Interactions between tellurium and mercury in murine lung and other organs after metallic mercury inhalation: a comparison with selenium

Selenium is known to form complexes with heavy metals in the blood and thus increase the retention time of the metals in several organs, especially in the reticulo-endothelial system. Selenium may similarly cause retention of mercury in the lung after metallic mercury (Hg0) inhalation. This study, comparing the effects of tellurium with those of selenium (both in group '6b' of the periodical system), showed that Te(IV) was as effective as Se(IV) and Se(VI) (all given in a dose of 10 mumol/kg body wt.) in retaining inhaled 203Hg0 (1.5 mumol/kg body wt.) in the lung (presumably 203Hg2+ after oxidation). Te(VI) had to be given in a dose of 100 mumol/kg body wt to produce the same effect. As in the lung, also in other organs tellurium caused a dose-dependent increase in mercury retention. At a dose level of 10 mumol Te(IV) per kg body wt. the mercury retention ratios (treated/control) were 140 for the lung and 8.6 for the whole body. The corresponding figures for Te(VI) (10, 30 and 100 mumol/kg body wt.) were 10, 73 and 120 and 3.7, 3.9 and 4.3, respectively. Retention of i.v. injected 203HgCl2 was increased by pre-administration of tellurium, again in a dose-dependent manner and Te(IV) being 3-10 times more effective than Te(VI). The kidney and the spleen were the dominant organs, as is the case after Se pretreatment. Anions of other elements, arsenite, arsenate, chromate, molybdate and wolframate (30 mumol/kg body wt.), did not affect the retention of 203Hg in lung or any other organ, or in the whole body after inhalation of 203Hg0. It is suggested that Te(IV) may easily be reduced to Te2- (in analogy with selenium) which may complex with Hg2+. The liability for Te(VI) to be reduced to Te2- appears to be approx. 10 times lower.     

Chelation therapy of incorporated plutonium-238 and americium-241: comparison of LICAM(C), DTPA and DFOA in rats, hamsters and mice

The carboxylated catechoylamide 3,4,3-LICAM(C) was tested for removal of 238Pu and 241Am from small laboratory rodents. The effectiveness of treatment was compared with that of two ligand preparations approved for clinical use: calcium-trisodium diethylenetriaminepentaacetate (DTPA) and desferrioxamine (DFOA). With early treatment and at the dosage used clinically for the decorporation of actinides with DTPA (30 mumol/kg body weight) LICAM(C) was superior to DFOA but when compared with DTPA, the effect of LICAM(C) on 238Pu was greater only in bone; as little as 1 mumol LICAM(C)/kg was as effective as 30 mumol DTPA/kg. However, in all animals treated with LICAM(C) there was a large increase in the 238Pu content of the kidney. With 241Am the effect of DTPA was always superior to that of LICAM(C). The best overall results early (1 day) after injection of 238Pu and 241Am were achieved by a combination of a single injection of LICAM(C) and DTPA with subsequent continuous administration of DTPA in drinking water. LICAM(C) affected the retention of 238Pu even if given orally; the data suggested that about 3 per cent of ingested LICAM(C) was absorbed. When the beginning of treatment was delayed, LICAM(C) became equally effective or less effective than DTPA even as far as 238Pu retention in bone was concerned, but it still increased the accumulation of 238Pu in the kidneys.     

The effect of X rays, DTPA, and aspirin on the absorption of plutonium from the gastrointestinal tract of rats

To measure the effect of radiation on plutonium transport, rats that were exposed to 250-kVp X rays were given 238Pu 3 days afterwards by either gavage or injection into a ligated segment of the duodenum. In a second group of experiments, rats were either injected intraduodenally with 238Pu-DTPA or administered the chelate intravenously and the 238Pu by gavage. In a third experiment, rats that had been gavaged with 200 or 400 mg/kg/day of aspirin for 2 days were injected intragastrically with 238Pu nitrate. Results of the first experiment showed a dose-dependent increase in 238Pu absorption between 800 and 1500 rad of lower-body X irradiation. Intravenous or intraduodenal injections of DTPA caused a marked increase in 238Pu absorption but resulted in decreased plutonium deposition in the skeleton and liver. Retention of 238Pu in the skeleton of rats given aspirin was double that of controls, but the effect on plutonium absorption was less marked than that of DTPA.     

