Genetic and other risk factors for suicidal ideation and the relationship with depression.

BACKGROUND: There is a genetic contribution to the risk of suicide, but sparse prior research on the genetics of suicidal ideation. METHODS: Active and passive suicidal ideation were assessed in a Sri Lankan population-based twin registry (n = 3906 twins) and a matched non-twin sample (n = 2016). Logistic regression models were used to examine associations with socio-demographic factors, environmental exposures and psychiatric symptoms. The heritability of suicidal ideation was assessed using structural equation modelling. RESULTS: The lifetime prevalence of any suicidal ideation was 13.0% (11.7-14.3%) for men; 21.8% (20.3-23.2%) for women, with no significant difference between twins and non-twins. Factors that predicted suicidal ideation included female gender, termination of marital relationship, low education level, urban residence, losing a parent whilst young, low standard of living and stressful life events in the preceding 12 months. Suicidal ideation was strongly associated with depression, but also with abnormal fatigue and alcohol and tobacco use. The best fitting structural equation model indicated a substantial contribution from genetic factors (57%; CI 47-66) and from non-shared environmental factors (43%; CI 34-53) in both men and women. In women this genetic component was largely mediated through depression, but in men there was a significant heritable component to suicidal ideation that was independent of depression. CONCLUSIONS: These are the first results to show a genetic contribution to suicidal ideation that is independent of depression outside of a high-income country. These phenomena may be generalizable, because previous research highlights similarities between the aetiology of mental disorders in Sri Lanka and higher-income countries.

Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma.

BACKGROUND: Pazopanib, an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-Kit, is approved in locally advanced/metastatic renal cell carcinoma (RCC). METHODS: Data from trials in advanced solid tumours and advanced/metastatic RCC were used to explore the relationships between plasma pazopanib concentrations and biomarker changes, safety, and efficacy. Initially, the relationships between pharmacokinetic parameters and increased blood pressure were investigated, followed by analysis of steady-state trough concentration (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries. RESULTS: Strong correlation between increased blood pressure and Cτ was observed (r(2)=0.91), whereas weak correlation was observed between Cτ and decline from baseline in sVEGFR2 (r(2)=0.27). Cτ threshold of >20.5 µg ml(-1) was associated with improved efficacy (PFS, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from Cτ >20.5 µg ml(-1). However, the association of Cτ with certain adverse events, particularly hand-foot syndrome, was continuous over the entire Cτ range. CONCLUSIONS: The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire Cτ range. Monitoring Cτ may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.

Depression, migraine with aura and migraine without aura: their familiality and interrelatedness.

Migraine is frequently comorbid with depression. There appear to be common aetiological factors for both disorders, but the aetiology of migraine within depressed patients, in particular the significance of aura, has been little studied. A large sample of concordantly depressed sibling pairs [the Depression-Network (DeNT) sample] was assessed as having migraine with aura (MA), migraine without aura (MoA), probable migraine or no migraine according to International Headache Society guidelines. Correlations between siblings' migraine status were used to assess the nature of familial liability to migraine. A multiple threshold isocorrelational model fit best, in which different syndromes are conceptualized as different severities of one underlying dimension rather than as having separate aetiologies. Thus, MA and MoA were found to be different forms of the same disorder, with MA occupying the more extreme end of the spectrum of liability. Implications for our understanding of the relationship between migraine and depression are discussed.

Dual neurokinin NK(1)/NK(2) antagonists: N-[(R,R)-(E)-1-arylmethyl-3-(2-oxo-azepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamides and 3-[N'-3,5-bis(trifluoromethyl)benzoyl-N-arylmethyl-N'-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamides.

Based on the structure of N-[(R,R)-(E)-1-(4-chlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1), attempts to improve the NK(2) affinity have resulted in the discovery of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (9, DNK333) exhibiting a 5-fold improved affinity to the NK(2) receptor in comparison to 1. Simplification of the structure via elimination of a chiral centre led to 3-[N'-3,5-bis(trifluoromethyl)benzoyl-N-(3,4-dichlorobenzyl)-N'-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamide (22), a potent and fairly balanced NK(1)/NK(2) antagonist.

