Drug Effects In Models Research Articles

Review article : Computer simulation of the progression of an acute myelocytic leukemia in the brown norway rat

Reduction and extrapolation of experimental data concerning both the perturbed and unperturbed growth characteristics of a malignant population was the reason for developing a simple descriptive mathematical model. Data were obtained by inoculating BN/Rij rats i.v. with 10 7 viable cells of a transplantable myelocytic leukemia (BNML). At various time points the tumor load in the bone marrow was determined by means of a clonogenic stemcell (LCFU-S) assay or by a dose–survival time bioassay (SVL). By fitting hypothetical growth curves to the LCFU-S datapoints, using a non-linear least squares computer algorithm, an optimal functional relationship between the BNML population size, N, and time after inoculation, t, was found. The unperturbed data are best explained by a curve that consists of an exponential part which, at a transition point, changes into a Gompertz curve to account for a steady state plateau phase. Chemotherapy applied for perturbation purposes consisted of a single dose (100 mg/kg) of cyclophosphamide (CY) given i.p. at day 13. The effect of the drug was modelled as either pulse-shaped or as a more gradual event. In the former case an instantaneous tumor load reduction occurs, after which regrowth can be modelled in a way similar to unperturbed growth. Different parameter values apply, resulting in slower population size increase and a lower level plateau phase. Statistical significance is rather poor though, owing to uncertainty in the observations. The tumor load reduction is somewhat larger than can be deduced from dose–response experiments (6.0 and 5.5 decades, respectively). Correction is possible, without changing the goodness of fit, by introducing a time delay in the early exponential phase. To model gradual drug influence various functions were tested, i.e. a constant level during some time, an exponentially decreasing level, parabolic increase and decrease, and a combination of the first two categories. This last one, when superimposed on the function for unperturbed growth, yielded the best fit to the observed LCFU-S datapoints. Taking the total correlation coefficient, TCC, as measure of goodness of fit (TCC tends to 1 with improving fit) it must be concluded that the instantaneous drug effect model is only slight better than the gradual model (TCC = 0.80253 and 0.84915, respectively). The SVL datapoints also indicate instaneous rather than gradual drug effect.

Cultured neurons for testing cerebroprotective drug effects in vitro

An attempt was made to establish hypoxic cultured neurons from chick embryo hemispheres as an in vitro model for testing cerebroprotective drug effects. Hypoxia was induced by adding 1 mmol/l KCN to the incubation medium of the cells. After various time periods (15–120 min), the cyanide-containing medium was replaced by fresh medium so that the cells could recover from hypoxia. High-energy phosphate levels of the cells and the protein content of the cultures were determined as indicators of the cell viability and response. The cells showed a rapid and pronounced decrease in the levels of high-energy phosphates during cytotoxic hypoxia, and after removal of cyanide the energy state was restored again within few minutes. The protein content of the cultures remained unchanged. Pentobarbital inhibited the breakdown of the high-energy phosphates during hypoxia and accelerated their restitution during the recovery period. The results suggest that hypoxic cultured neurons could be a useful model for testing Cerebroprotective drug effects.

Pharmacokinetic-pharmacodynamic modeling of CNS drug effects: An overview

Pharmacokinetic-pharmacodynamic modeling of CNS drug effects: An overview

Ro 15-1788, CGS 8216, picrotoxin, and pentylenetetrazol: Do they antagonize anxiolytic drug effects through an anxiogenic action?

Recent evidence suggests that agents that inhibit GABAergic function, particularly at sites on the GABA/benzodiazepine receptor complex, have intrinsic anxiogenic properties. The present experiments further characterize the behavioral effects of these receptor complex inhibitors, using the “defensive burying” test, which is reasonably selective for anxiolytics. Putative blockers of the GABA-receptor coupled chloride channel, picrotoxin and pentylenetetrazol, and the benzodiazepine receptor antagonists Ro 15-1788 and CGS 8216 each blocked the anxiolytic effect of chlordiazepoxide. However, these compounds failed to exert significant anxiogenic effects in the burying test. These findings suggest that different animal models of anxiolytic drug effects are not equally sensitive to the possible anxiogenic effects of drugs that act at the GABA/benzodiazepine receptor complex.

Diazepam tolerance and withdrawal assessed in an animal model of subjective drug effects

AbstractTolerance to and withdrawal from drugs of dependence involves subjective symptoms and physical signs. Until recently, only physical signs associated with these phenomena could be assessed in animals. Recently, however, drug discrimination methodology has been used to bioassay for the occurrence of subjective events in animals; the work reviewed in this paper describes extensions of this general technique to test for subjective aspects of withdrawal from and tolerance to benzodiazepine drugs in rats. The durg dicrimination procedure reinforces differential responding where the controlling stimulus is the presence or absence of a drug‐produced internal stimulus. Although it is impossible to determine the quality (subjective nature) of such stimuli in animals, it is possible to operationally define relationships between classes of stimuli. With regard to the discriminative stimulus produced by pentylenetetrazol (PTZ), data to date show that anxiogenic drugs substitute for PTZ and anxiolytic drugs block the PTZ stimulus. Because in humans severe anxiety is a frequently seen component of withdrawal from dependence on benzodiazepine drugs, this laboratory initiated experiments to determine if animals trained to detect PTZ and then given chronic treatment with benzodiazepines would substitute a withdrawal state for the PTZ stimulus. Data reviewed in this paper show that following diazepam administration, treatment with the benzodiazepine antagonist Ro 15‐1788 (RO) produced a dose‐related PTZ‐like stimulus. When given to nondependent animals, RO neither substituted for nor blocked nor enhanced the PTZ stimulus. In additional studies, RO produced a PTZ‐like stimulus when administered once every 3 d in rats maintained chronically on diazepam. Further, rats given a 2‐d regimen of diazepam, 80 mglkgl8 hr, were subsequently tolerant to the PTZ‐blocking action of diazepam. These data demonstrate that the discrimination of PTZ is a useful procedure for assessing subjective aspects of tolerance to and withdrawal from benzodiazepines in animals.