Synthesis and evaluation of Gd-DTPA-labeled arabinogalactans as potential MRI contrast agents

Arabinogalactan derivatives conjugated with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) by ethylenediamine (Gd-DTPA-CMAG-A2) or hexylamine (Gd-DTPA-CMAG-A6) have been synthesized and characterized by means of Fourier transform infrared spectra (FTIR), 13C nuclear magnetic resonance (13C NMR), size exclusion chromatography (SEC), and inductively coupled plasma atomic emission spectrometry (ICP-AES). Relaxivity studies showed that arabinogalactan-bound complexes possessed higher relaxation effectiveness compared with the clinically used Gd-DTPA, and the influence of the spacer arm lengths on the T1 relaxivities was studied. Their stability was investigated by competition study with Ca2+, EDTA, and DTPA. MR imaging of Wistar rats showed remarkable enhancement in rat liver and kidney after i.v. injection of Gd-DTPA-CMAG-A2 (0.079+/-0.002 mmol/kg Gd3+): The mean percentage enhancement of the liver parenchyma and kidney was 38.7+/-6.4% and 69.4+/-4.4% at 10-30 min. Our preliminary in vivo and in vitro study indicates that the arabinogalactan-bound complexes are potential liver-specific contrast agents for MRI.     

Enhanced decorporation of plutonium by DTPA encapsulated in small PEG-coated liposomes

The aim of the study was to demonstrate that decorporation of 238Pu is achieved more efficiently by an optimized liposomal formulation of diethylene triamine pentaacetic acid (DTPA) than by the usual free DTPA treatment. The optimized formulation consisted of polyethylene glycol-coated stealth liposomes with a mean diameter of 100 nm (SL-100 nm). Rats were intravenously injected with various Pu-phytate salt solutions in order to test different contamination conditions (activity and salt concentration) impacting liver kinetics and skeletal uptake of Pu. All treatments were given intravenously 1 h after contamination. Efficiency was evaluated 24 h, 7, 16 or 30 days later through their ability to promote Pu elimination and to reduce Pu burden in the skeleton and liver, the main organs of Pu deposition and radiotoxicological effects. Whatever the conditions of contaminations, a single injection of SL-100 nm (3.2 micromol kg(-1) DTPA) boosted urinary elimination of Pu to above 90% of the injected dose. In addition, liposomes strongly and significantly reduced the Pu burden of the liver and skeleton even 30 days after a single treatment: a dose of 0.3 micromol kg(-1) induced the same skeletal Pu reduction as four injections of free DTPA (30 micromol kg(-1)). A log dose-effect relation was found with SL-100 nm DTPA and Pu excretion in urine or Pu burden in the studied organs (liver, femurs, spleen and kidneys). This efficacy was attributed to an optimized targeting of DTPA to the main Pu retention organs and especially the liver.     

Stimulation of somatotropin secretion following peripheral administration of the tripeptide, syndyphalin 33 in sheep, pigs and rats

In the present study, a simple tripeptide alkylamine, syndyphalin 33 (SD33, Tyr-DMet (O)-Gly-methylphenethylamide) was shown to stimulate somatotropin (GH) secretion in sheep, hogs and rats following peripheral administration. Intravenous (i.v.) administration of SD33 at doses of 0.05, 0.1 and 0.2 mumol/kg stimulated a significant increase in circulating GH levels in sheep within 5 minutes post-injection. This response was not attenuated following repeated i.v. injections of SD33 (0.05 /mmol/kg) administered at 2 hour intervals. In addition, plasma GH levels were significantly stimulated following either subcutaneous (s.c.) or oral administration of SD33 in hogs and rats. Subcutaneous administration of SD33 at doses of 0.5, 1.0 and 2.0 mumol/kg stimulated a significant increase in plasma GH concentrations within 30 minutes of injection in both species. Oral administration of SD33 at 1.0, 10 or 100 mumol/kg in rats resulted in a significant elevation in plasma GH levels which peaked at 30 minutes post-gavage. In the pig, circulating GH levels were significantly increased within 30 minutes post-ingestion and remained elevated for at least 2 hours at the 2.0 mumol/kg dose level. The ability of naloxone to block SD33-stimulated GH secretion suggests that this peptide acts via mu opiate receptors.     

