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J Dow

Publications and source records attributed to J Dow.

At least 19 recordsLinked to original sources
PubMed2004

Biological monitoring of kidney function among workers occupationally exposed to trichloroethylene.

AIMS: To investigate the nephrotoxic potential of trichloroethylene in a currently exposed population using sensitive urinary markers of kidney toxicity. METHODS: Renal dysfunction was monitored in a cross-sectional study of 70 workers currently exposed to trichloroethylene. An age and sex matched control population of 54 individuals was drawn from hospital and administrative staff. RESULTS: The mean exposure to trichloroethylene, estimated from urinary trichloroacetic acid concentrations, was 32 ppm (range 0.5-252 ppm) with an average duration of exposure of 4.1 years (range 1-20 years). Significant differences between the exposed and control populations were found for nephrotoxicity markers N-acetylglucosaminidase (NAG) and albumin, and for the mode of action marker, formic acid. However, neither NAG nor albumin showed a significant correlation with either the magnitude or duration of exposure to trichloroethylene. There was a significant correlation between urinary formic acid and trichloroacetic acid concentrations. Within the exposed population there were dose dependent increases in urinary methylmalonic acid concentrations and urinary glutathione S-transferase alpha activity. Although still within the control range, these changes were clearly dose dependent and consistent with one of the proposed mechanisms of trichloroethylene induced kidney toxicity. CONCLUSION: Although there was no evidence of kidney toxicity within the population studied, the results suggest that kidney damage could occur at exposure concentrations higher (>250 ppm) than those encountered in this study.

Adult↗
PubMed2003

A pilot study of mifepristone in combination with sublingual or vaginal misoprostol for medical termination of pregnancy up to 63 days gestation.

Of the total women included in the study, 96 women chose to receive misoprostol 600 microg sublingually while 53 women received misoprostol 800 microg vaginally 36-48 h after receiving mifepristone 200 mg. Complete abortion occurred in 93 women (98.9%) in the sublingual and 51 women (96.2%) in the vaginal group (p = 0.27). The mean induction-to-abortion interval was 3.2 h (SD = 1.4) in the sublingual and 4.1 h (SD = 1.5) in the vaginal group (p = 0.02). The mean gestation at abortion in weeks was 7.1 (SD = 1.0) in the sublingual and 7.7 (SD = 1.3) in the vaginal group (p = 0.003). Women in the sublingual group experienced more vomiting (p = 0.03), diarrhea (p = 0.02) and unpleasant taste in their mouth (p = 0.0001) while those in the vaginal group experienced more headache (p = 0.002). Of women in the sublingual group, 77% were satisfied with the route of misoprostol administration compared to 68% in the vaginal group (p = 0.25). These findings now need to be assessed in the context of a randomized controlled trial.

Abortifacient Agents, Nonsteroidal↗
PubMed2002

Effect of high-intensity hypoxic training on sea-level swimming performances.

The objective of this study was to test the hypothesis that high-intensity hypoxic training improves sea-level performances more than equivalent training in normoxia. Sixteen well-trained collegiate and Masters swimmers (10 women, 6 men) completed a 5-wk training program, consisting of three high-intensity training sessions in a flume and supplemental low- or moderate-intensity sessions in a pool each week. Subjects were matched for gender, performance level, and training history, and they were assigned to either hypoxic [Hypo; inspired O2 fraction (Fi(O(2))) = 15.3%, equivalent to a simulated altitude of 2,500 m] or normoxic (Norm; Fi(O(2)) = 20.9%) interval training in a randomized, double-blind, placebo-controlled design. All pool training occurred under Norm conditions. The primary performance measures were 100- and 400-m freestyle time trials. Laboratory outcomes included maximal O(2) uptake (Vo(2 max)), anaerobic capacity (accumulated O(2) deficit), and swimming economy. Significant (P = 0.02 and <0.001 for 100- and 400-m trials, respectively) improvements were found in performance on both the 100- [Norm: -0.7 s (95% confidence limits: +0.2 to -1.7 s), -1.2%; Hypo: -0.8 s (95% confidence limits: -0.1 to -1.5 s), -1.1%] and 400-m freestyle [Norm: -3.6 s (-1.8 to -5.5 s), -1.2%; Hypo: -5.3 s (-2.3 to -8.3 s), -1.7%]. There was no significant difference between groups for either distance (ANOVA interaction, P = 0.91 and 0.36 for 100- and 400-m trials, respectively). Vo(2 max) was improved significantly (Norm: 0.16 +/- 0.23 l/min, 6.4 +/-8.1%; Hypo: 0.11 +/- 0.18 l/min, 4.2 +/- 7.0%). There was no significant difference between groups (P = 0.58). We conclude that 5 wk of high-intensity training in a flume improves sea-level swimming performances and Vo(2 max) in well-trained swimmers, with no additive effect of hypoxic training.