Effect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine.

AIMS: To investigate the effect of acute P-glycoprotein inhibition by the multidrug-resistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the pharmacokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). METHODS: In a double-blind, three-way crossover study, the pharmacokinetic and potentially adverse pharmacodynamic effects (reaction time, transcutaneous PCO2, blood pressure) of morphine were compared with and without acute inhibition of P-glycoprotein by PSC. The effects of PSC alone were also evaluated. The study was performed in 18 healthy male volunteers and pharmacodynamic effects analysed by measuring the area under the effect (AUE) curve. 150 mg PSC (or its placebo) was given as an i.v. infusion over 2 h. With the expected inhibition of Pgp 1 h after starting PSC infusion, 7.5 morphine HCl (or its placebo) was infused over 2 h. RESULTS: The infusion of PSC resulted in blood concentrations expected to inhibit Pgp mediated transport. While the pharmacokinetics of plasma morphine and M6G. were unaffected there was a small but statistically significant increase in the AUC and Cmax of M3G (11.8 and 8.3%, respectively). The t(1/2) and tmax were unaffected. The pharmacokinetic parameters of PSC were not affected by coadministration with morphine. PSC did not significantly affect the adverse events of morphine, as assessed by spontaneous reporting. Compared with PSC alone, morphine elicited an increase in reaction time (Emax 48 ms, compared with the predose absolute reaction time of 644 ms), which was not detected by the alertness-drowsiness score, indicating only slight sedation. There was a significant decrease in systolic blood pressure (Emin -9 mm Hg), and a trend for a fall in diastolic blood pressure (Emin -14.5 mm Hg) and respiratory rate (Emin -1.8 breath x min(-1)). For all these parameters, the effects of PSC/morphine were similar to that of PSC alone, suggesting some attenuation of morphine's effect. In contrast, morphine caused a significant increase in PCO2 (Emax 0.69 kPa) compared to PSC alone, indicating slight respiratory depression. This increase was similar to that of the PSC/morphine combination. CONCLUSIONS: Acute inhibition of P-glycoprotein by PSC in this setting does not affect the pharmacokinetic or safety-related pharmacodynamic profile of morphine in a clinically significant manner.

N-[(R,R)-(E)-1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl)-allyl]-N-methyl-3,5-bis-trifluoromethyl-benzamide: an orally active neurokinin NK1/NK2 antagonist.

The stereoselective synthesis of N-[(R,R)-(E)-1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl+ ++)-allyl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (4) and its NK1 and NK2 receptor binding properties are reported. In addition the potent inhibitory effects in vivo on sar9-SP- and beta-Ala-NKA-induced airway bronchoconstriction in guinea pigs are demonstrated.

Simultaneous LV and RV volumes by conductance catheter: effects of lung insufflation on parallel conductance.

One aspect in the measurement of ventricular volume using the conductance catheter technique is the assessment of parallel electrical conductivity of structures extrinsic to the ventricular blood pool. Because it is sometimes necessary to make volume measurements during ventilation or spontaneous respiration, the extent to which parallel conductance may vary with lung insufflation was investigated. Anesthetized pigs (11-15 kg) were ventilated and instrumented with both left (LV) and right ventricular (RV) conductance and pressure-tip catheters and end-hole catheters for injection of hypertonic saline into the inferior vena cava and pulmonary artery. Data were recorded during ventilation with tidal volumes of 10 and 20 ml/kg, and the associated fluctuations to LV and RV end-diastolic (EDV) and stroke (SV) volumes were measured. With the use of a saline dilution technique, parallel conductance (Vc) was determined for each ventricle with the ventilator off and lungs insufflated to 0, 10, and 20 ml/kg. Whereas ventilation caused marked oscillations in LV and RV EDV and SV, these variations could not be attributed to Vc, which remained statistically unchanged from their baseline values of 34.1 +/- 3.1 in the LV and 31.1 +/- 4.4 in the RV. These results indicate that the fluctuations that occur in conductance catheter-derived LV and RV volume signals with ventilation are not caused by any significant changes to parallel conductance.

