Acute Dose Studies Research Articles

Methodological improvements to meta-analysis of low dose rate studies and derivation of dose and dose-rate effectiveness factors.

Epidemiological studies of cancer rates associated with external and internal exposure to ionizing radiation have been subject to extensive reviews by various scientific bodies. It has long been assumed that radiation-induced cancer risks at low doses or low-dose rates are lower (per unit dose) than those at higher doses and dose rates. Based on a mixture of experimental and epidemiologic evidence the International Commission on Radiological Protection recommended the use of a dose and dose-rate effectiveness factor for purposes of radiological protection to reduce solid cancer risks obtained from moderate-to-high acute dose studies (e.g. those derived from the Japanese atomic bomb survivors) when applied to low dose or low-dose rate exposures. In the last few years there have been a number of attempts at assessing the effect of extrapolation of dose rate via direct comparison of observed risks in low-dose rate occupational studies and appropriately age/sex-adjusted analyses of the Japanese atomic bomb survivors. The usual approach is to consider the ratio of the excess relative risks in the two studies, a measure of the inverse of the dose rate effectiveness factor. This can be estimated using standard meta-analysis with inverse weighting of ratios of relative risks using variances derived via the delta method. In this paper certain potential statistical problems in the ratio of estimated excess relative risks for low-dose rate studies to the excess relative risk in the Japanese atomic bomb survivors are discussed, specifically the absence of a well-defined mean and the theoretically unbounded variance of this ratio. A slightly different method of meta-analysis for estimating uncertainties of these ratios is proposed, motivated by Fieller's theorem, which leads to slightly different central estimates and confidence intervals for the dose rate effectiveness factor. However, given the uncertainties in the data, the differences in mean values and uncertainties from the dose rate effectiveness factor estimated using delta-method-based meta-analysis are not substantial, generally less than 70%.

Hypoglycemic and anti-hyperglycemic study of Phaleria macrocarpa fruits pericarp.

Fruits of Phaleria macrocarpa are used in the traditional health system of the Indonesians and lower course of Malaysia, as effective remedy and management for diabetes mellitus. This study therefore investigated the hypoglycemic and anti-hyperglycemic effects of P. macrocarpa extracts in normal and diabetic rats, respectively. The fruits were sequentially extracted in petroleum ether, methanol and water to obtained 3 extracts. Blood glucose response to acute dose of the extracts (1g/kg b.w.) and intra-peritoneal glucose tolerance test (IPGTT) was performed in normal rats and a 12-day anti-hyperglycemic activity study was carried out in diabetic rats. The extracts exerted no effect in acute dose study. However, the methanol and water extracts showed a non significant blood glucose lowering effect between the 30 and 120 min in IPGTT, compared with the normal control. In diabetic rats, methanol extract only, lowered blood glucose by 56.25 and 58.33% (P<0.05) after a 12-day treatment compared with diabetic control (DC) and pre-treatment values, respectively; an effect similar to metformin, glibenclamide and insulin treated groups. Plasma insulin measured in the methanol extract-treated group was found to decrease by 75 and 50% compared with DC and pre-treatment values, respectively (P<0.05). This later effect only compared with the insulintreated control with respective reductions of 65 and 30% (P<0.05). Phytochemical thin layer chromatography (TLC) spray test of the methanol extract indicated the presence in abundance of flavonoids, terpenoids and tannins. The antidiabetic activity of P. macrocarpa was validated and this action which resides in the methanol fraction may be exerted by extra-pancreatic means.

Cholinergic system under aluminium toxicity in rat brain.