Adult↗
PubMed2000

Intramyocardial injection of DNA encoding vascular endothelial growth factor in a myocardial infarction model.

In a previous study, we observed that one injection of 500 microg of DNA for the plasmid encoding for vascular endothelial growth factor (ph VEGF(165)) into one site in a rat myocardial infarction model resulted in neovascularization confined to angiomatous structures that did not contribute to regional myocardial blood flow. The purpose of the present study was to determine whether a lower dose (125 microg DNA), which is the same as that being used in some clinical trials, injected into four separate sites could enhance collateral flow and vascularity to the ischemic bed without inducing angiomas. Rats received injections of 125 microg DNA of the plasmid encoding phVEGF(165) or control DNA at four separate sites within the anterior free wall of the left ventricle (LV) supplied by the left coronary artery. The left coronary artery was ligated and hearts analyzed at 4 weeks. In vitro studies confirmed that the phVEGF(165) used was capable of producing VEGF polypeptide in mammalian cells. The infarct size (percentage of endocardial circumference that infarcted) was similar in controls (42+/-6%) and treated hearts (39+/-7%); the LV cavity area did not differ between groups. The number of vascular structures per high-power field within the infarct scar was 10.50+/-0.68 in controls and 10.00+/-0.85 in phVEGF(165)-treated rats. Relative regional myocardial blood flow determined by radioactive microspheres and expressed as a ratio of radioactive counts within the scar divided by radioactive counts in the noninfarcted ventricular septum was similar in control (0.74+/-0.25) and treated hearts (0.88+/-0.30) (p=not significant). No angiomatous structures were observed. Injections of 125 microg of DNA of phVEGF(165) into myocardium to become ischemic had no effect on infarct size or LV cavity size. Unlike higher doses of 500 microg of DNA, it did not cause gross angiomatous structures; however, it failed to improve neovascularization or regional myocardial blood flow in this rodent model of acute myocardial infarction.

Animals↗
PubMed2000

Enantiomeric disposition of inhaled, intravenous and oral racemic-salbutamol in man--no evidence of enantioselective lung metabolism.

Aims To establish whether enantioselective metabolism of racemic (rac )-salbutamol occurs in the lungs by determining its enantiomeric disposition following inhalation, in the absence and presence of oral charcoal, compared with that following the oral and intravenous routes. Methods Fifteen healthy subjects (eight male) were randomized into an open design, crossover study. Plasma and urine salbutamol enantiomer concentrations were measured for 24 h following oral (2 mg) with or without oral charcoal (to block oral absorption), inhaled (MDI; 1200 microg) with or without oral charcoal and intravenous (500 microg) rac-salbutamol. Systemic exposure (plasma AUC(0,infinity) and urinary excretion (Au24h ) of both enantiomers were calculated, and relative exposure to (R)-salbutamol both in plasma (AUC(R)-/AUC(S)- ) and urine (Au(R)-/Au(S)- ) was derived for each route. Relative exposure after the inhaled with charcoal and oral routes were compared with the intravenous route. Results AUC(R)-/AUC(S)- [geometric mean (95% CI)] was similar following the intravenous [0.32 (0.28, 0.36)] and inhaled with charcoal rates [0.29 (0.24, 0.36); P=0.046], but was far lower following oral dosing [0.05 (0.03, 0.07); P<0.001]. Similar results were found when relative exposure was analysed using Au24h. Conclusions These results show no evidence of significant enantioselective presystemic metabolism in the lungs, whilst confirming it in the gut and systemic circulation, indicating that the (R)- and (S)-enantiomers are present in similar quantities in the airways following inhaled rac-salbutamol.

Administration, Inhalation↗
PubMed1998

Formic acid excretion in rats exposed to trichloroethylene: a possible explanation for renal toxicity in long-term studies.

