 X RFM)F1 donors marked with the distinctive T6 chromosome, and pre-sensitized against horseradish peroxidase (HRP) or sheep red blood cells (SRBC), were inoculated into RFM perinates. Cytogenetic studies revealed that replicating (T6 X RFM)F1 donor cells were present in low numbers in the spleens, but high numbers were found in the nodes of RFM hosts. After the transplantation of F1 cells sensitized to HRP, plasmacytoid cells with intracytoplasmic antibody to HRP were detected in the spleens and nodes of RFM recipients. Hemolytic plaque-forming cells and serum hemolysins were detected in RFM hosts that were perinatally inoculated with spleen cells from F1 donors sensitized to SRBC. The results suggested that F1 donor B cells had been engrafted, and then proliferated and matured into antibody-synthesizing cells. Their maturation was attributed to the allogeneic HVG effect, because there was no further exposure of the sensitized F1 donor B cells to antigen after transplantation, and because similar levels of mature F1 donor B cell activity were not found in T6/(T6 X RFM)F1 chimeras, which never develop HVG disease but become highly tolerant. These studies suggest a possible explanation for the seeming paradox of how hyperglobulinemia can develop in HVG mice that respond poorly to primary challenge with thymus-dependent antigen. It is proposed that primed, F1 donor B cells are stimulated into excessive production by the allogeneic reaction, whereas both donor and host B cells are poor primary responders because of the T cell deficiency induced by the same reaction.

Animals↗
PubMed1983

Confidence regions for constrained optima in response-surface experiments.

The precision of the estimated optimum from a response-surface experiment is often indicated via a confidence region about the optimum. Sometimes, because of associated secondary responses, unconstrained optima produce unrealistic operating conditions, even when the true response surface is known. We consider confidence intervals for constrained optima for which the constraint function is known or separately estimated. An example from a cancer combination chemotherapy experiment illustrates the construction of such a region.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1983

Comparison of effects of daily versus hyperfractionated split-course radiation schedules with and without cyclophosphamide on median survival, metastatic dissemination, tumor cure, and growth rates.

Daily fractions of 188, 250, 375, 500, and 750 rads were given to rats with hepatoma 3924A so that all groups received the same weekly dose of 1500 rads over a 6-week period, for total doses of 9000 rads when only radiation was given and 4500 rads when combined with cyclophosphamide. No tumors were cured (with two exceptions) with or without three doses of cyclophosphamide (150 mg/kg or 0.9 g/sq m) given 14 days apart. The addition of cyclophosphamide to the daily radiation treatment schedules did not change the time for tumors to reach 8 times the volume at time of treatment but did result in a longer median survival, which was attributed to a reduction of pulmonary metastases. A hyperfractionated radiation schedule using six 250-rad fractions given three times daily every 4 hr for 2 days combined with cyclophosphamide (150 mg/kg) 1 day later and repeated two additional times at 11-day intervals for a total dose of 4500 rads and cyclophosphamide (450 mg/kg) resulted in eradication of six of ten tumors, for a cure rate of 60%. Skin damage, determined by visually scoring the skin, appeared to be fully recovered by Day 126 and remained so until the end of the experiment on Day 384. The three courses of hyperfractionated radiation (total dose, 4500 rads), when given alone, were ineffective in producing tumor regression and cure. Combining cyclophosphamide with hyperfractionated split-course radiation schedules gave a major increase in tumor cure rate as compared with radiation alone at the same (4500 rads) or higher (9000 rads) doses. The major gains in effective utilization of the two modalities is greatly diminished or lost when the radiation is administered as daily fractions.

Animals↗
PubMed1982

Immunotherapy for remission maintenance in acute myeloblastic leukemia.

Forty-eight patients with acute myeloblastic leukemia in remission were treated with immunotherapy in addition to remission-maintenance chemotherapy. The first 16 patients were treated with weekly BCG and a leukemia cell vaccine (group 1). The next 32 patients were randomly allocated to receive BCG and a leukemia cell vaccine given once monthly (group 2) or BCG given monthly with no leukemia cell vaccine (group 3). There was no significant difference in remission duration or survival between the randomly allocated groups (2 and 3). Comparisons with group 1 are limited by the non-random allocation to this group, but selection bias was unlikely and clinical features were similar in the three patient groups. No significant difference in remission duration or survival was seen amongst the three groups studied. There was no advantage in the addition of leukemia cell vaccine (groups 1 and 2) to BCG alone (group 3) and no advantage to weekly (group 1) versus monthly immunotherapy (groups 2 and 3). Only 7 of the 48 patients achieved a second remission, and 4 of these were short-term partial remissions.

Adult↗
PubMed1982

Drug activity and therapeutic synergism in cancer treatment.

In work involving modeling of response surfaces to describe the effects of cancer chemotherapy treatments, it is important to define activity and therapeutic synergism in a statistically defensible manner. This requires the construction of confidence intervals around the estimated optimal treatment which has been achieved by use of an indirect method first proposed by Box and Hunter. Activity for a drug or a combination can be claimed at 100(1 - alpha)% level of confidence when the 100(1 - alpha)% confidence interval about the optimal treatment excludes a zero dose. Results of treatment of B16 melanoma and Lewis lung carcinoma with 3,4-dihydroxybenzohydroxamic acid are used to demonstrate this definition. Extensions of this concept lead to a statistically valid definition of therapeutic synergism. If the confidence region about the optimum combination of k drugs does not contact any of the k - 1 dimensional subspaces, then a k drug therapeutic synergism can be claimed. In the event that a k drug therapeutic synergism cannot be claimed, there may be subsets of the drugs which do combine with therapeutic synergy. These concepts are demonstrated by two- and three-drug combination experiments in L1210-bearing C57BL/6 x DBA/2 F1 (B6D2F1) mice. Razoxane and dacarbazine show therapeutic synergism at a 95% confidence level. A three-drug combination of 5-fluorouracil, Teniposide, and mitomycin C is considered. In this case, although the estimated optimum treatment includes 48.1 mg of 5-fluorouracil per kg, 15.9 mg of Teniposide per kg, and 3.9 mg of mitomycin C per kg, the confidence region generated failed to confirm at an 80% level of confidence that 5-fluorouracil was a necessary component of the best treatment.

Animals↗
PubMed1981

Analysis of survival data with nonproportional hazard functions.

The log-rank test or the proportional hazard model is a valuable, widely accepted method for analyzing time-to-response data from comparative clinical trials. When the hazard ratio is constant in time, this procedure is optimal. Indiscriminate or unthinking use of this approach results in problems in the determination of treatment differences. For example, when the true survival curves intersect, the hazard ratio cannot be constant, i.e., the hazard functions are not proportional. It is shown that by considering time-by-treatment interactions we gain flexibility in describing the relationships among hazard functions. In this paper we demonstrate with the results of a clinical trial how available methodology can be used to permit tests for the appropriateness of the model and to enable informative analysis of such data.

Clinical Trials as Topic↗
PubMed1980

Survival analysis of drug combinations using a hazards model with time-dependent covariates.

Hazard functions in cancer chemotherapeutic situations may not be proportional, so a nonproportional hazard model has been developed. The dose-response surface is explored by regression analysis of experimental data, and after the estimation of the underlying hazard function the quality of the fit of the model is assessed. Further, treatment levels may be optimized, and estimated survival distributions can be plotted for any treatment combination. In an example of two-drug treatment of murine L1210 leukemia, statistically significant nonproportionality is determined. Analysis permits extraction of potentially important information on drug interrelationships, which has been previously unavailable.

Altretamine↗
PubMed1979

Early diagnosis of relapse in acute myeloblastic leukemia: Serologic detection of leukemia-associated antigens in human marrow.

We tested serial bone-marrow samples from 47 adults with acute myeloblastic leukemia in remission for reactivity with heteroantiserums to leukemia-associated antigens, to determine whether imminent relapse could be detected in patients with acute leukemia. Of 26 patients who relapsed by standard morphologic criteria, 21 had increased immunoreactivity of bone marrow for one to six months (mean, 3.7 months) before relapse. High concordance was observed between a positive test and relapse during the period of study (chi-square = 27.53, P less than 0.001). The median time to relapse after a positive test was four months, as compared with the median remission duration of 19 months for the whole group (P less than 0.02, Peto's log-rank analysis). Serologic detection of leukemia-associated antigens in marrow may be a reliable indicator of imminent relapse in acute myeloblastic leukemia.

Animals↗