The present investigation envisages the toxic effects of aluminium on the cholinergic system of male albino rat brain. Aluminium toxicity (LD50/24 h) evaluated as per Probit method was found to be 700 mg/kg body weight. One-fifth of lethal dose was taken as the sublethal dose. For acute dose studies, rats were given a single lethal dose of aluminium acetate orally for one day only and for chronic dose studies, the rats were administered with sublethal dose of aluminium acetate once in a day for 25 days continuously. The two constituents of the cholinergic system viz. acetylcholine and acetylcholinesterase were determined in selected regions of rat brain such as cerebral cortex, hippocampus, hypothalamus, cerebellum, and pons-medulla at selected time intervals/days under acute and chronic treatment with aluminium. The results revealed that while acetylcholinesterase activity was inhibited, acetylcholine level was elevated differentially in all the above mentioned areas of brain under aluminium toxicity, exhibiting area-specific response. All these changes in the cholinergic system were subsequently manifested in the behavior of rat exhibiting the symptoms such as adipsia, aphagia, hypokinesia, fatigue, seizures, etc. Restoration of the cholinergic system and overt behavior of rat to the near normal levels under chronic treatment indicated the onset of either detoxification mechanisms or development of tolerance to aluminium toxicity in the animal which was not probably so efficient under acute treatment.

Zinc toxicity to aminergic neurotransmitters in rat brain

The present study was aimed to evaluate zinc toxicity to aminergic system in different areas of the brain of male albino rat, Rattus norvegicus. Zinc toxicity, evaluated as per Probit method was found to be 500 mg/kg body weight. For acute-dose studies, rats were given a single lethal dose of zinc chloride for one day only and for chronic-dose studies, the rats were administered with sub-lethal doses (1/10th of lethal dose) of zinc chloride every day for 90 days continuously. Various constituents of the aminergic system viz. dopamine, norepinephrine, and epinephrine and the catabolizing enzyme, monoamine oxidase (MAO) were determined in different regions of rat brain such as olfactory lobe, hippocampus, cerebellum, and pons-medulla on selected time intervals/days under acute and chronic treatment with zinc. The results revealed that while the levels of all aminergic neurotransmitters were elevated differentially in the above mentioned areas of brain, MAO activity registered nonsignificant inhibition in all brain regions under zinc toxicity. All these changes in the aminergic system were subsequently manifested in the behavior of rat exhibiting the symptoms of mild tremors, reduced locomotor activity and emotions, restlessness followed by lacrymation, salivation, etc. From these observations, it was obvious that zinc treatment caused severe perturbations in the functions of the nervous system. Restoration of the aminergic system along with behavior to the near normal levels under chronic treatment indicates the onset of detoxification mechanisms or development of tolerance to zinc toxicity in the animal which was not probably so efficient under acute treatment.

Repeated dosing with oral cocaine in humans: Assessment of direct effects, withdrawal, and pharmacokinetics.

Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1-4 & Days 9-12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5-8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13-40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours.

NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo.

Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid beta protein (Abeta42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid beta protein precursor (APP) transgenic mice, and plasma and brain levels of Abeta and the drug were evaluated. These studies show that (a). eight FDA-approved NSAIDs lower Abeta42 in vivo, (b). the ability of an NSAID to lower Abeta42 levels in cell culture is highly predicative of its in vivo activity, (c). in vivo Abeta42 lowering in mice occurs at drug levels achievable in humans, and (d). there is a significant correlation between Abeta42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Abeta42 levels in broken cell gamma-secretase assays, indicating that these compounds directly target the gamma-secretase complex that generates Abeta from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Abeta42 levels to the greatest extent. Because R-flurbiprofen reduces Abeta42 levels by targeting gamma-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Abeta42 lowering agent.

Ketoconazole increases cocaine and opioid use in methadone maintained patients

Stress plays an important role in substance abuse problems. For example, in studies with rodents stress induces reinstatement of opioid and cocaine self-administration. In addition, attenuation of the stress response by pharmacological adrenalectomy using ketoconazole, a cortisol synthesis inhibitor, reduces cocaine self-administration in rodents. In contrast, studies in primates and humans have produced conflicting results using cortisol synthesis inhibitors for attenuating cocaine-related behaviors and subjective effects. To explore the treatment implications of these findings, ketoconazole's (600–900 mg daily) ability to reduce heroin and cocaine use was compared with placebo in 39 methadone maintained patients with a history of cocaine abuse or dependence during a 12-week double blind trial. Contrary to the predicted effects, both heroin and cocaine use increased after patients were stabilized on methadone and ketoconazole. Depressive and withdrawal symptoms improved no more with ketoconazole than with placebo treatment, and side effects were greater on ketoconazole than placebo. As reported before with methadone treatment, morning cortisol levels were significantly lower than normal values throughout the clinical trial, but were not lower with ketoconazole than placebo treatment. Thus, in agreement with the negative results from acute dosing studies in primates and humans, chronic ketoconazole treatment does not appear to reduce cocaine or opioid use in humans maintained on methadone.

