Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872)

MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered intravenously to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance. The range of values for the pharmacokinetic parameters were as follows: clearance, 0.26 to 0.51 ml/min/kg; half-life, 5.2 to 7.6 h; and distributive volume, 0.11 to 0.27 liters/kg. The level of protein binding of MK-0991 was determined to be 96% in mouse and human serum. The compound exhibited high affinities for human serum albumin and at least two lipid components. The rationale for the selection of MK-0991 as a drug development candidate was based on its two- to threefold superior pharmacokinetic performance in chimpanzees over the performance of an otherwise equivalent analog, L-733,560. Once-daily dosing for MK-0991 is indicated by a graphical comparison of levels in the circulations of chimpanzees and mice. In a study of the pharmacokinetics of MK-0991 in mouse tissue, the organs were assayed following intraperitoneal administration. The area under the concentration-versus-time curves (AUC) segregated the tissues into three exposure categories relative to plasma. The tissues with greater exposure than that for plasma were liver (16 times), kidney (3 times), and large intestine (2 times). The exposure for small intestine, lung, and spleen were equivalent to that for plasma. Organs with lower levels of exposure were the heart (0.3 times that for plasma), thigh (0.2 times), and brain (0.06 times). Kinetically, drug was cleared more slowly from all tissues than from plasma, indicating that terminal-phase equilibrium had not been achieved by 24 h. Thus, some measure of accumulation is predicted for all tissues. Single daily doses of MK-0991 should provide adequate systemic levels of fungicidal activity as a result of its long half-life pharmacokinetics, wide distribution, and slowly accumulating concentrations in tissue.     

Antifungal efficacy, safety, and single-dose pharmacokinetics of LY303366, a novel echinocandin B, in experimental pulmonary aspergillosis in persistently neutropenic rabbits

LY303366 is a novel semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1,3)-beta-D-glucan synthase. The antifungal efficacy and safety of LY303366 were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment study groups were either not treated (controls) or treated with amphotericin B (AmB) at 1 mg/kg of body weight per day or with LY303366 at 1, 5, 10, and 20 mg/kg/day. In rabbits treated with LY303366, there was a significant improvement in survival and a reduction in organism-mediated pulmonary injury measured by the number of infarcts, total lung weight, and ultrafast computerized tomography scan pulmonary lesion score. Rabbits receiving prophylactic LY303366 also demonstrated significant improvement in survival and reduction in organism-mediated pulmonary injury. AmB and LY303366 had comparable therapeutic efficacies by all parameters with the exception of reduction in tissue burden of A. fumigatus, where AmB was superior to LY303366. LY303366 demonstrated a dose-dependent effect on hyphal injury with progressive truncation, swelling, and vacuolization. LY303366 administered in single doses of 1, 5, 10, and 20 mg/kg demonstrated dose-proportional increases in the maximum concentration of drug in plasma and the area under the concentration-time curve from 0 to 72 h with no changes in plasma drug clearance. The 1-mg/kg dosage maintained plasma drug levels above the MIC for 18 h, and dosages of >/=5 mg/kg maintained plasma drug levels above the MIC for the entire 24-h dosing interval. There was no significant elevation of the concentrations of hepatic transaminases or creatinine in serum in LY303366-treated rabbits. In summary, LY303366 improved survival and decreased pulmonary injury with no apparent toxicity in the treatment and prevention of invasive pulmonary aspergillosis in persistently neutropenic rabbits.     

Granulocyte colony-stimulating factor and azole antifungal therapy in murine aspergillosis: role of immune suppression

Outbred ICR mice were immune suppressed either with hydrocortisone or with 5-fluorouracil and were infected intranasally with Aspergillus fumigatus. Beginning 3 days before infection some groups of mice were given recombinant human granulocyte colony-stimulating factor (G-CSF), SCH56592 (an antifungal triazole), or both. Corticosteroid-pretreated mice responded to SCH56592 and had reduced counts in lung tissue and prolonged survival. In these mice, G-CSF strongly antagonized the antifungal activity of SCH56592. Animals treated with both agents developed large lung abscesses with polymorphonuclear leukocytes and large amounts of Aspergillus. In contrast, mice made neutropenic with 5-fluorouracil and then infected with A. fumigatus conidia benefited from either G-CSF or triazoles, and the effect of the combination was additive rather than antagonistic. Host predisposing factors contribute in different ways to the outcome of growth factor therapy in aspergillosis.     