Rats exposed to trichloroethylene, either by gavage or by inhalation, excreted large amounts of formic acid in urine which was accompanied by a change in urinary pH, increased excretion of ammonia, and slight increases in the excretion of calcium. Following a single 6-h exposure to 500 ppm trichloroethylene, the excretion of formic acid was comparable to that seen after a 500 mg/kg dose of formic acid itself, yet the half-life was markedly different. Formate excretion in trichloroethylene treated rats reached a maximum on day 2 and had a half-life of 4-5 days, whereas urinary excretion was complete within 24 h following a single dose of formic acid itself. Formic acid was shown not to be a metabolite of trichloroethylene. When rats were exposed to 250 or 500 ppm trichloroethylene, 6 h/day, for 28 days, the only significant effects were increased formic acid and ammonia excretion, and a change in urinary pH. There was no evidence of morphological liver or kidney damage. Long-term exposure to formic acid is known to cause kidney damage suggesting that excretion of this acid may contribute to the kidney damage seen in the long-term studies with trichloroethylene.

Administration, Inhalation↗
PubMed1998

A small animal model of non-ischemic cardiomyopathy and its evaluation by transthoracic echocardiography.

BACKGROUND: Costs for large animal studies have escalated. Therefore there is a need to develop small animal models of non-ischemic cardiac failure and accurate non-invasive techniques that will allow serial quantitation of left ventricular function. OBJECTIVES: The purpose of our study was to determine the efficacy and reliability of adriamycin for inducing cardiomyopathy in rats. We hypothesized that high frequency transthoracic 2-dimensional and M-mode echocardiography would allow for serial testing of cardiac function in this small animal model. METHODS: Adriamycin was administered at a dose of 2.5 mg/kg intravenously once a week for 10 weeks in 54 rats. Transthoracic echocardiography by use of a 7.5 MHz transducer was performed in 19 rats at baseline and additionally at 12 weeks after beginning of adriamycin therapy to measure left ventricular dimensions and calculate fractional shortening. RESULTS: The mortality rate during the treatment period was 11%, but increased to 52% at 13 weeks. Transthoracic echocardiography provided adequate visualization of left ventricular dimensions and cardiac function in a parasternal short axis view. In follow-up echocardiography, pericardial effusion was detected in 8/19 rats (42%). Compared to baseline, end-diastolic diameters increased from 0.56 +/- 0.06 to 0.64 +/- 0.08 mm (p < 0.001), end-systolic diameters increased from 0.27 +/- 0.03 to 0.42 +/- 0.08 mm (p < 0.001), and fractional shortening decreased from 52.8 +/- 4.0 to 34.3 +/- 7.1% (p < 0.001) at 12 weeks. Electron microscopy in a subset of rats revealed cardiomyocyte degeneration, mitochondrial and sarcoplasmatic reticular edema, numerous intracellular vacuoles and 'onion-ring' shaped mitochondrial cristae, characteristic for adriamycin cardiotoxicity in human patients. CONCLUSION: Adriamycin at an intravenous dose of 2.5 mg/kg over 10 weeks can be used to create a reliable model of non-ischemic dilated cardiomyopathy with a high success rate. For in-vivo diagnostic purposes, transthoracic echocardiography provides a reliable technique to non-invasively assess cardiac function quantitatively and qualitatively in follow-up studies in rat cardiomyopathy. This small animal model can easily be used for testing new therapeutic strategies in cardiac failure.

Animals↗
PubMed1997

The role of glutathione conjugation in the development of kidney tumours in rats exposed to trichloroethylene.

Trichloroethylene is metabolised to a very minor extent (< 0.01% of the dose) by conjugation with glutathione, a metabolic pathway which leads to the formation of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a bacterial mutagen and nephrotoxin activated by the renal enzyme beta-lyase. The role of this metabolic pathway in the development of the nephrotoxicity and subsequent tumour formation seen in rats exposed to trichloroethylene has been evaluated. The pathway has been assessed quantitatively in vivo in rats, and in rats, mice and humans in vitro. Trichloroethylene was found to be a very weak nephrotoxin. There was no evidence of morphological change in the kidneys and only small increases in biochemical markers of kidney damage in rats dosed with 2000 mg/kg trichloroethylene by gavage for 42 days. N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine was detected in the urine of rats dosed with 500 and 2000 mg/kg trichloroethylene for up to 10 days at levels equivalent to 0.001-0.008% of the dose. In vitro, the rate of conjugation of trichloroethylene with glutathione in the liver was higher in the mouse, 2.5 pmol/min per mg protein, than the rat, 1.6 pmol/min per mg protein, and in human liver the rates were extremely low, 0.02-0.37 pmol/min per mg protein. Comparisons of the metabolism of DCVC by renal beta-lyase and N-acetyl transferase showed that metabolism by N-acetyl transferase was two orders of magnitude greater than that by beta-lyase and that beta-lyase activity in rat kidney was 11-fold greater than that in human kidney. When the nephrotoxicity of DCVC was compared in rats and mice, the mouse was found to be 5-10 fold more sensitive than the rat. The no effect level in the rat was 10 mg/kg, a dose which is three orders of magnitude higher than the amount of DCVC formed from trichloroethylene in vivo. The lack of correlation between metabolism by this pathway and the rat specific tumours, together with questions concerning the potency of DCVC at the levels formed from trichloroethylene, suggests that DCVC may not be involved in the renal toxicity and subsequent tumour development seen in rats and that further evaluation of the mechanism(s) involved in the nephrotoxic response is warranted.

