Tenfold Increase In Dose Research Articles

DOSE-DEPENDENDENT HISTOCHROME EFFECTS OF KIDNEY IN RATS

THE AIM.Histochrome is a native antioxidant drug isolated from natural sourse. The study of pharmacological activity of histochrome showed a wide spectrum of dose-range action. The aim of this study was to investigate the renal effects changes when administered various doses of histochrome in rats.MATERIALS AND METHODS.The study was conducted on outbred stock Wistar rats. The test group of animals (n = 15) was administered subcutaneously histochrome at a dose of 1 mg/kg for 10 days, and the control group (n = 20) was treatment of 10 mg/kg of the drug. Since 3-d day every two days of experiment were measured daily urine output, excretion of Na+ and K+, creatinine excretion, and excretion of histochrome.RESULTS.The tendency of daily urination increase recorded at histochrome administration at a dose of 1 mg/kg. In the comparison group increased diuresis led to a fivefold magnification of parameter on the 7th day. Dynamic renal creatinine excretion during treatment with 1 mg / kg histochrome had a stable character throughout the experiment, while the ten-fold increase in dose was associated with a significant elevation of the factor. Natriuresis steadily increased, exceeding the initial value 5 times in under-test group of animals. In the comparison group the ion excretion increased by 2 times. Potassium excretion have similar dynamics using both histochrome doses. The native form histochrome was not detected in the urine in any of the animal groups.CONCLUSION.The experimental results showed that the behavior of the excretory renal function is histochrome dosedependent and may be due to its metabolites.

Effect of phosphine dose on sorption in wheat

In spite of the extensive use of phosphine fumigation around the world to control insects in stored grain, and the knowledge that grain sorbs phosphine, the effect of concentration on sorption has not been quantified. A laboratory study was undertaken, therefore, to investigate the effect of phosphine dose on sorption in wheat. Wheat was added to glass flasks to achieve filling ratios of 0.25-0.95, and the flasks were sealed and injected with phosphine at 0.1-1.5 mg L(-1) based on flask volume. Phosphine concentration was monitored for 8 days at 25 degrees C and 55% RH. When sorption occurred, phosphine concentration declined with time and was approximately first order, i.e. the data fitted an exponential decay equation. Percentage sorption per day was directly proportional to filling ratio, and was negatively correlated with dose for any given filling ratio. Based on the results, a tenfold increase in dose would result in a halving of the sorption constant and the percentage daily loss. Wheat was less sorptive if it was fumigated for a second time. The results have implications for the use of phosphine for control of insects in stored wheat. This study shows that dose is a factor that must be considered when trying to understand the impact of sorption on phosphine concentration, and that there appears to be a limit to the capacity of wheat to sorb phosphine.

Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance

17-DMAG is a hydrophilic derivative of the molecular chaperone inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG; NSC-330507), which is currently being evaluated for the treatment of cancer in clinical trials. 17-DMAG offers a potential advantage over 17-AAG because its aqueous solubility eliminates the need for complicated formulations that are currently used for administration of 17-AAG. In addition, 17-DMAG undergoes only limited metabolism compared to 17-AAG. The present results are from preclinical toxicity studies evaluating 17-DMAG in rats and dogs. Doses of 0, 2.4, 12 and 24 mg/m2 per day were administered to rats, while dogs received doses of 0, 8 or 16 mg/m2 per day. In both species, 17-DMAG was administered i.v. (slow bolus for rats; 1-h infusion for dogs) daily for 5 days. An additional cohort of dogs received 16 mg/m2 per day orally for 5 days. Clinical observations were noted, and standard hematology and clinical chemistry parameters were monitored. Selected tissues were evaluated microscopically for drug-related lesions. Tissue and plasma 17-DMAG concentrations were measured by HPLC/MS at selected time-points on days 1 and 5. Daily i.v. administration of 17-DMAG at doses of 24 mg/m2 per day in rats or 16 mg/m2 per day in dogs produced lethality on day 6, approximately 24 h following the last dose. Body weight loss was common in rats and dogs. Drug-related gastrointestinal, bone marrow and hepatic toxicities were also common in rats and dogs. Dogs also exhibited signs of renal and gallbladder toxicity. Plasma concentrations of 17-DMAG increased proportionately with dose in rats and disproportionately with dose in dogs. In rat tissues, however, only fourfold to sixfold increases in 17-DMAG concentrations were observed with a tenfold increase in dose. The highest concentrations of 17-DMAG were found in the liver of rats, with progressively lower concentrations in the spleen, lung, kidney and plasma. Regardless of the route of administration, higher drug concentrations were present in plasma (rat and dog) and tissue (rat) samples obtained on day 5 compared to those obtained on day 1. Although plasma concentrations decreased with time, 17-DMAG was still detected in dog plasma for at least 24 h after drug administration. With the recent approval of 17-DMAG for clinical use, the data generated from these preclinical studies will provide guidance to clinicians as they administer this drug to their patients. The MTD of 17-DMAG was 12 mg/m2 per day in rats and 8 mg/m2 per day in dogs; therefore, the recommended starting dose for phase I trial is 1.3 mg/m2 per day for 5 days. Gastrointestinal and bone marrow toxicity were dose-limiting in rats, and gastrointestinal, renal, gallbladder and bone marrow toxicity were dose-limiting in dogs. All adverse effects were fully reversible in surviving animals after treatment was complete.

