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Biomedical subjects

M C Berenbaum

Publications and source records attributed to M C Berenbaum.

At least 37 records · Page 2Linked to original sources
PubMed1985

The expected effect of a combination of agents: the general solution.

Interactions between agents (drugs, carcinogens, physiological stimuli, environmental pollutants, etc.) in producing their effects are of fundamental interest and practical importance in virtually every branch of biology and medicine. A combination of agents is said to show interaction when the magnitude of its effect is greater or smaller than expected, expectation being based on the dose-effect relations of the individual agents in the combination. The crux of the matter is to decide what is expected, and various rules have been proposed to this end (for example, that the expected effect is the sum of the effects of the individual constituents of the combination, or that it is the product of these effects, or that it may be calculated from the law of mass action). These rules are valid for combinations of agents with particular and rather restricted types of dose-effect relations, but they have no general validity. A general solution to this problem is given here, that enables the effects of non-interactive combinations to be calculated directly from the dose-effect relations of the individual agents (whether expressed algebraically or numerically), regardless of the particular types of dose-effect relations involved. This solution is based on the fact that, when an effect of particular magnitude is produced by a combination of n agents which do not interact to produce that effect, the point representing the combination in the n-dimensional space spanned by the dose-axes of the individual agents lies in the same (n-1)-dimensional hyperplane as those representing other combinations iso-effective with it and iso-effective amounts of the individual agents. Methods for calculating the effect of a non-interactive combination as the sum or product of the effects of its constituents, or from the law of mass action, each of which is correct in appropriate cases, may be deduced (without invoking mechanisms of action) by applying this general principle to particular types of dose-effect relations.

Dose-Response Relationship, Drug↗
PubMed1985

Consequences of synergy between environmental carcinogens.

As it is generally impossible to determine dose-response relationships for carcinogens at the low concentrations in which they occur in the environment, risk-benefit considerations are by consensus based on the linear, no-threshold model, on the assumption that this represents the worst case. However, this assumption does not take into account the possibility of synergistic interactions between carcinogens. It is shown here that, as a result of such interactions, the dose-response curve for added risk due to any individual carcinogen will generally be steeper at lower doses than at higher doses, and consequently the risk at low environmental levels will be higher than would be expected from a linear response. Moreover, this excess risk at low doses is shown to increase as the general level of environmental carcinogens rises and, independently of this effect, it may also increase with the number of carcinogens present.

Carcinogens, Environmental↗
PubMed1985

Wavelength and light-dose dependence in tumour phototherapy with haematoporphyrin derivative.

Red light (c. 630 nm) is almost universally used in tumour phototherapy as it is the most penetrating of the porphyrin excitation wavebands. However, measurements of tumour attenuation of light of different wavelengths and of the excitation spectrum of haematoporphyrin derivative in vitro suggested that green light might be more efficient than red in destroying thin tumours. Experimentally, we confirmed this for tumours up to approximately 1.2 mm thick, a depth exceeding that of most carcinomas-in-situ. The superiority of green light over red in terms of the illumination time required to produce equivalent depths of necrosis may extend to greater depths (3-4 mm) if the former is produced by an argon laser and the latter by an argon-pumped dye laser. The relation between depth of necrosis Zn and light dose D is shown to be Zn = sigma gamma-1 1n(D/theta gamma) where sigma gamma is the attenuation coefficient for light at wavelength gamma and theta gamma the threshold light dose for producing necrosis at that wavelength. This logarithmic relationship suggests that it may be difficult to eradicate large tumours merely by increasing the light dose, and indicates the need for other approaches.

Animals↗
PubMed1983

Synergy with double and triple antibiotic combinations compared.

Combinations of two sets of antibiotics (gentamicin-carbenicillin-rifampicin and trimethoprim/sulphamethoxazole-carbenicillin-rifampicin) were tested against isolates of Pseudomonas maltophilia. An abbreviated checker-board method permitted tests with combinations of all three antibiotics and of each of the possible three pairs in each set. Triple combinations were usually synergistic, whereas 25% of combinations of pairs were antagonistic or additive. The modal degree of synergy was greater with combinations of three antibiotics than with combinations of any two. For any isolate, greater synergy was generally obtained with a triple than with a double combination, and the mean degree of synergy was always greater with triple than with double combinations. It was advantageous to add to double combinations even an antibiotic to which the organism was resistant. Organisms multiply resistant to three antibiotics were also resistant to 25% of combinations of pairs, but never resistant to combinations of all three. Synergy was more likely to be present at all antibiotic ratios with triple than with double combinations. Since ratios at the site of action may differ greatly from that of the administered combination, there would be substantial clinical benefit in identifying sets of antibiotics of which combinations at all ratios showed synergy. The search for these may entail exploring multicomponent combinations and, with conventional methods, this raises a considerable logistic problem. A strategy is therefore proposed, designed to find antibiotic sets showing synergy at all ratios.