Validation of a telemetry system for measurement of blood pressure, electrocardiogram and locomotor activity in beagle dogs.

A model is described for the continuous recording of arterial blood pressure, electrocardiogram and locomotor activity by telemetry in conscious unrestrained beagle dogs. Validation of the system was accomplished by simultaneous acute catheterisation and telemetry recording ten weeks after implantation, under anaesthesia. Systolic, mean and diastolic pressures, measured over 30-40 mm Hg, were not significantly different. Telemetric measurements in their home cage over several days revealed clear diurnal variations in blood pressure, heart rate, locomotor activity and contractility (QA-interval). Despite these diurnal variations the 24 h mean values were highly reproducible. This model was further characterised by pharmacological interventions designed to increase contractility (ouabain) and blood pressure (NG-nitro-L-arginine methyl ester) and to lower blood pressure (isosorbide-5 mononitrate and molsidomine). The high daily reproducibility of cardiovascular parameters allowed each dog to be used as its own control and allowed investigation of these long-acting active agents, which would not have been possible with conventional methods for cardiovascular measurement. These findings demonstrate the utility of this model for investigations into blood pressure regulation as well as the potential for pharmacological intervention.

Initial reactions in anaerobic ethylbenzene oxidation by a denitrifying bacterium, strain EB1.

Initial reactions in anaerobic oxidation of ethylbenzene were investigated in a denitrifying bacterium, strain EB1. Cells of strain EB1 mineralized ethylbenzene to CO2 under denitrifying conditions, as demonstrated by conversion of 69% of [14C]ethylbenzene to 14CO2. In anaerobic suspensions of strain EB1 cells metabolizing ethylbenzene, the transient formation and consumption of 1-phenylethanol, acetophenone, and an as yet unidentified compound were observed. On the basis of growth experiments and spectroscopic data, the unknown compound is proposed to be benzoyl acetate. Cell suspension experiments using H2(18)O demonstrated that the hydroxyl group of the first product of anoxic ethylbenzene oxidation, 1-phenylethanol, is derived from water. A tentative pathway for anaerobic ethylbenzene mineralization by strain EB1 is proposed.

Prevention of vascular nitroglycerin tolerance by inhibition of protein kinase C.

We investigated whether in vivo inhibition of protein kinase C (PKC) can prevent the development of vascular tolerance and restore the sensitivity of isolated vessels to nitroglycerin (NTG). Tolerance was induced in male Wistar rats by a constant i.v. infusion of NTG 1 mg kg-1 h-1, a dose which did not alter blood pressure. After 72 h, the aorta was removed and the sensitivity of aortic rings to NTG tested. Chronic NTG infusion resulted in a 5.5 fold decrease in NTG-sensitivity as compared with controls (vehicle), indicating the development of vascular tolerance. The simultaneous in vivo administration of the specific PKC inhibitor N-benzoyl-staurosporine (30 mg kg-1 day-1) prevented this decrease in NTG sensitivity. These results suggest a role for PKC activation in the development of vascular NTG tolerance.

Conductance catheter measurement of left ventricular volume: evidence for nonlinearity within cardiac cycle.