Radiation Dose and Image Quality in Spiral Computed Tomography: Results of a Multi-Centre Study at Eight Radiological Institutions

To evaluate radiation dose (expressed as PCTDI or D AVE ) in correlation to image quality, seven clinical protocols were measured in eight radiological departments provided with six different types of high-end spiral CT scanners of the latest generation. Central and surface PCTDI for seven clinically applied protocols and one standardised liver protocol were determined with a dedicated phantom and ionisation chamber. For low contrast measurements, a cylindrical 3D phantom (different sized spheres of defined contrast) was tiled. Image noise was measured with a cylindrical water phantom, high contrast resolution with a Perspex hole phantom. Images were randomised, made anonymous and read by eight radiologists (one from each institution). Radiation output (PCTDI per 100 mA.s) for six different scanners varied by a factor between 1.7 (central PCTDI) and 2.0 (surface PCTDI) for the standardised protocol and by a factor of 4.3 for the 1 mm inner ear protocol. For seven clinically applied protocols of six radiological departments doses (expressed as D AVE /pitch) varied by factors between 1.7 (head protocol) and 8.3 (abdomen paediatric protocol). Low contrast detectability correlated closely with dose. An improvement in detection from 8 mm to 4 mm sized spheres needed approximately a tenfold increase in dose. Differences of modern CT scanner technology seem to he of minor importance for radiation exposure compared with selection of protocol parameters in different radiological institutes. Future discussion on guidelines, e.g. reference doses, should consider optimisation of tube current according to the individual patient and the clinical indication.

Radiation dose and image quality in spiral computed tomography: multicentre evaluation at six institutions.

The purpose of this study was to evaluate the correlation of radiation dose with image quality in spiral CT. Seven clinical protocols were measured in six different radiological departments provided with four different types of high specification spiral CT scanners. Central and surface absorbed doses were measured in acrylic. The practical CT dose index (PCTDI) was calculated for seven clinical examination protocols and one standardized protocol using identical parameters on four different spiral CT scanners with a dedicated ionization chamber inserted into PMMA phantoms. For low contrast measurements, a cylindrical three-dimensional (3D) phantom (different sized spheres of defined contrast) was used. Image noise was measured with a cylindrical water phantom and high contrast resolution with a Perspex hole phantom. Image quality phantoms were scanned using the parameters of the clinical protocols. Images were randomized, blinded and read by six radiologists (one from each institution). PCTDI values for four different scanners varied up to a factor between 1.5 (centre) and 2.2 (surface) for the standardized protocol. A greater degree of variation was observed for seven clinical examination protocols of the six radiological departments. For example, PCTDI varied up to a factor between 1.7 (cerebrum protocol) and 8.3 (abdomen paediatric protocol). Low contrast resolution correlates closely with dose. An improvement in detection from 8 mm to 4 mm sized spheres needs approximately a ten-fold increase in dose. Noise shows a moderate correlation with PCTDI. High contrast resolution of clinical protocols is independent of PCTDI within a certain range. Differences in modern CT scanner technology seem to be of less importance for radiation exposure than selection of protocol parameters in different radiological institutes. Future discussion on guidelines regarding optimal (patient adapted) tube current for clinical protocols is desirable.