Animals↗
PubMed1997

Prediction of the pharmacokinetic parameters of reduced-dolasetron in man using in vitro-in vivo and interspecies allometric scaling.

1. Dolasetron (Anzemet) is a potent and selective 5-HT3 receptor antagonist which is rapidly and extensively reduced to yield its major pharmacologically active metabolite, reduced dolasetron (RD). RD is further metabolized by CYP450 enzymes as well as undergoing renal excretion. As both in vitro and in vivo data on RD were available from animals and man, two approaches to predict the human pharmacokinetic parameters of RD were assessed. 2. First, in vitro studies, using liver microsomes from animal species and man, were undertaken to measure Vmax and K(m) and to assess the intrinsic clearance (CLint). With appropriate liver weight and liver blood flow scaling factors the predicted in vivo metabolic clearance (CLm-pred) was calculated. Human CLm-pred was underestimated by a factor of 5 when it was calculated using the above scaling factors. As, in a prospective study, the observed human in vivo metabolic clearance (CLm-obs) is unknown, CLm-pred was substituted into the least-squares correlation equation obtained from a plot of CLm-pred against CLm-obs' using animal data. The estimate of human CLm-obs was improved as it was only underestimated by a factor of 1.5. 3. Second, allometric scaling of in vivo animal pharmacokinetic data, using body weight, was performed to predict pharmacokinetic parameters in man. Good predictions of human pharmacokinetic parameters of RD were obtained for plasma clearance (1.7 l/min predicted versus 1.61/min observed), half-life (6.0 h predicted versus 5.6 h observed), and volume of distribution (860.91 predicted versus 770.41 observed). 4. The integration of in vitro metabolic data from microsomes gave similar results to conventional allometric scaling, whereas the normalization of clearance by brain weight resulted in an approximately three-fold underestimation of human clearance. 5. For RD, a drug that is eliminated by both renal and metabolic clearance, retrospective conventional allometric scaling allowed accurate prediction of pharmacokinetic parameters in man, whereas in vitro-in vivo scaling resulted in an underestimation of in vivo CLm. Although these results are somewhat at variance, ideally both scaling methods should be applied to improve the prediction of human pharmacokinetic parameters.

Animals↗
PubMed1996

Use of electrospray ionization liquid chromatography-mass spectrometry to study the role of CYP2D6 in the in vitro metabolism of 5-hydroxytryptamine receptor antagonists.

An electrospray ionization liquid chromatographic-mass spectrometric (ESI-LC-MS) method has been developed to study the involvement of the cytochrome P450 isoenzyme CYP2D6 in the in vitro metabolism of the indole containing 5-hydroxytryptamine (5-HT(3)++) receptor antagonists tropisetron, ondansetron and dolasetron in human liver microsomes. Compounds were eluted using linear gradients of acetonitrile-20 mM ammonium acetate, solvent A, (10:90, v/v) (pH 6.0) and solvent B, (60:40, v/v) (pH 6.0) and a Nucleosil C(4) column. Microsomal incubations were analysed using selected ion monitoring of the molecular ion of parent drug and the molecular ion of hydroxylated metabolites. The involvement of CYP2D6 in drug metabolism was assessed by inhibition studies using quinidine (5 mu M), a specific inhibitor of human CYP2D6, as well as by incubating compounds with microsomes prepared from cells transfected with cDNA encoding human CYP2D6. Results showed that the oxidation of all three compounds involved CYP2D6, but only that of tropisetron was inhibited by over 90% in the presence of quinidine. The present method can be applied to pre-clinical compounds, at an early stage of drug discovery, to assess the involvement of CYP2D6 in their metabolism and to screen for those compounds where CYP2D6 is the only isoenzyme implicated in the formation of major metabolites.