The conductance catheter gain factor, alpha, is usually determined by an independent measure of stroke volume and, as such, is assumed to be constant. However, nonlinearity of the conductance-volume relation has been proposed on theoretical grounds. The present study was designed to establish the extent of nonlinearity, or variability of alpha, within the cardiac cycle using magnetic resonance imaging (MRI) as the reference method. Pentobarbital-anesthetized minipigs (n = 10, 10-13 kg) were instrumented with left ventricular (LV) conductance and Millar catheters. Conductance catheter signals were recorded, and volumes were corrected for parallel conductance using a saline-dilution technique. Animals were then placed in a 4.7-T magnet, and first time derivative of LV pressure-gated transverse MRI images (5-mm slices) acquired during isovolumic contraction (end diastole) and relaxation (end systole). LV cavity volumes were then determined using a third-order polynomial model. The gain alpha was computed three ways: by dividing conductance stroke volume by MRI stroke volume (alpha SV), by dividing conductance end-diastolic volume by MRI end-diastolic volume (alpha ED), and by dividing conductance end-systolic volume by MRI end-systolic volume (alpha ES). alpha SV was 0.62 +/- 0.15, with alpha ED (0.71 +/- 0.17) significantly lower than alpha ES (0.81 +/- 0.21; P < 0.001). Using alpha SV to adjust conductance gain (i.e., assuming constant gain) resulted in a significantly larger end-diastolic volume (25.8 +/- 4.6 ml) and smaller ejection fraction (46.8 +/- 7.2%) than those obtained with MRI (23.0 +/- 4.1 ml and 53.1 +/- 7.3%, respectively; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase, on the frequency-dependence of the contraction-relaxation cycle of the guinea-pig isolated atrium.

1. The relevance of a functional sarcoplasmic reticulum (SR) membrane system to the contraction-relaxation cycle and to the force-frequency relationship of guinea-pig atrial tissue was investigated. Cyclopiazonic acid (CPA) was used to inhibit selectively the activity of the SR Ca(2+)-ATPase. IC50 values of 0.2 microM or 1.0 microM were measured in guinea-pig isolated SR membranes in the absence or presence of millimolar ATP, respectively. CPA (0.3-30 microM) did not inhibit the activity of the sarcolemmal Na(+)-Ca(2+)-exchanger as measured in isolated cardiac cell membrane preparations. 2. In guinea-pig isolated left atrium paced at 2.5 Hz (30 degrees C), CPA (1-100 microM) produced a concentration-dependent reduction in developed tension and a fall in the maximum rate of tension increase (+dT/dtmax) and decrease (-dT/dtmax). The twitch duration was markedly increased due to a prolongation of the time to peak tension, and in particular, the relaxation phase. 3. The contraction-relaxation cycle of the left atrium showed a marked dependence on the frequency of stimulation. The developed tension and +dT/dtmax showed a progressive increase from 0.5 Hz, reaching peak values at a stimulation rate of 1.5-2.5 Hz, the positive staircase phenomenon. Higher frequencies of stimulation caused a fall in these parameters. Resting tension was unaffected. The time-course of the contraction-relaxation cycle was also frequency-dependent, with both time to peak tension and relaxation time showing a progressive fall from 2.0-3.5 Hz. 4. The addition of CPA (30 microM) caused marked alterations in the frequency-dependence of the contraction-relaxation cycle. The frequency-dependence of developed tension, + dr/dtmax and dT/dt max was shifted downwards, particularly at higher frequencies, and the frequency at which peak values of+ dT/dtmax and - dT/dtmax were reached was shifted leftwards. The resting tension of the tissues in the presence of 30 micro M CPA was increased markedly at frequencies greater than 2 Hz. The time-course of the contraction-relaxation cycle was markedly prolonged between 1.0 and 3.5 Hz, due to an effect on both time to peak tension and relaxation time.5. In conclusion, these results show that CPA is a highly selective inhibitor of the cardiac SR Ca2+-ATPase, without effect on the sarcolemmal Na+-Ca2+-exchanger, and suggest that a functional SR Ca2+-ATPase is necessary for the normal contraction-relaxation cycle of guinea-pig cardiac tissue.Additionally, the results suggest an increasing dependence of tension development on SR Ca2+-ATPase with increasing frequency, which may reflect either a frequency-dependent activation of this enzyme or the diminished contribution of the Na+-Ca2+ exchanger. These results also provide novel support for the mechanism of the depressed force-frequency relation found in cardiac tissue of heart failure patients, in which there is a reduced expression of Ca2+-ATPase.