In vitro activity of the echinocandin antifungal agent LY303,366 in comparison with itraconazole and amphotericin B against Aspergillus spp

LY303,366 (LY) is a novel derivative of the echinocandin class of antifungal agents. The in vitro activities of LY, itraconazole (ITZ), and amphotericin B (AMB) were assessed against 60 Aspergillus isolates, including 35 isolates of A. fumigatus, eight isolates of A. terreus, eight isolates of A. flavus, eight isolates of A. niger and one isolate of A. nidulans. Four A. fumigatus isolates were resistant to ITZ. Susceptibility testing for all drugs was performed with a broth microdilution procedure. LY was tested in two media: antibiotic medium 3 (AM3) and Casitone with 2% glucose (CAS) with an inoculum of 2 x 10(3) spores/ml. ITZ and AMB were tested in RPMI 1640 with 2% glucose with an inoculum of 1 x 10(6) spores/ml. All tests were incubated at 37 degrees C for 48 h. A novel end point was used to determine a minimal effective concentration (MEC) for LY, i. e., almost complete inhibition of growth save a few tiny spherical colonies attached to the microplate. MICs were measured for ITZ and AMB with a no-growth end point. Ranges and geometric mean (GM) MECs were from 0.0018 to >0.5 and 0.0039 mg/liter and from 0.0018 to >0.5 and 0.008 mg/liter for LY in AM3 and LY in CAS, respectively. Differences between species were apparent, with A. flavus being significantly less susceptible to LY than any other species tested with both media (P 16 and 0.7 mg/liter for ITZ and from 0.25 to 16 and 1.78 mg/liter for AMB. Minimal fungicidal concentrations (MFCs) were also determined for all drugs. GM MFCs were 0.018, 0.09, 19.76, and 12.64 mg/liter for LY in AM3, LY in CAS, ITZ, and AMB, respectively. LY in AM3 and LY in CAS were fungicidal for 86.7 and 68% of isolates, respectively (98% killing). In comparison, ITZ and AMB were fungicidal for 35 and 70% of isolates, respectively (99.99% killing). A reproducibility study was performed on 20% of the isolates. For 12 isolates retested, the MEC or MIC was the same or was within 1 dilution of the original value for 11, 11, 10, and 9 isolates for LY in AM3, LY in CAS, ITZ, and AMB, respectively. In conclusion, LY seems to be a promising antifungal agent with excellent in vitro activity against Aspergillus spp.     

L-(-)-desmethylselegiline, a metabolite of selegiline [L-(-)-deprenyl], protects mesencephalic dopamine neurons from excitotoxicity in vitro

Selegiline [L-(-)-deprenyl], a monoamine oxidase B inhibitor, has been used in the treatment of Parkinson's disease as a putative neuroprotective agent. Selegiline is metabolized rapidly in the gastrointestinal tract and liver to desmethylselegiline (DMS) and methamphetamine. We have previously shown that selegiline protects dopamine neurons in mesencephalic cultures from toxicity resulting from activation of glutamate receptors. In the present study we examined whether DMS has similar neuroprotective effects. Our data show that DMS protects dopamine neurons from N-methyl-D-aspartate receptor-mediated excitotoxic damage. The efficacy of DMS is greater than that of selegiline, as it can cause protection at lower concentrations and provide significantly greater levels of protection at the same concentrations. Our results suggest that DMS might be the active compound responsible for the neuroprotective properties of selegiline.     