Chromatography, Liquid↗
PubMed1996

Comparison of the pharmacokinetics of dolasetron and its major active metabolite, reduced dolasetron, in dog.

Dolasetron mesilate (Anzemet) ((2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-1 H-indole-3-carboxylate monomethane-sulfonate) is a 5-HT3 receptor antagonist, which is in development for the treatment of chemotherapy-induced emesis. The ketone moiety of dolasetron is rapidly reduced by carbonyl reductase to form an alcohol, reduced dolasetron (red-dolasetron), which is the major pharmacologically active metabolite in humans. The pharmacokinetics of dolasetron and red-dolasetron were compared in dog, after single intravenous (i.v.) (2 mg/kg) and oral (p.o.) (5 mg/kg) administration of [14C]dolasetron or [14C]red-dolasetron. Pharmacokinetic parameters of dolasetron showed a terminal elimination half-life (t1/2) of 0.1 h, total body plasma clearance (Cltot) of around 109 mL/min/kg, apparent volume of distribution (aVd beta) of 0.83 L/kg, and bioavailability (F) of 7%. Pharmacokinetic parameters of red-dolasetron, calculated after dolasetron or red-dolasetron administration, were very similar. The t1/2 was around 4.0 h, Cltot 25 mL/min/kg, aVd beta 8.5 L/kg, and F around 100%. The apparent first-order formation rate constant (ki) of red-dolasetron was 7 h-1, which was similar to the first-order elimination rate constant (kel) of dolasetron. Cmax of red-dolasetron was similar, after po administration of either compound, but the median Tmax was 0.33 h after dolasetron, compared with 1.5 h after red-dolasetron. The first-order absorption rate constants (ka) of dolasetron and red-dolasetron were 14 h-1 and 2 h-1, respectively. Dolasetron transport across Caco-2 cell monolayers was also higher than that of red-dolasetron. Thus dolasetron was more quickly absorbed than red-dolasetron, and its administration led to the more rapid appearance of red-dolasetron in plasma. There appears to be no advantage in the direct administration of the metabolite, especially as in humans oral administration of dolasetron, 30 min before chemotherapy, has been shown to be effective in preventing emesis.

Animals↗
PubMed1996

Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron. Comparison with other indole-containing 5-HT3 antagonists.

Dolasetron mesilate [(2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-1H-indole-3-c arboxylate monomethane-sulfonate], is a 5-HT3 receptor antagonist, which is in development for the treatment of chemotherapy-induced emesis. The compound is rapidly reduced by carbonyl reductase to form its major pharmacologically active metabolite reduced dolasetron (red-dolasetron), which us further metabolized by cytochrome P450 (CYP450). Studies were conducted, using human liver microsomes, to characterize the CYP450 enzymes responsible for the in vitro metabolism of red-dolasetron. Red-dolasetron underwent oxidation of the indole aromatic ring at positions 5, 6, and 7, and also N-oxidation. Enzyme-selective inhibition and correlation studies showed that hydroxylation of red-dolasetron was CYP2D6-dependent, and N-oxidation was conducted by CYP3A4. The rate of formation of 6-hydroxy red-dolasetron was significantly correlated with that of 5-hydroxy red-dolasetron, which further suggested that these metabolites were formed by the same CYP450 enzyme(s). Inhibition studies also demonstrated that 6-hydroxylation was, to a lesser extent, CYP3A4-dependent. This was confirmed by correlation experiments, wherein formation of this metabolite was significantly correlated with that of N-oxide formation, in quinidine-inhibited microsomes. Results were compared with those obtained with two other indole-containing 5-HT3 receptor antagonists: tropisetron and ondansetron. Tropisetron hydroxylation was CYP2D6-dependent, whereas that of ondansetron was both CYP2D6- and CYP2E1-dependent. Results were further confirmed, when compounds were incubated with microsomes containing recombinant human liver CYP2D6, CYP3A4, and CYP2E1. Red-dolasetron was a competitive inhibitor of CYP2D6, with an IC50 value of 70 microM, which is 2 orders of magnitude above maximum plasma concentrations found in humans. The implications of these in vitro results to the in vivo metabolism of these compounds in humans and their potential pharmacokinetic consequences is discussed.