Parallel tolerance between platelet cyclic GMP and preload effects of nitroglycerin in anaesthetized mini-pigs.

The effects of acute intravenous nitroglycerin (NTG) administration on platelet cyclic GMP in relation to changes in indices of preload (end-diastolic volume) and afterload (effective arterial elastance) were evaluated in the anaesthetized mini-pig, using pressure-volume analysis. NTG (1-30 micrograms kg-1 min-1, i.v.) elicited a dose-dependent fall in preload and afterload, and an increase in arterial blood platelet cyclic GMP. Repeated doses of NTG (30 micrograms kg-1 min-1) resulted in tolerance to the preload but not afterload effects. The increases in platelet cyclic GMP were also attenuated, being highly correlated with the preload changes. Therefore, platelet cyclic GMP appears to reflect NTG-induced venous tolerance, rather than arterial responsiveness. The measurement of platelet cyclic GMP may represent a simple approach for monitoring the degree of venous tolerance to NTG in animals or patients, facilitating further mechanistic investigations.

Metabolism of cysteinyl leukotrienes in monkey and man.

The proinflammatory cysteinyl leukotrienes are inactivated in primates by (a) intravascular degradation, (b) hepatic and renal uptake from the blood circulation, (c) intracellular metabolism of leukotriene E4 (LTE4), and (d) biliary and renal excretion of LTC4 degradation products. We have analyzed cysteinyl leukotriene metabolites excreted into bile and urine of the monkey Macaca fascicularis and of man. In both species, hepatobiliary leukotriene elimination predominated over renal excretion. In a representative healthy human subject at least 25% of the administered radioactivity were recovered from bile and 20% from urine within 24 h. In monkey and man intravenous administration of 14,15-3H2-labeled LTC4 resulted in the biliary and urinary excretion of labeled LTE4, omega-hydroxy-LTE4, omega-carboxy-LTE4, omega-carboxy-dinor-LTE4, and omega-carboxy-tetranor-dihydro-LTE4. Small amounts of N-acetyl-LTE4 were detected in human urine only. Oxidative metabolism of LTE4 proceeded more rapidly in the monkey resulting in the formation of higher relative amounts of omega-oxidized leukotrienes in this species as compared to man. [3H]H2O amounted to less than 2% of the administered dose in monkey and human bile and urine samples. Incubation of isolated human hepatocytes with [3H2]LTC4, [3H2]LTD4, and [3H2]LTE4 showed that only [3H2]LTE4 underwent intracellular oxidative metabolism resulting in the formation of omega- and beta-oxidation products. N-Acetylated LTE4 derivatives were not detected as products formed by human hepatocytes. By a combination of reversed-phase high-performance liquid chromatography and radioimmunoassay, endogenous LTE4 and N-acetyl-LTE4 were detected in human urine in concentrations of 220 +/- 40 and 24 +/- 3 pM, corresponding to 12 +/- 1 and 1.5 +/- 0.2 nmol/mol creatinine, respectively (mean +/- SEM; n = 10). Endogenous LTD4 and LTE4 were detected in human bile (n = 3) in concentrations between 0.2-0.9 nM. Our results demonstrate that LTD4 and LTE4 are major LTC4 metabolites in human bile and/or urine and may serve as index metabolites for the measurement of endogenously generated cysteinyl leukotrienes. Moreover, omega-oxidation and subsequent beta-oxidation from the omega-end contribute to the metabolic degradation of LTE4 not only in monkey but also in man.

Essential fatty acid-deficient rats are resistant to oleic acid-induced pulmonary injury.

