Administration Of Intermediate Doses Research Articles

Numerical optimisation of chemotherapy dosage under antiangiogenic treatment in the presence of drug resistance

We consider a two‐compartment model of chemotherapy resistant tumour growth under angiogenic signalling. Our model is based on the one proposed by Hahnfeldt et al. (1999), but we divide tumour cells into sensitive and resistant subpopulations. We study the influence of antiangiogenic treatment in combination with chemotherapy. The main goal is to investigate how sensitive are the theoretically optimal protocols to changes in parameters quantifying the interactions between tumour cells in the sensitive and resistant compartments, that is, the competition coefficients and mutation rates, and whether inclusion of an antiangiogenic treatment affects these results. Global existence and positivity of solutions and bifurcations (including bistability and hysteresis) with respect to the chemotherapy dose are studied. We assume that the antiangiogenic agents are supplied indefinitely and at a constant rate. Two optimisation problems are then considered. In the first problem a constant, indefinite chemotherapy dose is optimised to maximise the time needed for the tumour to reach a critical (fatal) volume. It is shown that maximum survival time is generally obtained for intermediate drug dose. Moreover, the competition coefficients have a more visible influence on survival time than the mutation rates. In the second problem, an optimal dosage over a short, 30‐day time period, is found. A novel, explicit running penalty for drug resistance is included in the objective functional. It is concluded that, after an initial full‐dose interval, an administration of intermediate dose is optimal over a broad range of parameters. Moreover, mutation rates play an important role in deciding which short‐term protocol is optimal. These results are independent of whether antiangiogenic treatment is applied or not.

Influence of incremental zeranol implant doses on the chemical and physical characteristics of third metacarpal bone and chemical composition of liver and soft tissue from feedlot steers.

Chemical and physical characteristics of third metacarpal bones and liver and rib soft tissue composition from feedlot steers were determined. Steers were selected (32 from each experimental location) to represent the range in slaughter weight and composition for each treatment group in three (total n = 1,088) feedlot experiments. Steers were implanted with 0, 24, 36, 48, 60, 72, 84, or 96 mg of zeranol at approximately 140 d before slaughter. Cattle at each location were fed for the same number of days and slaughtered as a group. Zeranol dose had no effect on the chemical composition of bone, liver, or rib soft tissue with the following exceptions: zeranol decreased (P < .01) bone Ca concentration and increased (P < .07) liver P concentration. Zeranol implantation decreased medullary cavity anterioposterior (AP) diameters and AP cortical width (P < .08). Loads withstood by the bones up to flexure (P < .08) and the strain at flexure (P < .09) were inversely related to the quadratic of zeranol dose. However, modulus of elasticity at flexure and breaking increased numerically with zeranol dose. Stress withstood by bones at flexure was greater (P < .09) for implanted steers. Strain data indicate that metacarpals from steers receiving zeranol would exhibit less deformation upon loading to flexure (P < .09) than controls. These data indicate that administration of intermediate doses of zeranol altered bone deposition of Ca, which resulted in modified third metacarpal physical and mechanical characteristics.

Pharmacokinetics of meptazinol in man following repeated intramuscular administration.

A study was performed in 6 healthy volunteers to determine whether 50 mg intramuscular doses of meptazinol repeated four hourly for 24 h would lead to accumulation of the drug. The first dose of meptazinol was rapidly absorbed with a subsequent mean (+/- SD) elimination half-life of 1.6 +/- 0.33 h. This value was unaffected by the administration of intermediate doses. There was no significant accumulation of the drug; 95% of the steady-state plasma concentration was achieved after a mean (+/- SD) of 1.9 +/- 0.39 and 99% after a mean (+/- SD) of 2.9 +/- 0.63 doses. These findings are consistent with the theoretical prediction for a rapidly absorbed drug with a plasma elimination half-life of 1.6 h. No clinically relevant changes were seen in pulse blood pressure, haematological or biochemical screens. Reported side effects were of a subjective and minor nature.

Germinal center in rat lymphatic tissues after the administration of L-asparaginase.

During the few last years the immune reaction of the germinal center to an antigen and/or immuno-depressive drug was extensively studied. The present experiment was designed to investigate the immune reaction of the germinal center induced by the enzymatic drug L-asparaginase. This compound can: 1st, depress lymphocyte blastogenesis (1), and, consequently, all the reactions connected with cell-immunity (2). This depression of lymphocyte blastogenesis is caused by quantities of L-asparaginase sufficient to deplete the exogenous L-asparagine, which is the specific substrate for L-asparaginase. 2nd, depress the antibody production, i.e., the humoral-immunity (3–5). Since the inhibition of antibody production occurs only after administration of large doses of L-asparaginase, this effect is probably not mediated by specific L-asparaginase activity. On the other hand, the administration of intermediate doses of that enzymatic compound induces the formation of specific anti-asparaginase antibodies (6,7).

VITAMIN C THERAPY AND PROPHYLAXIS IN EXPERIMENTAL POLIOMYELITIS

1. A group of 34 monkeys were infected intracerebrally with 0.1 cc. of a 10 per cent virus suspension. Following infection, 9 animals were treated with daily injections of 700 to 100 mg., 16 with 50 to 10 mg. and 9 with 5 mg. of vitamin C for a period of 2 weeks. In the whole group there were 6 animals that survived without showing any evidence of paralysis. 2 of these had received 50 to 10 mg. while 4 had received 5 mg. All of 19 untreated control monkeys, infected simultaneously with the same amount of virus, developed paralysis. 2. Another group of 6 monkeys were infected intracerebrally with 0.05 cc. of virus. Following infection, one animal was treated in the same manner with 25 mg. and 5 with 5 mg. of vitamin C. In the whole group there was one animal that survived without showing any evidence of paralysis. This animal had received 5 mg. All of 7 untreated control monkeys, infected simultaneously with the same amount of virus, developed paralysis. 3. A third group of 22 monkeys were infected intracerebrally with 0.01 cc. of virus. Following infection, one animal was treated in the same manner with 100 mg., 2 with 50 to 10 mg., and 19 with 5 mg. of vitamin C. In the whole group there were 12 animals that survived without showing any evidence of paralysis. One of these had received 10 mg., while 11 had received 5 mg. Of 12 untreated control monkeys, infected simultaneously with the same amount of virus, 2 failed to show any paralytic symptoms and 10 developed paralysis. 4. A summary of the results obtained in all three groups shows: (a) that among a total of 62 treated monkeys, 19 survived without paralysis and 43 succumbed to the disease, while of a total of 38 untreated controls, only 2 failed to develop paralysis and 36 succumbed to the disease; (b) that treatment with large doses of vitamin C was without any beneficial effect (all 10 monkeys which had received 700 to 100 mg. developing paralysis, that the administration of intermediate doses was followed by occasional survival without paralysis of the treated animal (3 monkeys surviving of a total of 19 which had received 50 to 10 mg.), and that nearly one-half of the animals which had received small doses escaped the disease (16 monkeys surviving of a total of 33 which had received 5 mg.). 5. Attempts to protect monkeys against subsequent intracerebral infection by the prophylactic administration of vitamin C, either per os or parenterally, have produced negative results. 6. The pathogenesis of infantile paralysis is discussed in the light of the experimental findings and the possibility is suggested that vitamin C represents one of the deficiency factors in the susceptibility problem of the human disease.