Cytochrome P-450 CYP2D6↗
PubMed1995

Isocratic high-performance liquid chromatographic method for the separation of testosterone metabolites.

An isocratic reversed-phase high-performance liquid chromatographic (HPLC) method using an Ultrasphere IP column has been developed for the determination of testosterone and its metabolites after incubation of 4-14C-labelled or unlabelled testosterone with rat liver microsomes. Compounds were eluted with methanol-water-tetrahydrofuran (35:55:10, v/v, pH 4.0) and detected by ultraviolet (UV) absorption at 245 nm. UV or on-line radioactivity detection can be used although, due to differences in detector cell volumes, peak resolution is slightly better with UV detection. Selectivity was validated by collecting HPLC peaks and verifying their identity by gas chromatography-mass spectrometry after derivatization by N,O-bis(trimethylsilyl)trifluoroacetamide-trimethylchlorosilane. A three-day validation was performed to determine the linearity, repeatability, reproducibility and accuracy of the method, using corticosterone as internal standard. The method is applicable to the measurement of cytochrome P-450 isoenzyme activities in rat liver.

Animals↗
PubMed1995

Stereoselectivity of the carbonyl reduction of dolasetron in rats, dogs, and humans.

The initial step in the metabolism of dolasetron or MDL 73,147EF [(2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H- quinolizin-8-yl 1H-indol-3-carboxylate, monomethanesulfonate] is the reduction of the prochiral carbonyl group to give a chiral secondary alcohol "reduced dolasetron." An HPLC method, using a chiral column to separate reduced dolasetron enantiomers, has been developed and used to measure enantiomers in urine of rats, dogs, and humans after dolasetron administration. In all cases, the reduction was enantioselective for the (+)-(R)-enantiomer, although the dog showed lower stereoselectivity, especially after iv administration. An approximate enantiomeric ratio (+/-) of 90:10 was found in rat and human urine. The contribution of further metabolism to this enantiomeric ratio was considered small as preliminary studies showed that oxidation of the enantiomeric alcohols by human liver microsomes demonstrated only minor stereoselectivity. Further evidence for the role of stereoselective reduction in man was obtained from in vitro studies, where dolasetron was incubated with human whole blood. The enantiomeric composition of reduced dolasetron formed in human whole blood was the same as that found in human urine after administration of dolasetron. Enantioselectivity was not due to differences in the absorption, distribution, metabolism, or excretion of enantiomers, as iv or oral administration of rac-reduced dolasetron to rats and dogs lead to the recovery, in urine, of essentially the same enantiomeric composition as the dose administered. it is fortuitous that the (+)-(R)-enantiomer is predominantly formed by carbonyl reductase, as it is the more active compound.

Administration, Oral↗
PubMed1995

Pharmacokinetics and pharmacodynamics of the acetylcholinesterase inhibitor 2,2,2-trifluoro-1-(3-trimethylsilylphenyl) ethanone in dog. Potential for transdermal patch delivery.

MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl) ethanone, CAS 132236(18-1) is a novel tight-binding inhibitor of acetylcholinesterase (AChE), which is in development as a potential therapeutic compound in the symptomatic treatment of Alzheimer's disease. Pharmacokinetics and pharmacodynamics of the compound were studied in the dog after single intravenous (i.v. 2 mg/kg), oral p.o. 10 mg/kg) and sub-cutaneous (s.c., 10 mg/kg) administrations of [14C]-MDL 73,745. Plasma concentrations of total radioactivity were much higher than those of parent drug after i.v., p.o. and s.c. administration, indicating extensive metabolism of the compound, although this was less after, s.c. administration than after p.o. administration. The bioavailability (F) was 34% after s.c. administration, compared with 4% after p.o. administration. The low bioavailability after p.o. administration was not due to poor drug absorption, as over 64% of the dose was absorbed. Pharmacokinetic parameters, calculated after i.v. administration, showed a terminal elimination half-life of 24 h, total body plasma clearance of around 70 ml/min/kg and apparent volume of distribution of 150 l/kg. AChE activity was almost 100% inhibited after i.v. administration, and over 80% inhibited 1 h after p.o. administration. In both cases, AChE activity returned to baseline levels by 12 h. AChE was around 80% inhibited 4 h after s.c. administration, and did not return to baseline levels until 36 h after drug administration. A combined pharmacokinetic-pharmacodynamic (PK-PD) effect model demonstrated that the extent of AChE inhibition could be correlated with plasma levels of the parent compound. As s.c. administration increased F, and led to longer AChE inhibition, transdermal (t.d.) delivery was assessed in the same animals. Patches, corresponding to a dose of 50 mg/kg, were applied to the shaved lateral abdominal skin for a period of 96 h. Sustained plasma concentrations of the parent drug were observed over the 96 h period of t.d. application. Mean (+/- SD) maximum plasma concentrations (Cmax) of 26.9 +/- 4.3 ng/ml were found 3.7 +/- 2.5 h after t.d. patch application und F was around 13%. AChE inhibition reached a maximum of 72% at 6 h after t.d. application and was still 35% at 96 h. The rate of release from the delivery system, per unit surface area, (ko) was calculated to be 7.7 micrograms/cm2. Transdermal delivery of MDL 73,745 thus decreased the important hepatic first-pass effect, and led to sustained plasma concentrations of drug, thus avoiding peaks and troughs which could lead to side-effects or poor efficacy.

