Substance Abuse in Pregnancy: Approach for family physicians.

Drug-dependent pregnancies are on the increase, are high risk, and require skilled medical attention. Unfortunately, because they fear the "system," many addicted women do not receive this medical care, putting both mother and baby at risk. We describe a case in which we tried to make the system more approachable. The family physician is essential for providing the continuity of care necessary to improve prenatal care, establish a support system, and facilitate family development.

The effect of post-irradiation anisotonic treatment on cell survival and repair of DNA damage.

V79 379A cells were irradiated and then exposed to anisotonic PBS for 20 min. This enhanced the radiation effect resulting from the fixation of potentially lethal damage. The induction of DNA single- and double-strand breaks is not increased by this treatment. Anisotonic treatment delayed the onset of repair of DNA damage. However when cells were returned to normal medium, they repaired the damage to a similar extent as cells not exposed to the anisotonic treatment. We suggest that the fixation of damage by post-irradiation anisotonic treatment is mediated through an increased probability of misrepair of DNA damage due to the delay in the onset of repair. This is supported by the observation that there is a reduced effect of post-irradiation anisotonic treatment on cells that have a markedly reduced ability to repair double-strand breaks.

Survival of V79 cells following simultaneous irradiation with X-rays and neutrons in air or hypoxia.

V79 Chinese hamster cells have been irradiated with X-rays and neutrons given simultaneously. The oxygen enhancement ratio and r.b.e. were measured as a function of the proportion of the dose due to the neutrons, which varied from 0 to 100 per cent. These were compared with the values calculated assuming the two types of radiation act independently, following an approach suggested by Curtis. The o.e.r. was less than the predicted value when the neutrons contributed less than about 40 per cent of the total dose. The r.b.e. also did not vary as predicted on the basis of independent action. The 'oxygen gain factor' reached half its maximum value when the proportion of the dose due to neutrons was only about 27 per cent. The results imply that there may be interaction between the damage caused by X-rays and neutrons and that beams having only 20 to 30 per cent of their dose due to high l.e.t. radiation, could be of therapeutic benefit.

A comparison of the ability of some radiosensitizers undergoing clinical trials to act as chemosensitizers.

The abilities of misonidazole, Ro 05-9963, Ro 03-8799 and Sr-2508 to enhance the action of the drugs cyclophosphamide (CY) and melphalan (L-PAM) have been compared in two mouse fibrosarcomas at acute and chronic sensitizer doses. SR-2508 was not effective with either CY or L-PAM in either tumor. Some enhancement of CY was obtained with Ro 05-9963 and Ro 03-8799; however, the degree of enhancement varied according to tumor and acute or chronic sensitizer dose. In all cases, the degree of enhancement was less than that obtained with an equivalent dose of misonidazole in both tumor systems. Of the four compounds tested, MISO would appear to have the most potential as a chemosensitizer.

The effect of prolonged high dose misonidazole on tumor response to radiation.

WHFIB and SA F tumors were exposed to misonidazole (MISO) concentrations of 2.5 mM or more for up to 4 hours (SA F) or 6 hours (WHFIB). There was no increase in the MISO enhancement ratio (SER) in the SA F for a 4 hour exposure to MISO relative to that following a single injection. In the WHFIB tumor, the ER increased from 2.2 for a single MISO injection to 2.5 for a 4 hour contact with MISO for tumor growth delay, and from 2.1 to 2.3 for a cloning assay. (These differences may not be statistically significant) Prolonged contact with MISO was toxic and reduced the body temperature by 4 to 5 degrees C. For WHFIB cells in vitro, when the contact time (in hypoxia) with 2.5 mM MISO was increased from 0.5 to 2.5 hours, the ER increased from 2.1 to 2.9 at 37 degrees C and from 1.9 to 2.5 at 33 degrees C.

The effect of sequential irradiation with X-rays and fast neutrons on the survival of V79 Chinese hamster cells.

V79 Chinese hamster cells have been exposed to X-rays or fast neutrons or to the two radiations given sequentially. Cells exposed to a priming dose of X-rays and then exposed immediately to a series of neutron doses regard the X-ray dose as equivalent to a neutron dose giving the same surviving fraction (iso-effective). If the cells are exposed to a neutron dose followed by X-rays the resulting survival is higher than would be obtained if the primary dose had been an iso-effective X-ray dose. However, it is lower than would be expected if the two radiations acted independently. The results imply that there is interaction between the damage caused by X-rays and fast neutrons. If the two radiations are given 3 hours apart they act independently.

The effect of radiosensitizers on the pharmacokinetics of melphalan and cyclophosphamide in the mouse.

Misonidazole (MISO) has been shown to affect the pharmacokinetics of both cyclophosphamide (CY) and melphalan (MEL) in WHT mice resulting in increased plasma levels of the cytotoxic drugs. The effect is not solely due to the reduction in body temperature observed with large single doses of MISO, as a change in MEL pharmacokinetics was still observed when the mice were maintained at 37 degrees C. Inhibition of cytotoxic drug metabolism may also be a possible mechanism. Such a pharmacokinetic effect could account for part of the potentiation of MEL and CY action observed in tumours with large single doses of MISO. However, a chronic low dosing schedule of MISO did not affect the plasma half-life of either cytotoxic drug, although a significant potentiation of each drug in combination with a chronic MISO dose has been obtained in some tumours. These results suggest that potentiation of chemotherapeutic drug action by MISO in the clinical situation is unlikely to be due to changes in drug pharmacokinetics.

Enhancement of the action of alkylating agents by single high, or chronic low doses of misonidazole.

Misonidazole (MISO) given as a large single dose enhanced the action of cyclophosphamide (Cy) and melphalan (L-PAM) in two mouse tumours. Below a dose of about 500 mg kg-1 it had no chemosensitizing effect. When MISO was given as a series of small doses by repeat injection over an 8 h period, in order to stimulate human pharmacokinetics, it significantly enhanced the action of Cy in the SA F tumour. It also enhanced the action of Cy and L-PAM in the WHFIB tumour as assayed by tumour cell survival in vitro following treatment in vivo but not when the assay was tumour growth delay. There was no enhancement by MISO of the leukopenia due to Cy or L-PAM. The results suggest that, in some tumours there may be benefit from the combination of clinically relevant MISO doses with alkylating agents. The leucopenia induced by these agents should not be enhanced by the MISO.

The effect of cytotoxic drugs with or without misonidazole on leucopenia in three strains of mice.

Leucopenia is a major dose-limiting effect of many cytotoxic drugs. We have measured the effect of melphalan and four other drugs either alone, or with misonidazole on total white cell count in mice. Three strains were used, though not with all drugs. White cell counts were determined 3, 5, and 7 days after giving the cytotoxic drugs either with or without misonidazole. For all the drugs used, the nadir in white cell count was at 3 to 5 days when the dose-effect curves were approximately expotential. Only in the case of chlorambucil and mitomycin-C did misonidazole enhance the leucopenia. There was no enhancement of the effects of melphalan, cyclophosphamide or CCNU. In the case of mitomycin C the effect of misonidazole was to delay the recovery in the white cell count. It would appear that enhanced leucopenia from the combination of misonidazole with cytotoxic drugs may depend on the drug used. With three of the five drugs, the absence of an effect of misonidazole implies that any enhanced damage to tumors would represent a true increase in therapeutic effectiveness.