Computer simulation of the progression of an acute myelocytic leukemia in the brown Norway rat

Reduction and extrapolation of experimental data concerning both the perturbed and unperturbed growth characteristics of a malignant population was the reason for developing a simple descriptive mathematical model. Data were obtained by inoculating BN/Rij rats i.v. with 10 7 viable cells of a transplantable myelocytic leukemia (BNML). At various time points the tumor load in the bone marrow was determined by means of a clonogenic stemcell (LCFU-S) assay or by a dose-survival time bioassay (SVL). By fitting hypothetical growth curves to the LCFU-S datapoints, using a non-linear least squares computer algorithm, an optimal functional relationship between the BNML populations size, N, and time after inoculation, t, was found. The unperturbed data are best explained by a curve that consists of an exponential part which, at a transition point, changes into a Gompertz curve to account for a steady state plateau phase. Chemotheraphy applied for perturbation consisted of a single dose (100 mg/kg) of cyclophosphamide (CY) given i.p. at day 13. The effect of the drug was modelled as either pulse-shaped or as a more gradual event. In the former case an instantaneous tumor load reduction occurs, after whicregrowth can be modelled in a way similar to unperturbed growth. Different parameter values apply, resulting in slower population size increase and a lower level plateau phase. Statistical significance is rather poor though, owing to uncertainty in the observations. The tumor load reduction is somewhat larger than can be deduced from dose-response experiments (6.0 and 5.5 decades, respectively). Correction is possible, without changing the goodness of fit, by introducing a time delay in the early exponential phase. To model gradual drug influence various functions were tested, i.e. a constant level during some time, an exponentially decreasing level, parabolic increase and decrease, and a combination of the first two categories. This last one, when superimposed on the function for unperturbed growth, yielded the best fit to the observed LCFU-S datapoints. Taking the total correlation coefficient, TCC, as measure of goodness of fit (TCC tends to 1 with improving fit) it must be concluded that the instantaneous drug effect model is only slight better than the gradual model (TCC = 0.85023 and 0.84915, respectively). The SVL datapoints also indicate instantaneous rather than gradual drug effect.

In vivo potencies of antipsychotic drugs in blocking alpha 1 noradrenergic and dopamine D2 receptors: Implications for drug mechanisms of action

In addition to being dopamine antagonists, all antipsychotic drugs are potent antagonists of alpha-1 noradrenergic receptors. Nevertheless, the contribution of alpha blockade to the clinical therapeutic effects of the antipsychotic drugs has never attracted extensive study. In particular, the relative alpha-1 noradrenergic antagonist potency of antipsychotic drugs has rarely been determined in vivo during extended treatment, although such treatment would provide a better model of clinical drug effects than the determination of potencies in in vitro systems, such as assays of competition for binding sites in tissue homogenates, as is most often done. To estimate the physiological efficacy of antipsychotic drugs as dopamine and alpha adrenergic antagonists, we treated rats for four weeks with daily IP injections of the following antipsychotic drugs: Fluphenazine, 1 mg/kg; haloperidol, 1 mg/kg; chlorpromazine, 25 mg/kg; thioridazine, 25 mg/kg; and clozapine, 25 mg/kg. Effective antagonism should lead to an increase in density of the relevant receptors. After two drug-free days, rats were sacrificed and the affinity and density of dopamine D2 and alpha-1 noradrenergic receptors were determined in striatum and brain exclusive of striatum, respectively. Alpha 1 noradrenergic receptor density but not dopamine receptor density was increased after all treatments. Thus, preliminary experiments with this in vivo model suggest that all antipsychotic drugs are effective antagonists at alpha 1 noradrenergic receptors, while not all are effective antagonists at dopamine D2 receptors.

The Effect of Prolonged Pentobarbital Anaesthesia on Cardiac Electrophysiology and Inotropy of the Dog Heart in Situ

The effect of prolonged pentobarbital anaesthesia was tested on the dog heart in situ by means of His bundle electrography and programmed electrical stimulation, monophasic action potential recordings from the right ventricle and measurements of peak dp/dt obtained by Millar tip transducer in the left ventricle. Sixteen dogs were used. Immediately after catheterization during anaesthesia, a slight decreased heart rate, a reduction in the conduction velocity and an increase in the functional refractory period of the atrioventricular node occurred. From 15 to 30 min. after catheterization we observed no change in cardiac electrophysiology during the 8 hrs observation period. A slight decrease in contractility, however, appeared towards the end of the period. We conclude that dogs anaesthetized with pentobarbital could serve as a suitable model for testing drug effect on cardiac electrophysiology and contractility. The limitations of the model area are discussed.

Dual action effects of morphine on the electrical activity of the dorsal tegmentum

The midbrain tegmentum has been identified as an important locus for development of negative reinforcement with electrical stimulation of the brain. It also plays a central role in the motivational-affective component of pain, and is a site of the analgesic action of morphine. The present study reports the effects of morphine on the electrical activity of areas of the dorsal tegmentum of rats that were also tested for the aversive effects of brain stimulation. The results of spectral analysis of the EEG indicated that IP injections of 16 mg/kg of morphine significantly depressed intensity of EEG, while 8 mg/kg of morphine tended to increase intensity. The results were interpreted in terms of the dual action hypothesis of morphine action and Winter's model of drug effects of electrical activity of the brain. It was concluded that morphine may produce complementary inhibitory and excitatory effects on the negative and positive reinforcement systems of the brain respectively.