Transgenic and natural mouse models of proteolipid protein (PLP)-related dysmyelination and demyelination

Several studies have shown binding of a variety of lectins to breast cancer cells in tissue sections. In particular, binding of the lectin from the Roman snail, Helix pomatia agglutinin (HPA), to breast cancer cells is linked with a poor prognosis. The molecular basis for lectin binding to metastatic breast cancers is not known. To elucidate this in a model system, lectin-binding patterns of seven human breast cancer cell lines were investigated, their cell membranes were isolated, and HPA binding was assessed. In addition, the influence of fixation and processing on lectin-binding sites was also investigated. Binding of lectins to the tumor cells was very heterogeneous between and within the different cell lines and was influenced by fixation and processing. However, some cell lines showed HPA-binding sites both in vivo and in tissue sections. Analysis of the isolated cell membrane glycoproteins from these cell lines on Western blots revealed that HPA can bind to several membrane glycoproteins. In contrast, human milk shows only one major milk glycoprotein that is HPA-positive. Therefore, a switch in glycosylation appears to be taking place during the transformation to a metastatic phenotype.     

Effects of amphetamine, morphine and dizocilpine (MK-801) on spontaneous alternation in the 8-arm radial maze

The induction of psychomotor activation, behavioural sensitization and of perseverative behaviours, resulting in reduced behavioural variability, have been proposed to be common properties of drugs of abuse. The present investigation tested whether these drug effects could be measured using spontaneous alternation in an 8-arm radial maze. Behavioural effects of repeated treatment with amphetamine (2 and 4 mg/kg, i.p.), morphine (1.25 and 10 mg/kg, i.p.) and the non-competitive NMDA receptor antagonist, MK-801 (0.1 and 0.2 mg/kg, i.p.), on spontaneous alternation were evaluated in this paradigm. All drugs induced psychomotor activation. Sensitized as well as reduced locomotor activity could be observed after repeated treatment depending on drug and dose. Analysis of the sequences of arm entries revealed that all drugs induced perseverative locomotor patterns, but the pattern induced by amphetamine and morphine differed qualitatively from the pattern induced by MK-801.     

Pharmacokinetic and clinical studies on biapenem (L-627) in the pediatric field

Pharmacokinetic and clinical studies on biapenem (L-627), a newly developed carbapenem, were performed and the following results were obtained. 1. Absorption/excretion: Pharmacokinetics of biapenem was studied in 14 children at doses of 6 mg/kg and 12 mg/kg administered through 30 minutes-drip infusion. Peak plasma levels and plasma half-lives of the 2 doses were 22.5, 29.9 micrograms/ml, and 0.84, 0.85 hours, respectively. Their urinary recovery rates were 54.5 to 76.1% and 37.3 to 59.5%, respectively. Cerebrospinal fluid levels of biapenem in two patients with purulent meningitis were 0.88 and 2.72 micrograms/ml, and the penetration rates were 3.7 to 8.3%. 2. Clinical study: Forty-nine patients were treated with biapenem at doses exceeding 90 to 100 mg/kg/day for purulent meningitis and at doses between 15.0 and 36.0 mg/kg/day for other infections. Biapenem gave "Excellent" or "Good" responses in 48 cases, hence an efficacy rate of 98.0% was obtained. Only one patient with pneumonia showed a fair response. No adverse reactions were observed. Abnormal laboratory test results were noted in 7 patients including elevation of GOT, GPT, and eosinophils. In no cases the treatment had to be discontinued.     

Stress and a glycinergic intervention interact in the modulation of MK-801-elicited mouse popping behavior

Cancer mortality in a population-based cohort of 10,322 parkinsonian patients (448 deaths observed during 1987 to 1994) was compared with that of the Italian province of Rome using the standardized mortality ratio (SMR). The overall cancer mortality risk was lower in this cohort than in the reference population (SMR, 56; 95% CI, 51 to 61). This reduction included most cancer sites as well as both smoking-related (SMR, 51; 95% CI, 42 to 60) and nonsmoking-related cancers (SMR, 58; 95% CI, 52 to 65). The observed reduction in cancer mortality risk in this cohort cannot be explained entirely by the hypothesis that smokers are less likely to develop PD.     