Pharmacokinetics of buspirone as determined by ex vivo (3H)-DPAT binding

Ex vivo (3H)-8-hydroxy-2-(di-n-propylamino)-tetraline ((3H)-DPAT) binding to the hippocampus has been utilized to determine the pharmacokinetic parameters of buspirone after i.v. (30 mumol/kg) and oral (100 mumol/kg) administration of this drug to rats. Intravenous buspirone rapidly penetrated the brain as demonstrated by a maximum inhibition of (3H)-DPAT binding at 1 min. Elimination of drug from the brain was biphasic, with a first component half-life of 24.8 min and a second component half-life of 96 min. Oral buspirone at 3 times the i.v. dose produced less than one-third the maximum inhibition of (3H)-DPAT binding compared to that observed with i.v. buspirone. The pharmacokinetic parameters of buspirone observed in the present study are in agreement with those reported previously. Thus, the ex vivo binding assay could be utilized to determine the bioavailability of the drug to the brain, and its duration of action.     

Determination of acteoside in Cistanche deserticola and Boschniakia rossica and its pharmacokinetics in freely-moving rats using LC-MS/MS

A sensitive LC-MS/MS method with a simple solid-phase extraction for the determination of acteoside in rat plasma and tissue homogenates was established for the investigation of bioavailability and brain distribution in freely-moving rats. Acteoside in Cistanche deserticola and Boschniakia rossica was also determined. Acteoside and internal standard were separated on a RP-select B column (125mmx4.6mm i.d., particle size 5microm). The mobile phase consisted of 35% methanol and 65% acetic acid-water (1:100, v/v) at a flow-rate of 1mL/min. Acteoside and the internal standard were monitored using the multiple-reaction monitoring (MRM) mode at m/z transitions of 623-->161 and 609-->301, respectively. The acteoside content was 38.4+/-2.4mg/kg (n=3) for B. rossica, which is obviously lower than 21134.2+/-805.5mg/kg (n=3) of C. deserticola. The protein binding in rat plasma was 75.5+/-1.8%. The brain distribution result indicated that acteoside was evenly distributed in brain tissues (brain stem, cerebellum, the rest of the brain, cortex, hippocampus and striatum) which was about 0.45-0.68% of that in plasma (4.5+/-0.5microg/mL) after 15min of acteoside administration (10mg/kg, i.v.). After acteoside was given (3mg/kg, i.v.; 100mg/kg, p.o.), the oral bioavailability (AUC(p.o.)/dose(p.o.))/(AUC(i.v.)/dose(i.v.)) was only 0.12%.     

The effect of mass on the gastrointestinal absorption of plutonium and neptunium

Absorption and retention of plutonium were determined in mice after intragastric administration of either 6 X 10(-4) or 1.5 mg/kg in bicarbonate, citrate, or nitrate media. At the higher concentration, absorption of the citrate was greater than that of the nitrate; at the lower concentration, chemical form was not an important factor in absorption. Concentration and chemical form had much less influence on absorption by the neonatal (versus the adult) rat. The transfer factor (f1) for neonates was between one and two orders of magnitude higher than for adults. Absorption and retention of neptunium were determined in rats and/or mice after intragastric administration at doses ranging from 2.2 X 10(-7) to 43 mg/kg in nitrate solutions of pH 1.5. At the higher concentrations, absorption was 1.5 to 2.7%. For lower concentrations, absorption was 25 to 65 times less. In contrast to results obtained in adult animals, absorption of neptunium by neonates decreased with increasing dose. The data obtained in adult animals suggest that the f1 factor recommended by the ICRP for plutonium should be increased by a factor of 10, but the neptunium f1 factor, in contrast, should be decreased by a factor of 10.     

Pharmacokinetics of an antiangiogenic ribozyme (ANGIOZYME) in the mouse.