Acetophenones↗
PubMed1994

Myocardial protection by a cardioselective free radical scavenger.

Oxygen-derived free radicals are involved in myocardial reperfusion injury. In the present study MDL 74,405 (S-(-)-3,4-dihydro-6-hydroxy-N,N,N-2,5,7,8-heptamethyl-2H-1-benzo pyran-2-ethanaminium 4-methylbenzenesulfonate), a hydrophilic derivative of alpha-tocopherol, has been shown to inhibit lipid peroxidation in rat brain homogenate, ex vivo lipid peroxidation in mouse heart and to accumulate in myocardial tissue. Infused i.v. MDL 74,405 induced a dose-related reduction of myocardial infarct size in pentobarbitone-anaesthetised rats subjected to 60 min coronary artery ligation followed by 30 min reperfusion. Similarly i.v. infusion of MDL 74,405 beginning 10 min before coronary artery occlusion (60 min) until 30 min after the onset of reperfusion (8 days) caused a decrease of infarct size associated with an increase in aortic flow. Plasma levels of creatine phosphokinase were significantly reduced. In isolated infarcted hearts, obtained from MDL 74,405-treated rats after 8 days of reperfusion and perfused according to the Langendorff technique, an increase in the contractility index (+) and (-) dP/dtmax was apparent. In isolated non-infarcted rat hearts subjected to 30 min no-flow global ischaemia, perfusion with MDL 74,405 resulted in an increase in heart rate and the contractility indices (+) dP/dtmax, and left ventricular systolic pressure during reperfusion. In conclusion MDL 74,405, is a cardioselective free radical scavenger, that reduces myocardial infarct size and attenuates post-ischaemic dysfunction.

Animals↗
PubMed1993

Protection of infarcted, chronically reperfused hearts by an alpha-tocopherol analogue.

Free radicals may cause part of the irreversible injury which occurs during myocardial infarction and reperfusion. In the present study MDL 73404, a hydrophilic, cardioselective, free radical scavenger analogue of alpha-tocopherol, was evaluated for its effects on infarct size as well as on indicators of reperfusion injury. A pentobarbitone-anaesthetised rat model of coronary artery ligation (60 min; followed by 8 days of reperfusion) was used. Intravenous infusion of MDL 73404 (3 mg/kg per h) began 10 min before occlusion until 30 min after the onset of reperfusion. MDL 73404 reduced (P < 0.02) the elevated serum levels of thiobarbituric acid reactive substances and plasma levels of creatine phosphokinase (P < 0.01). An increase in cardiac output and heart rate together with a decrease (P < 0.01) in infarct size was evident in rats that had received MDL 73404, 8 days previously. Isolated infarcted hearts obtained from rats after 8 days of reperfusion had greater (P < 0.01) + dP/dt max, -dP/dt max, left ventricular systolic pressure and coronary flow after MDL 73404 compared to saline-treated controls. Infusion of [14C]MDL 73404, during the time of occlusion resulted in a concentration of 14.5 +/- 2.2 mg eq/g in the non-ischaemic ventricular tissue and a concentration of 3.0 +/- 0.4 mg eq/g in the area at risk. After infusion for the 30 min of reperfusion, 6.4 +/- 0.2 mg eq/g was detected in the non-ischaemic ventricular tissue but only 3.1 +/- 0.5 mg eq/g in the area at risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