The effect of dizocilpine (MK-801) on conditional discrimination learning in the rat

OBJECTIVES: To report the effects of the anti-oestrogen tamoxifen on biochemical and haematological parameters. DESIGN: Randomized, double-blind comparison of tamoxifen 20 mg per day and placebo, over two years. SETTING: A university hospital. SUBJECTS: Forty-six healthy late-postmenopausal women (mean, SD time since menopause; 11, seven years). MAIN OUTCOME MEASURES: Blood specimens were drawn in the fasting state at baseline, six months and two years for measurement of haemoglobin, haematocrit, erythrocyte mean cell volume, mean erythrocyte haemoglobin, leucocyte count, platelet count, urea, electrolytes, creatinine and albumin. RESULTS: There was a significant decline in the haemoglobin concentration in the tamoxifen group (-4.4, 1.2 g/L; mean, SE) and its levels were lower in this group than in those receiving placebo (P = 0.004). Similarly, haematocrit, erythrocyte count and total leucocyte count were lower in those on placebo (P = 0.002, P = 0.01 and P = 0.01, respectively) and platelet count showed a similar trend (P = 0.08). In the tamoxifen group, the level of serum albumin fell significantly (-2.2, 0.4 g/L) and was lower throughout the study than that in the placebo group (P = 0.006). That of serum urea tended to fall (-0.4, 0.2 mmol L) but the between-groups comparison was not significant (P = 0.18). CONCLUSIONS: These data suggest that tamoxifen exerts a haemodilutory effect in normal postmenopausal women. Since a similar effect has been reported in response to postmenopausal oestrogen therapy, it is likely that the observed changes represent another oestrogenic effect of tamoxifen in postmenopausal women. Haemodilution may contribute to the reduced incidence of cardiovascular disease reported in tamoxifen-treated women, and, therefore, its assessment in the new oestrogen agonists/antagonists being developed for cardiovascular disease prevention may be important.     

Studies on the efficacy and safety of biapenem (L-627) against infections in pediatrics

The efficacy and the safety of biapenem (L-627), a new carbapenem antibiotic, against infections in pediatrics were studied. The obtained results are summarized as follows. 1. L-627 at dose levels of 5.4 mg/kg to 12.4 mg/kg (daily doses of 16.2 mg/kg to 37.2 mg/kg) was administered by intravenous drip infusion 3 times daily for 5 to 7 days to 2 cases of pneumonia, 3 cases of skin and soft-tissue infections and 1 case of urinary tract infection for a total of 6 cases. As results, all the cases showed good or better responses including 4 excellent and 2 good results. Bacteriological efficacies in all of the 3 eligible cases were assessed as "eradicated". 2. As for the safety, a decrease in the WBC count and slight elevation of GOT and GPT were observed in 1 case as abnormal changes in the laboratory tests results, only incidence of side effect observed was the eruption in 1 case. 3. The results above indicate that L-627 is useful for the treatment of general infections in pediatrics.     

Does dizocilpine (MK-801) inhibit the development of morphine-induced behavioural sensitization in rats?

Intermittent morphine pretreatment (10 mg/kg/day for 14 days) induced long-lasting (one month post-treatment) sensitization to the locomotor effects of morphine and amphetamine in rats. Co-administration of the non-competitive NMDA-receptor antagonist dizocilpine (MK-801) (0.1 mg/kg) with morphine did not prevent the development of long-term behavioural sensitization. However, this dose of MK-801 did cause long-term sensitization to its own locomotor effects. Co-administration of 0.25 mg/kg MK-801 with morphine caused death in 60% of the animals. In the animals that survived MK-801 plus morphine pretreatment, neither short-term (3 days) nor long-term morphine-induced sensitization was observed. MK-801 alone (0.25 mg/kg/day for 14 days) induced short-term cross-sensitization to morphine. Thus, the development of long-term morphine-induced locomotor sensitization could only be prevented by a dose of MK-801 that yields a lethal combination with morphine. In addition, MK-801 induced sensitization to its own locomotor effects and cross-sensitization to morphine. These findings seriously question whether MK-801 can be used to study the development of morphine-induced behavioural sensitization.     

The meaning(s) of conditionals: Conditional probabilities, mental models, and personal utilities.

[Correction Notice: An erratum for this article was reported in Vol 29(6) of Journal of Experimental Psychology: Learning, Memory, and Cognition (see record 2007-16865-001). On page 684, Table 4, all correlations should have been identified as having a pp then q") as indicating a high conditional probability P(q|p). Participants estimated the probability that a given conditional is true (Experiments 1A, 1B, and 3) or judged whether a conditional was true or false (Experiments 2 and 4) given information about the frequencies of the relevant truth table cases. Judgments were strongly influenced by the ratio of pq to p?q cases, supporting the conditional probability account. In Experiments 1A, 1B, and 3, judgments were also affected by the frequency of pq cases, consistent with a version of mental model theory. Experiments 3 and 4 extended the results to thematic conditionals and showed that the pragmatic utility associated with believing a statement also affected the degree of belief in conditionals but not in logically equivalent quantified statements. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Twenty-four-hour L-[1-(13)C]tyrosine and L-[3,3-(2)H2]phenylalanine oral tracer studies at generous, intermediate, and low phenylalanine intakes to estimate aromatic amino acid requirements in adults

Daily pattern and rates of whole-body tyrosine oxidation and phenylalanine hydroxylation were determined in young adults (15 men, 1 woman) receiving [13C]tyrosine and [(2)H2]phenylalanine via primed, constant oral infusion and [(2)H4]tyrosine by vein (five subjects also received [(2)H3]leucine simultaneously by vein) continuously for 24 h (12 h fast then 12 h fed). Subjects were given a diet supplying 96.6 (n = 5), 35.6 (the proposed requirement; n = 5), and 18.5 mg phenylalanine x kg(-1) x d(-1) (n = 6) based on an otherwise adequate L-amino acid mixture for 6 d before the 24-h tracer study began. [Each diet was low in tyrosine: 6.79 mg x kg(-1) x d(-1).] Our hypothesis was that subjects would be in tyrosine equilibrium, positive balance, or both, at the 96.6- and 35.6-mg intakes and in distinctly negative balance at the 18.5-mg intake. The diurnal pattern in phenylalanine and tyrosine kinetics was dependent on the intake and, presumably, on the adequacy of dietary phenylalanine. Wholebody tyrosine balances, determined from rates of phenylalanine hydroxylation and tyrosine input and oxidation were negative (0.05 < P < 0.1 from zero balance) with the low (18.5 mg) phenylalanine intake [total aromatic amino acid (AAA) intake: 25.3 mg x kg(-1) x d(-1)] but at equilibrium (P > 0.05 from zero balance) with the two higher phenylalanine intakes. Whole-body AAA balance (AAA intake - tyrosine oxidation) was negative (P < 0.05 from zero balance) with the low intake, at equilibrium with the intermediate intake, and apparently distinctly positive (P < 0.05) with the generous intake. Despite model limitations, as discussed, these findings lend further support for a proposed, tentative value for a total mean requirement of 39 mg AAA x kg(-1) x d(-1).     

Chromosome variation and anomalous karyotypes in the red-backed mouse Clethrionomys rufocanus (Rodentia, Microtinae)

G-banding and C-banding of chromosomes were studied in populations of the red-backed mouse Clethrionomys rufocanus from 11 localities of eastern Russia. Intrapopulation polymorphism of autosome 3 caused by the deletion-duplication of the short-arm heterochromatin (2n = 56; NFa = 56-58) was demonstrated. The karyotype of Cl. rufocanus from continental populations and Sakhalin Island was shown to have a large subtelocentric chromosome of pair 3 (NFa = 58), whereas in the population from Kunashir Island, chromosomes of this pair were acrocentric (NFa = 56). One animal from the population of the Kedrovaya Pad' Reserve (Primorsk krai) had a pericentric inversion (acrocentric morphology) of the Y chromosome. In two animals, a female from the Ussuriiskii Reserve (Primorsk krai) and a male captured near the Tomari Settlement (Sakhalin Island), a pericentric inversion of one chromosome of pair 6 was found (NFa = 59). The inversion detected in the animal from the Sakhalin population was accompanied by the loss of the centromeric heterochromatin. In contrast, the inversion of the chromosome pair 6, which was found in the mouse from the Primorsk krai population, did not involve the loss of centromeric heterochromatin. Analysis of our results and data from the literature showed that the karyotype of Cl. rufocanus is not constant, as was thought earlier. The percentage of animals with abnormal karyotype (1.6%) was higher than in other groups of red-backed mice studied (0.12-0.7%).