Vascular endothelial growth factor (VEGF) is a growth factor that contributes to the angiogenesis of developing tumors. To interfere with the action of VEGF, a nuclease-stabilized ribozyme, ANGIOZYME, has been developed against VEGF receptor subtype Flt-1 mRNA. To determine which routes of administration would be useful for systemic delivery of this ribozyme, a dose of 30 mg/kg [32P]ANGIOZYME was administered as an i.v., i.p., or s.c. bolus. Concentrations of ANGIOZYME in plasma, femur, kidney, liver, and lung were examined. ANGIOZYME was well absorbed after i.p. (90%) or s.c. administration (77%), with peak plasma concentrations occurring 30 minutes after dosing. Total body clearance after a single dose of 30 mg/kg ANGIOZYME was 20 ml/min/kg, and the elimination half-life was 33 minutes. The apparent volume of distribution at steady-state ranged from 0.5 to 1.3 L/kg. ANGIOZYME was detected in the four tissues examined through the 3 hour sampling period after i.v. or i.p. administration. After s.c. administration, ANGIOZYME was detected in femur, kidney, and lung but not in the liver. The highest concentrations of ANGIOZYME were found in kidney and femur with all three routes. Because of the rapid and extensive absorption after extravascular injections, either i.p. or s.c. administration could be considered for use in pharmacodynamic studies examining the effects of ANGIOZYME or other ribozymes with similar chemical modifications.     

Decorporation Approach Following Rat Lung Contamination with a Moderately Soluble Compound of Plutonium Using Local and Systemic Ca-DTPA Combined Chelation

Decorporation efficacy of prompt pulmonary delivery of DTPA dry powder was assessed following lung contamination with plutonium nitrate and compared to an intravenous injection of DTPA solution and a combined administration of both DTPA compounds. In addition, efficacy of a delayed treatment was assessed. In case of either early or late administration, insufflated DTPA was more efficient than intravenously injected DTPA in reducing the plutonium lung burden due to its high local concentration. Prompt treatment with DTPA powder was also more effective in limiting extrapulmonary deposits by removing the early transportable fraction of plutonium from lungs prior its absorption into blood. Translocation of DTPA from lungs to blood may also contribute to the decrease in extrapulmonary retention, as shown by reduced liver deposit after delayed pulmonary administration of DTPA. Efficacy of DTPA dry powder was further increased by the combined intravenous administration of DTPA solution for reducing extrapulmonary deposits of plutonium and promoting its urinary excretion. According to our results, the most effective treatment protocol for plutonium decorporation was the early pulmonary delivery of DTPA powder supplemented by an intravenous injection of DTPA solution. Following inhalation of plutonium as nitrate chemical form, this combined chelation therapy should provide a more effective method of treatment than conventional intravenous injection alone. At later stages following lung contamination, pulmonary administration of DTPA should also be considered as the treatment of choice for decreasing the lung burden.     

Central injection of nicotine increases hepatic and splenic interleukin 6 (IL-6) mRNA expression and plasma IL-6 levels in mice: involvement of the peripheral sympathetic nervous system.

Accumulating evidence suggests that plasma levels of interleukin 6 (IL-6), a major cytokine stimulating the synthesis of acute-phase proteins, are intimately regulated by the central nervous system. Nicotine, one of the major drugs abused by humans, has been shown to affect immunological functions. In the present study, effects of intracerebroventricular (i.c.v.) injection of nicotine on plasma IL-6 levels were investigated in mice. Nicotine administered i.c.v. dose-dependently increased plasma IL-6 levels; the lowest effective dose was 0.3 ng/mouse and the maximal effect was attained with the dose of 105 ng/mouse. The nicotine (105 ng/mouse, i.c.v.)-induced plasma IL-6 levels peaked at 3 h and approached basal levels 6 h after injection. Mecamylamine, a nicotinic receptor antagonist, blocked nicotine-induced plasma IL-6 levels. Depletion of peripheral norepinephrine with 6-hydroxydopamine [100 mg/kg, intraperitoneal (i. p.)] inhibited the nicotine-induced plasma IL-6 levels by 57%, whereas central norepinephrine depletion with 6-hydroxydopamine (50 microgram/mouse, i.c.v.) had no effect. Pretreatment with prazosin (alpha1-adrenergic antagonist; 1 mg/kg, i.p.), yohimbine (alpha2-adrenergic antagonist; 1 mg/kg, i.p.), and ICI-118,551 (beta2-adrenergic antagonist; 2 mg/kg, i.p.), but not with betaxolol (beta1-adrenergic antagonist; 2 mg/kg, i.p.), inhibited nicotine-induced plasma IL-6 levels. Among the peripheral organs, including the pituitary, adrenals, heart, lung, liver, spleen, and lymph nodes, nicotine (105 ng/mouse, i.c.v.) increased IL-6 mRNA expression only in the liver and spleen, which was inhibited by peripheral norepinephrine depletion. These results suggest that stimulation of central nicotinic receptors induces plasma IL-6 levels and IL-6 mRNA expression in the liver and spleen via the peripheral sympathetic nervous system, alpha1-, alpha2-, and beta2-adrenoreceptors being involved.     