Ambulatory blood pressure monitoring in the assessment of antihypertensive therapy

Before an antihypertensive drug is approved for use in clinical practice it must undergo rigorous clinical testing. Basic pharmacokinetic data are usually first obtained in healthy, normal individuals and thereafter in patients with renal or hepatic disease or in sub-groups such as the young or elderly. Acute dosing studies over a wide dosage range are then required prior to initiating longer-term studies. After one or more dosage levels have been selected and the appropriate dosing interval established, investigators may proceed with studies of four to twelve weeks duration, comparing the new drug with placebo or other standard therapies such as a thiazide diuretic or a beta-blocker. A key element in the evaluation process is the assessment of the drug

Behavioral Sensitization to Cocaine in the Absence of Altered Brain Cocaine Levels

We conducted experiments investigating the role of altered cocaine distribution in behavioral sensitization. The first was designed to determine whether carry-over from one injection to the next occurs after acute cocaine administration. Female, Sprague–Dawley rats were administered 5 mg/kg 3H-cocaine and 24 h later were challenged with either 5 mg/kg unlabeled cocaine or saline. Animals were sacrificed 15 min after drug administration. There was no difference between groups in cocaine levels in brain, liver, or plasma, thus indicating that carry-over did not occur following acute cocaine administration. The second experiment was designed to determine whether bound cocaine could be released following acute or multiple dose cocaine administration. In the acute dose study, animals were administered either 20 mg/kg cocaine or saline, challenged 24 h later with 5 mg/kg 3H-cocaine, and sacrificed 5 min after drug administration. Animals with previous cocaine experience exhibited a significant increase in the number of rearings. The groups did not differ in brain or plasma cocaine levels. In the multiple dose study, animals were injected daily for 4 days with 20 mg/kg cocaine or saline, challenged with 5 mg/kg 3H-cocaine on day 5, and sacrificed 10 min after drug administration. Animals with previous cocaine experience exhibited significantly greater locomotor activity and number of rearings. There was no difference between groups in cocaine levels in various brain regions, plasma, or liver. Brain cocaine content in various regions was significantly correlated, though heterogeneously distributed within the various regions. The highest cocaine levels were found in hippocampus, striatum, thalamus/hypothalamus, and cortex. These results provide further evidence that behavioral sensitization is not the result of cocaine redistribution following repeated administration.

Effect of repeated haloperidol administration on phencyclidine discrimination in rats

Wiley, Jenny L.: Effects of repeated haloperidol administration on phencyclidine discrimination in rats. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1995, 19(4): 699–711. 1. 1. Previous research has shown that acute doses of haloperidol block many of themotor stimulatory effects of phencyclidine (PCP) and other PCP-like drugs. In addition, when given acutely, haloperidol produces partial attenuation of PCP's discriminative stimulus effects in rats. 2. 2. Haloperidol is often administered chronically in clinical situations; hence, it is important to investigate the effects of repeated, as well as acute, dosing with this drug. 3. 3. The purpose of the present study was to examine the effects of repeated administration of haloperidol on PCP discrimination in rats. Rats were trained to discriminate PCP (2.0 mg/kg) from saline in a two-lever drug discrimination procedure and were tested with cumulative doses of PCP before and after repeated administration of saline and of haloperidol (0.5 mg/kg/day). 4. 4. Discrimination training was suspended during the two 14–15-day repeated dosing regimens. Suspended training with repeated saline administration had little effect on the dose-effect curve for % PCP-lever responding. 5. 5. Repeated administration of haloperidol produced some diminution of PCP discrimination. After haloperidol, the ED 50 for % PCP-lever responding was 1.4 mg/kg, compared to the pre-haloperidol ED 50 of 0.7 mg/kg. 6. 6. These results are consistent with those of acute dosing studies with haloperidol in PCP-trained rats and suggest that repeated administration of haloperidol may disrupt PCP's discriminative stimulus effects, although most rats were still able to discriminate the higher doses of PCP.