Anti-Bacterial Agents↗
PubMed1982

Increased therapeutic efficiency of a lipid-soluble alkylating agent incorporated in liposomes.

A highly hydrophobic alkylating agent, 1-N,N-bis(beta-bromoethyl) amino-3-methylnaphthalene, given as the free drug in oil, cured a substantial proportion of mice bearing the PC6 myeloma in the dose range 2-7 mg/kg. However, these doses were toxic, and the LD50 was 6-7 mg/kg. When incorporated in liposomes, similar curative effects were obtained at doses of 10-41 mg/kg without material toxicity, even at the highest dose. Liposome entrapment therefore greatly increases the therapeutic efficiency of this agent.

1-Naphthylamine↗
PubMed1982

In vivo biological activity of the components of haematoporphyrin derivative.

The in vivo biological activity of various fractions and components of haematoporphyrin derivative (HpD) have been determined by measuring the depth of necrosis of implanted tumours in mice exposed to light after the administration of standard doses of porphyrins dissolved in alkali. In this assay, haematoporphyrin, hydroxyethylvinyldeuteroporphyrin and protoporphyrin are inactive, but the mono- and di-acetates of haematoporphyrin (which are major components of HpD) and acetoxyethylvinyldeuteroporphyrin are active. However, the situation appears to be more complex than this. The normal method for preparing HpD for injection involves an alkali treatment which causes hydrolysis and elimination of the acetoxy functions, and the only recognized products (haematoporphyrin, hydroxyethylvinyldeuteroporphyrin and protoporphyrin) are inactive in the in vivo assay. It is concluded that the active component here is a porphyrin, possibly a dimer or oligomer, which is retained on the column during the normal separation by HPLC. This conclusion is supported by the observations that (i) the crude material obtained from the spent column is active without further alkali treatment, and (ii) activity develops over 30 min, when HpD or the mono- or diacetates of haematoporphyrin are treated with sodium bicarbonate in aqueous DMSO. The advantages of working with a pure substance (e.g. haematoporphyrin diacetate) rather than a mixture (HpD) are stressed.

Animals↗
PubMed1981

Neutrophil function during chemotherapy for Hodgkin's disease.

Simultaneous measurement of neutrophil migration, phagocytic activity, candidacidal and bactericidal activity were made during quadruple chemotherapy of advanced Hodgkin's disease (HD). Measurements were also made in normal individuals, hospital patients not on chemotherapy, untreated patients with advanced HD and patients off chemotherapy for over a year. Neutrophil migratory activity was usually normal in untreated HD patients and those on chemotherapy, but less than 20% of all tests showed depressed values, some of which were corrected by plasma. Similar results were found with neutrophil phagocytosis. Abnormalities in these functions were found in both early and late cycles, but there was a tendency for migration to deteriorate during later chemotherapy cycles. Neutrophil candidacidal and bactericidal activity were frequently depressed in patients on treatment and there was deterioration in candidacidal activity during the chemotherapy cycle. These abnormalities of killing activity were frequently corrected in control plasma. Neutrophil function is normal in most patients with advanced HD and in patients in remission. In a minority of patients on treatment there are marked functional defects, especially in killing activity. These defects are partly cell-associated and partly plasma-related. Susceptibility to infection during chemotherapy of HD may be partly due to defective neutrophil function.

Candida↗
PubMed1979

Subcutaneous Corynebacterium parvum in bladder cancer: a controlled study of its immunological effects.

Fourteen out of 26 patients with invasive bladder cancer were randomly assigned to receive weekly subcutaneous injections of Corynebacterium parvum (CP) in addition to standard treatment. Peripheral blood T lymphocyte percentage, K cell activity, mitogen responsiveness, and monocyte and polymorph leucotaxis were measured at intervals over a period of 1 to 2 years. The only consistent difference between the CP-treatment patients and the controls was a slightly higher level of K cell activity in the former, who, however, fared rather worse than the controls in terms of survival.

Cell Survival↗
PubMed1979

The immunosuppressive effects of 5-fluorocytosine and 5-fluorouracil.

5-Fluorocytosine (5-FC) is weakly immunosuppressive when given in lethal doses to mice, and inhibits the responses of mouse and human lymphoid cells to plant lectins at concentrations of 1 mg/ml or more. 5-FC has about 1% of the immunosuppressive activity of 5-fluorouracil in vivo and 0.1% in vitro. Deamination of small amounts of 5-FC to 5-FU or conversion to other toxic metabolities may account for its immunosuppressive effects. The in vitro effects of 5-FC could also be accounted for by the presence of traces (0.1%) of 5-FU as a contaminant.

Animals↗
PubMed1979

Time-dependence and selectivity of immunosuppressive agents.

The effects of a variety of agents on the mouse antibody response to sheep red cells (SRC) and Escherichia coli lipopolysaccharide (LPS) were investigated. Agents formed two broad groups according to the time-dependence of their effects. Class I agents inhibited responses if given at any time over a broad period from before administration of antigen to 1-2 days afterwards. They included ionizing radiation, cortisone acetate, cholera toxin and several alkylating agents. Class II agents inhibited responses substantially only if given 1-2 days after the antigen. These agents were all either antimetabolites or vinca alkaloids. Class II agents had only moderate selectivity. When given at the time of maximal effectiveness they usually suppressed the response to SRC more than that to LPS. Some class I agents had striking selectivity. Radiation, cortisone acetate, and cholera toxin markedly suppressed the SRC response but had much less effect on the LPS response. In contrast, mitoclomine and its analogues, which are lipid-soluble alkylating agents, suppressed the response to LPS far more than that to SRC. Possible reasons for these differences in time-dependence and selectivity are discussed.

Alkylating Agents↗
PubMed1978

A method for testing for synergy with any number of agents.

The standard checkerboard titration for detecting synergy between antibiotics is practicable for combinations of two antibiotics, laborious for combinations of three, and not feasible for combinations of four or more. Nevertheless, methods for testing of combinations of several antibiotics are urgently needed because some combinations might be superior to those in use and enable the successful treatment of infections resistant to current therapy. A simple method for measurement of synergy (or antagonism) with combinations of any number of agents has been developed which requires less effort than the standard checkerboard titration of two agents. With this method, the concentrations of each of n agents producing some specified effect (such as minimal inhibitory concentration or minimal bactericidal concentration) are determined. A reference combination made up of 1/n of each of these concentrations is titrated to find a dilution that produces the specified effect. The degree of dilution required is equal to the sum of the fractional inhibitory concentrations (concentration of each agent in combination/concentration of each agent alone) as conventionally determined by checkerboard titrations; sums of less than 1, 1, and greater than 1 indicate synergy, additivity, and antagonism, respectively.

Anti-Bacterial Agents↗
PubMed1976

Synergistic effect of cortisol and prostaglandin E2 on the PHA response. Relation to immunosuppression induced by trauma.

Surgical and thermal trauma in man are followed by depressed immunological responses in vivo and reduced lymphocyte reactivity in vitro. The possibility that these are related to trauma-induced rises in tissue levels of cortisol and prostaglandins was examined by studying the effect of a wide range of concentrations of cortisol and prostaglandin E2 (PGE2), separately and together on the phytohaemagglutinin (PHA) response of human peripheral blood lymphocytes. These effects were plotted on two-dimensional dose:effect graphs; the shapes of the curves connecting combinations of equal effect (isoboles) showed that these agents acted with marked synergy in suppressing the response, provided they were present while the response was taking place. Synergy was also shown by using a simple equation relating the concentrations of the agents producing a given effect when used in combination to the concentrations needed to produce the same effect when used separately. Cortisol at concentrations reached in the peripheral blood after trauma in man (1-4 X 10(-6)M) and PGE2 at concentrations to be expected in traumatized tissues (up to 4 X 10(-7)M) each suppressed the response only slightly. The former reduced the response to 0-7 of controls and the latter 0-5 (means of seven subjects). When both were present together at these concentrations, the response was markedly depressed (mean 0-06, range 0-02--0-13 of controls). However, when lymphocytes were incubated at 37 degrees C with cortisol and PGE2 for 20 hr and then washed before exposure to PHA, the response was not inhibited, even by substantially higher concentrations than the above, and was usually moderately enhanced. Therefore, these in vitro experiments do not explain the depressed PHA response observed in peripheral blood lymphocytes after trauma. It is possible, however, that raised cortisol and prostaglandin levels depress the reactivity of lymphocytes while they remain in the traumatized region and its lymph drainage area.

Adult↗