Pharmacokinetics of oestrone-3-O-sulphamate

The sulphatase pathway is thought to be the major route of oestrogen synthesis in breast tumours in postmenopausal women. There is currently considerable interest in developing a potent steroid sulphatase inhibitor to block oestrogen synthesis by this route. One of the most potent inhibitors discovered so far is oestrone-3-O-sulphamate (EMATE) which is active in vivo. In this study we report the preparation of a formulation for the administration of EMATE by the oral route. A method, using high-performance liquid chromatography (HPLC), was also established to measure concentrations of EMATE in rat plasma after its oral or i.v. administration. Using the oral formulation and HPLC assay, EMATE was readily detected in rat plasma after oral administration. Plasma EMATE concentrations were related to the dose of drug administered orally over the 10–40 mg/kg range. To examine the pharmacokinetics of EMATE, the compound (40 mg/kg, single dose) was administered either orally (in the formulation) or i.v. (in propylene glycol) with plasma samples being collected for up to 6 h. After oral administration, EMATE was rapidly absorbed, with the peak plasma concentration being detected at 30 min, after which plasma concentrations rapidly decreased. After i.v. administration a plasma EMATE concentration was detected at 1 h similar to that after oral administration. The clearance of EMATE from plasma followed a bi-phasic curve, showing an initial half-life of 30 min, followed by a slower half-life of 4 h 30 min. Little evidence was obtained for any metabolism of EMATE to oestrone. Rat liver sulphatase activity was almost completely inhibited (>99%) within 30 min of oral or i.v. administration of EMATE.     

Comparison of the pharmacokinetics of subcutaneous and intravenous administration of a phosphorothioate oligodeoxynucleotide in cynomolgus monkeys

The pharmacokinetics of subcutaneous (s.c.) administration of a phosphorothioate oligodeoxynucleotide (PS-ODN) was evaluated in cynomolgus monkeys. In a single dose study, monkeys were injected s.c. or intravenously (i.v.) with doses of either 1 or 5 mg/kg ISIS 2302. The bioavailability of s.c. injection ranged from 26% to 55% and appeared to be dependent on the concentration of the dosing solution rather than the dose. The bioavailability of a subcutaneously administered 5 mg/kg dose of ISIS 2302 was 55% using a 50 mg/ml dosing solution and only 26% using a 10 mg/ml dosing solution. Slow absorption from the s.c. injection site significantly blunted the maximal concentration (Cmax) compared with i.v. administration. The time to peak plasma concentration (Tmax) increased slightly with increasing dose, from 0.5 to 1 hour for the 1 mg/kg dose to 1 to 2.5 hours for the 5 mg/kg dose. Plasma half-lives were prolonged after s.c. administration, indicating more dependence on absorption than elimination. The half-lives after s.c. administration averaged 3 hours, whereas after i.v. administration, the half-lives were <1 hour. Metabolism of the ISIS 2302 after s.c. injection was consistent with exonucleolytic cleavage, as previously observed after i.v. administration. In summary, s.c. administration of PS-ODN resulted in prolonged and extensive absorption of the ODN.     