Receptor-mediated pharmacodynamics of prednisolone in the rat.

A pharmacokinetic/pharmacodynamic model describing receptor-mediated effects of prednisolone is presented. The basis of the model is the generally accepted mechanism of action of steroid hormones in which corticosteroids bind to cytosolic receptors forming steroid-receptor complexes, which are activated and translocated into the nucleus. There the complexes associate with specific DNA sequences and modulate the rate of transcription of DNA into specific RNAs that code for the synthesis of proteins that elicit biological responses. Prednisolone, 5 or 50 mg/kg, was administered intravenously to adrenalectomized rats. Total plasma, free plasma, CBG-free plasma, and liver prednisolone concentrations were measured simultaneously with free hepatic cytosolic glucocorticoid receptor concentrations and tyrosine aminotransferase (TAT) activity of the liver as a function of time. The association/dissociation kinetics of prednisolone binding to the glucocorticoid receptor were measured separately in vitro at 37 degrees C. Total plasma, free plasma, and CBG-free plasma prednisolone concentrations could be used equally well in the model to account for the time course of receptor concentrations and TAT activity. However, use of liver steroid concentrations resulted in an overestimation of receptor depletion. Steroid concentrations in plasma increased 20 to 30-fold with a tenfold increase in dose, but receptor occupancy and TAT activity over time increased about threefold. While prednisolone pharmacokinetics were dose-dependent, parameters describing receptor kinetics and TAT activity were constant at each prednisolone dose. The major determinants of receptor-mediated glucocorticoid activity are confirmed to be the availability of the receptor, drug-receptor dissociation rate, and corticosteroid persistence in the biophase.

Suppression of in vitro lymphocyte reactivity by cyclosporin A: existence of a population of drug-resistant cytotoxic lymphocytes.

Cyclosporin A (CS-A) is an unusual endecapeptide isolated from the fungi Cylindrocarpon lucidum Booth and Trichoderma polysporum. It is a potent immunosuppressive drug that prevents rejection of kidney and heart allografts whilst having a low myelotoxicity. Its mode of action is still unclear but its main target appears to be the T lymphocyte. The mixed lymphocyte reaction (MLR) and cell-mediated lymphocytoxicity (CML) used here are generally regarded as in vitro correlates of allograft rejection. Our data show that CS-A is a powerful inhibitor of MLR reactivity, regardless of whether the cells were obtained from normal or presensitized donors; that the CML of lymph node cells is likewise totally inhibited if the drug is added early during cell culture; and that, by contrast, the cytotoxic response of spleen cells from presensitized but not from normal mice is only partially inhibited, even with a tenfold increase in dose. It is therefore suggested that there exists a population of cytotoxic spleen cells that is relatively resistant to the action of this drug.

Hepatic uptake of insulin in man.

The hepatic uptake of unlabeled insulin (5--50 mU/kg) was determined in 45 nondiabetic patients without hepatic disease. Thirty patients were studied at normoglycemia and 15 at moderate steady hyperglycemia, induced by intraportal infusion of 80 or 200 mg glucose per h and per kg. The first pass fractional hepatic uptake of insulin (FH) was estimated by comparing the results after a portal and a peripheral infusion of unlabeled insulin in each patient. It varied negatively with the amount of insulin given, decreasing about 50% after a tenfold increase in dose. FH was markedly smaller during steady hyperglycemia than at normoglycemia, regardless of insulin dose. For low doses (5--10 mU/kg), giving insulin concentrations within the physiological range, FH was 0.43 (5 mU/kg) and 0.40 (10 mU/kg) at normoglycemia and 0.16 (10 mU/kg) at hyperglycemia. FH did not vary with the fasting or the glucose-stimulated, endogenous insulin levels recorded before insulin infusion. It is suggested that glucose is more important than insulin in modulating the fractional hepatic uptake of insulin.