The bioavailability and nonlinear pharmacokinetics of MK-679 in humans

MK-679 (R(?)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3-(dimethylamino)-3-oxopropyl)thio)methyl)thio(propanoic acid) is a potent and specific LTD₄-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration—time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg ¹⁴C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.     

Suppurative corneal ulceration in Bangladesh

Suppurative keratitis is an important preventable cause of blindness, particularly in the developing world. This study analyses 142 cases of suppurative keratitis referred to Chittagong Eye Infirmary, Bangladesh. Some 53.5% of cases were bacterial and 35.9% were fungal. The five most common pathogens were: Pseudomonas sp. 24%, Streptococcus pneumoniae 17%, Aspergillus sp. 13%, Fusarium sp. 7% and Curvularia sp. 6%. Gram stain and culture results were consistent in 62.6% of cases. Previous antibiotic treatment was a significant factor for failure of culture isolation and less so for Gram stain failure. On Gram stain, 55.9% of pseudomonal cases were missed, but only 2% of fungal cases were missed. Over all, Gram stain had a sensitivity of 62% and positive predictive value of 84% for bacterial cases, and 98% and 94% for fungal cases, respectively. Fungal ulcers were typically filamentous, but an antecedent history of trauma was not common. The most frequent injury was due to rice grains, but the inoculum appeared to be introduced during eye washing with contaminated water. Pseudomonal ulcers occurred most frequently in the monsoon season, and Fusarium cases were seen only in the hot, dry season.     

Psychiatric mental health nursing: challenge and change

. We invited Dr Peplau to provide a personal reflection on the recent history of psychiatric nursing and her thoughts on immediate challenges facing the profession. The paper is an individual scholar's commentary on the way that psychiatry has waxed and waned over the years, in relation to nursing. This historical review discovers and reports a challenge to current practice. Dr Peplau describes a professional shift that is pulling nurses toward the subordinate role observed earlier this century. The paper draws attention to how contemporary practice can be positively influenced, e.g., by giving a structure to the allocation and conduct of nurse–patient time.     

Role of Tyrosine Kinase in Desflurane-induced Preconditioning

Background: Short administration of volatile anesthetics preconditions myocardium and protects the heart against the consequences of subsequent ischemia. Activation of tyrosine kinase is implicated in ischemic preconditioning. The authors investigated whether desflurane-induced preconditioning depends on activation of tyrosine kinase.

Methods: Sixty-four rabbits were instrumented for measurement of left ventricular pressure, cardiac output, and myocardial infarct size (IS). All rabbits were subjected to 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Rabbits underwent a treatment period consisting of either no intervention for 35 min (control group, n = 12) or 15 min of 1 minimum alveolar concentration desflurane inhalation followed by a 10-min washout period (desflurane group, n = 12). Four additional groups received the tyrosine kinase inhibitor genistein (5 mg/kg) or lavendustin A (1.3 mg/kg) at the beginning of the treatment period with (desflurane-genistein group, n = 11; desflurane-lavendustin A group, n = 12) or without desflurane inhalation (genistein group, n = 9; lavendustin A group, n = 8).

Results: Hemodynamic values were similar in all groups during baseline (left ventricular pressure, 87 +/- 14 mmHg [mean +/- SD]; cardiac output, 198 +/- 47 ml/min), during coronary artery occlusion (left ventricular pressure, 78 +/- 12 mmHg; cardiac output, 173 +/- 39 ml/min), and after 2 h of reperfusion (left ventricular pressure, 59 +/- 17; cardiac output, 154 +/- 43 ml/min). IS in the control group was 55 +/- 10% of the area at risk. The tyrosine inhibitors had no effect on IS (genistein group, 56 +/- 13%; lavendustin A group, 49 +/- 13%; each P = 1.0 vs. control group). Desflurane preconditioning reduced IS to 40 +/- 15% (P = 0.04 vs. control group). Tyrosine kinase inhibitor administration had no effect on IS reduction (desflurane-genistein group, 44 +/- 13%; desflurane-lavendustin A group, 44 +/- 16%; each P = 1.0 vs. desflurane group).     

Stimulation of choline/Mg2+ antiport in rat erythrocytes by mefloquine.

In non Mg(2+)-loaded and non malaria-infected rat erythrocytes, mefloquine (100 micromol x l (-1)) stimulated choline/Mg2+ antiport without affecting the Na+/Mg2+ antiport. The stimulation of the choline/Mg2+ antiport by mefloquine, found in this study, and by trifluoperazine and fluvoxamine, reported previously [Ebel et al. Biochim Biophys Acta 2004; 1167: 132-40], was associated with CF3 groups attached to the quinoline or benzene ring. The effect of mefloquine on choline/Mg2+ antiport in vitro was not related to the antimalarial action of mefloquine in vivo. In rat erythrocytes, the choline/Mg2+ antiport can be differentiated from the Na+/Mg2+ antiport through the use of cinchonine that inhibited the choline/Mg2+ antiport [Ebel et al. Biochim Biophys Acta 2002; 1559: 135-44], and mefloquine that stimulated the choline/Mg2+ antiport, whereby the Na+/Mg2+ antiport was not affected by either drug at proper concentrations. The Na+/Mg2+ antiport and choline/Mg2+ antiports behave as different molecular entities.     

Distribution of cholinergic neurons in the chick spinal cord during embryonic development. Comparison of ChAT immunocytochemistry with AChE histochemistry.

The location of cholinergic neurons was studied during the development of the chick embryo spinal cord. A comparison between choline acetyltransferase (ChAT) immunocytochemistry and acetylcholinesterase (AChE) histochemistry was performed. ChAT-positive neurons could be detected only from embryonic day 9 (E9) onwards by the FITC technique and from E12 onwards by the PAP technique. These neurons were located mainly in the medial and lateral motor columns in the ventral horn of the gray matter and some of them were observed in the intermediate region of the spinal cord. AChE-containing cell bodies were much more numerous than the ChAT immunoreactive ones and were distributed in the ventral horn of the gray matter, the intermediate gray region and mostly off the apical part of the dorsal horn. ChAT should provide a reliable and specific marker for cholinergic neurons.     

Accelerated 3D echo-planar spectroscopic imaging at 4 Tesla using modified blipped phase-encoding.

Whole-brain echo-planar spectroscopic imaging (EPSI) often substantially lengthens MRI/MRSI (magnetic resonance spectroscopic imaging) protocols. To halve acquisition time, application of a blipped phase-encoding (PE) gradient during the EPSI readout (RO) was previously suggested by PE of the even RO echoes in k-space at an interstitial location along k(PE), separated from the odd RO echoes, effectively reducing the number of PEs by a factor of 2. However, the approach is very susceptible to phase inconsistencies between even and odd RO echoes in the presence of B(0) inhomogeneities and gradient imbalance, leading to ghosting in the PE direction. In this work, the blipped PE gradient is placed in between pairs of even/odd RO gradient lobes to avoid these problems. This approach is demonstrated in a phantom and in normal human brain in vivo at 4T. While the proposed method allows substantial reduction in metabolite ghosting, it may be limited by the presence of a relatively large spurious signal at the Nyquist frequency.