Mechanism of dimethylsulfoxide protection against the teratogenicity of secalonic acid D in mice

Dimethylsulfoxide (DMSO) is known to antagonize the teratogenic effects of secalonic acid D (SAD) in mice. To establish the optimum protective dose of DMSO, pregnant CD-1 mice were treated, i.p., with 30 mg/kg of SAD in 5% (w/v) NaHCO3, containing 0, 10, 20, or 30% (v/v) DMSO on day 11 of gestation. Data indicate that at 10% and 20% levels, DMSO affords an apparent dose-related protection against SAD-induced cleft palate, whereas 30% DMSO enhanced fetal resorption with no reduction in the incidence of cleft palate. Ultraviolet spectra and TLC mobility indicated that DMSO at 20% did not directly interact with SAD. Distribution and elimination of 14C-SAD was studied in fetal and maternal tissues from pregnant mice at 24 and 48 hr after exposure to 30 mg/kg of 14C-SAD, i.p., in NaHCO3 (control) or in 20% DMSO. Compared with those not receiving DMSO, maternal exposure to DMSO: 1) significantly reduced (42-75%) radioactivity in fetal heads and bodies, placenta, and maternal tissues other than liver; 2) significantly increased (up to 222%) the radioactivity in maternal liver; and 3) significantly reduced (44-58%) fecal and urinary elimination of SAD-derived radioactivity. These results suggest that the antiteratogenic effect of DMSO against SAD may be at least partly mediated by increased SAD (or its metabolites) retention by maternal liver leading to reduced SAD uptake by the fetus.     

硫化氢对大鼠心肌缺血/再灌注损伤的保护作用及其对c-Fos蛋白表达的影响

为探讨硫化氢(hydrogen sulfide,H2S)对大鼠心肌缺血,再灌注(ischemia/reperfusion,I/R)损伤的保护作用及机制,雄性Sprague-Dawley大鼠被随机分为对照组(假手术组)、I/R组、2.8μmol/kg体重NaHS干预组、14 μmol/kg体重NaHS干预组.结扎冠状动脉前降支30 min后,松扎再灌注60 min,心电图Ⅱ导联检测和TTC染色测定心肌梗死面积评价制作的心肌I/R模型:测定血浆中H2S浓度变化;监测血流动力学指标(LVSP,LV±dp/dtmax);HE染色和透射电镜观察心肌形态学改变;免疫组织化学方法测定心肌组织中c-Fos蛋白表达.结果显示:心肌I/R后血浆中H2S浓度明显低于对照组[(30.32±5.26)vs(58.28±7.86)μmol/L,P<0.05]:2.8和14μmol/kg体重NaHS均可显著改善I/R引起的心功能改变,且14μmol/kg体重NaHS较2.8 μmol/kg体重NaHS作用强;14 μmol/kg体重NaHS明显减轻心肌形态学及超微结构损伤,同时降低大鼠I/R心肌组织中c-Fos蛋白表达(0.20±0.06vs0.32±0.10,P<0.05).以上结果提示,H2S对大鼠心肌的I/R损伤有保护作用,这可能与其降低c-Fos蛋白表达有关.     

The Effect of O,O-DIMETHYL-O-(2,4,5-Trichlorophenyl) Phosphorothioate (Fe Nc H Lor Phos) On Cholinesterases in the Blue Fox (Alopex Lagopus)

Four blue fox bitches were used in the experiments. Two foxes were given fenchlorphos in the feed, one 100 mg/kg body weight and the other 200 mg/kg daily for 30 days. The maximum inhibition of plasma Cholinesterase was 65 and 69 %, respectively. The corresponding values of the erythrocyte acetylcholinesterase were 43 and 63 %. For the third bitch given 0.4 mg/kg as a single dose i.v. the effect was only measurable as a small transient decrease of the plasma Cholinesterase level. Eighty % of the plasma Cholinesterase of the fourth fox, given 500 mg/kg as a single oral dose, was inhibited on the third day. The erythrocyte acetylcholinesterase activity level only showed a slight decline. This fox vomited during feeding the day after administration. Symptoms as salivation, tremors, diarrhea, pinpoint pupils and respiratory distress were never seen in any of the foxes. It was concluded that fenchlorphos administration in the feed in doses recommended to dogs is well tolerated by healthy foxes as far as Cholinesterase inhibition is concerned.     