Because leukotrienes and prostaglandins are inflammatory mediators derived from arachidonic acid, their potential role in oleic acid-induced lung injury was evaluated in control and in essential fatty acid-deficient (EFAD) rats depleted of arachidonic acid substrate. In control rats, oleic acid (0.06 ml/kg iv) increased the pulmonary permeability index (measured by scintigraphy) from -10 +/- 13 x 10(-6) s-1 to 217 +/- 20 x 10(-6) s-1 and 118 +/- 13 x 10(-6) s-1 at 5 and 50 min (P less than 0.05), respectively. It also caused arterial hypoxemia at 30 min (P less than 0.05). Compared with saline controls, oleic acid increased bronchoalveolar lavage fluid levels of immunoreactive (i) LTC4/D4, iLTB4, (P less than 0.01), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) (P less than 0.05). In EFAD rats, oleic acid failed to significantly increase the lung permeability index at 5 and 50 min. In contrast to control rats, oleic acid failed to cause hypoxemia in the EFAD rats. Bronchoalveolar lavage levels of iLTB4 and i6-keto-PGF1 alpha after oleic acid in EFAD rats were lower compared with oleic acid controls, whereas iLTC4/D4 in the oleic acid EFAD group was not decreased. Treatment with intraperitoneal ethyl arachidonate (400 mg over 2 wk) reversed the resistance of EFAD rats such that the pulmonary edema (P less than 0.05) was evident after oleic acid. This latter group also manifested a significant (P less than 0.05) rise in the bronchoalveolar lavage levels of iLTB4 and i6-keto-PGF1 alpha. These results suggest that arachidonic acid metabolites contribute to oleic acid-induced pulmonary permeability.

Oleic acid-induced pulmonary injury in rats: potential role of sulfidopeptide leukotrienes.

Lung injury following intravenous oleic acid is characterized by pulmonary edema, leukopenia and hypoxemia. Because leukotrienes can increase permeability and cause leukocyte adherence, we evaluated their potential role in oleic acid-induced lung injury in the anesthetized rat using a selective LTD4/E4 antagonist, LY171883. 99mTc-albumin and 99mTc-red blood cells (99mTc-RBC) were used to measure changes in the pulmonary permeability index and intravascular space by non-invasive scintigraphy. Intravenous oleic acid (0.06 ml/kg) increased the pulmonary permeability index 11 (P less than 0.01) and 5.8 fold (P less than 0.01) at 5 and 50 min after its injection compared to baseline, but had no effect on mean pulmonary arterial pressure or pulmonary distribution of 99mTc-RBC. Oleic acid also induced arterial hypoxemia, and increased bronchoalveolar lavage-fluid levels of immunoreactive (i) leukotriene LTC4 from 0.40 +/- 0.14 ng/ml to 2.27 +/- 0.55 ng/ml (mean +/- S.E.M., n = 4, P less than 0.05) and iLTB4 (from 0.42 +/- 0.05 ng/ml to 1.91 +/- 0.63 ng/ml, n = 5-7, P less than 0.01). LY171883 attenuated the elevated permeability by 24% and 68% at 5 (P less than 0.05) and 50 min (P less than 0.01), but did not alter the hypoxemia. These results support the hypothesis that oleic acid elevates leukotriene levels which may increase pulmonary vascular permeability. Furthermore, they suggest that the prevention of elevated pulmonary vascular permeability and edema may be necessary, but are clearly not sufficient to prevent arterial hypoxemia following oleic acid injury in the rat.

w-oxidation products of leukotriene E4 in bile and urine of the monkey.

The intravenous administration of [3H]leukotriene C4 in the monkey Macaca fascicularis results in the biliary and urinary elimination of [3H]leukotriene D4 and [3H]leukotriene E4 in addition to more-polar metabolites. Separation of these polar metabolites and chromatographic comparison with synthetic w-oxidized leukotrienes indicated the in vivo formation of w-hydroxy-[3H]leukotriene E4 and w-carboxy-[3H]leukotriene E4. Time course studies of the [3H]leukotriene metabolite pattern in bile and urine showed that w-hydroxy-leukotriene E4 was decreasing as w-carboxy-leukotriene E4 and additional polar derivatives were increasing.