Mercuric chloride-induced nephrotoxicity in the rat following unilateral nephrectomy and compensatory renal growth

The nephropathy induced by mercuric chloride was assessed in unilaterally nephrectomized (NPX) and sham-operated (SO) rats using histological and urinalysis techniques. This assessment was carried out in order to test whether or not rats are more susceptible to the nephrotoxic effects of mercuric chloride after unilateral nephrectomy and a period allowing for compensatory renal growth. Twelve days after surgery both NPX and SO rats were given a single 1.5, 2.0 or 2.5 mumol/kg dose of mercuric chloride (i.v.). Twenty-four hours after the 1.5 or 2.0 mumol/kg dose of mercuric chloride was administered, cellular and tubular necrosis in the pars recta segments of proximal tubules in the outer medulla was more severe in NPX rats than in SO rats. Moreover, the urinary excretion of a number of cellular enzymes (e.g. lactate dehydrogenase) and plasma solutes (e.g. albumin) was greater in NPX rats than in SO rats. At the 2.5 mumol/kg dose of mercuric chloride, renal tubular damage was quite extensive in both groups of rats; to such an extent that possible differences in renal tubular damage between the NPX and SO rats could not be determined histologically. However, the urinary excretion of alanine aminopeptidase was greater in the NPX rats than in the SO rats. Therefore, based on the aforementioned findings, rats that have undergone and adapted to a reduction in renal mass (i.e. unilateral nephrectomy) appear to be more vulnerable to the nephrotoxic effects of mercuric chloride than rats with two normal kidneys.     

In vivo dose response relationship between physostigmine and cholinesterase activity in RBC and tissues of rats

Dose response of physostigmine (Phy) was studied in rat using various doses (25-500 micrograms/kg i.m.). Rats were sacrificed 15 min after Phy administration. Blood and tissues were analyzed for ChE activity by radiometric method and Phy concentration by HPLC method. A comparison of ChE values in different tissues of rats indicated that ChE activity was highest in brain (7.11 mumol/min/g) and least in diaphragm (0.67 mumol/min/g). The enzyme activity was eleven times more in brain as compared to diaphragm. Phy produced a dose-dependent inhibition of ChE in RBC (18-42%), brain (23-35%) and diaphragm (25-35%) from 50 to 200 micrograms/kg, then ChE inhibition was plateaued from 200 to 500 micrograms/kg in these tissues. A dose related ChE inhibition was seen in heart (16-50%) and thigh muscle (8-53%) from 50 to 500 micrograms/kg. Phy concentration increased linearly from 50 to 400 micrograms/kg in plasma, brain, heart and thigh muscle. These results indicate that ChE inhibition is linear up to 200 micrograms/kg in RBC, 150 micrograms/kg in brain and 300 micrograms/kg in heart. This linearity is not consistent in other tissues.     

Pharmacokinetics and metabolism of formestane in breast cancer patients

Formestane (Lentaron(R), 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) injection. To investigate the pharmacokinetics, bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose of 1 mg of 14C-labelled formestane. The plasma kinetics after i.m. dosing confirmed a sustained release of formestane from the site of injection. Within 24-48 h of the first dose, the circulating drug reached a C(max) of 48.0+/-20.9 nmol/l (mean+/-S.D.; N=7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3+/-1.8 nmol/l. The kinetic variables did not significantly change during prolonged treatment. Intramuscular doses appear to be fully bioavailable. Following i.v. injection of 14C-formestane, the unchanged drug disappeared rapidly from plasma, the terminal elimination half-life being 18+/-2 min (N=3). Plasma clearance, CL was 4.2+/-1.3 l/(h kg) and the terminal distribution volume V(z) was 1.8+/-0.5 l/kg. The drug is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14C-compounds in urine and faeces totals up to 98.9+/-0.8% of the i.v. dose after 168 h. The 14C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3beta,4beta-dihydroxy-5alpha-androstane-17-one and 3alpha,4beta-dihydroxy-5alpha-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro.