Cross-disciplinarity in the advance of Antarctic ecosystem research.

The biodiversity, ecosystem services and climate variability of the Antarctic continent and the Southern Ocean are major components of the whole Earth system. Antarctic ecosystems are driven more strongly by the physical environment than many other marine and terrestrial ecosystems. As a consequence, to understand ecological functioning, cross-disciplinary studies are especially important in Antarctic research. The conceptual study presented here is based on a workshop initiated by the Research Programme Antarctic Thresholds - Ecosystem Resilience and Adaptation of the Scientific Committee on Antarctic Research, which focussed on challenges in identifying and applying cross-disciplinary approaches in the Antarctic. Novel ideas and first steps in their implementation were clustered into eight themes. These ranged from scale problems, through risk maps, and organism/ecosystem responses to multiple environmental changes and evolutionary processes. Scaling models and data across different spatial and temporal scales were identified as an overarching challenge. Approaches to bridge gaps in Antarctic research programmes included multi-disciplinary monitoring, linking biomolecular findings and simulated physical environments, as well as integrative ecological modelling. The results of advanced cross-disciplinary approaches can contribute significantly to our knowledge of Antarctic and global ecosystem functioning, the consequences of climate change, and to global assessments that ultimately benefit humankind.

Tissue disposition of glyceryl trinitrate, 1,2-glyceryl dinitrate, and 1,3-glyceryl dinitrate in tolerant and nontolerant rats.

The tissue distribution of glyceryl trinitrate (GTN) and its two dinitrate metabolites 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl trinitrate (1,3-GDN), was studied in GTN-tolerant and nontolerant male Sprague-Dawley rats. The concentrations of GTN, 1,2-GDN, and 1,3-GDN were measured in plasma, heart, brain, liver, aortic tissue, and adipose tissue at various time points after a subcutaneous dose of GTN (50 mg/kg). At the first time point (5 hr), concentrations of GTN, 1,2-GDN, and 1,3-GDN in plasma were equal for tolerant and nontolerant rats, but the elimination rate was altered for the tolerant rats as compared with nontolerant rats. In adipose tissue, the concentration of GTN was significantly higher as compared with concentrations of the dinitrate metabolites. In contrast, the other tissues studied showed significantly higher concentrations of the GDNs when compared with GTN. The 1,3-GDN/1,2-GDN ratio decreased with time for both tolerant and nontolerant rats. This study indicates that long-term GTN administration results not only in tolerance development, but also in altered pharmacokinetics of GTN, 1,2-GDN, and 1,3-GDN. The results also show that the 1,3-GDN/1,2-GDN ratio is dependent on the GTN concentration.

Tissue levels of glyceryl trinitrate and cGMP after in vivo administration in rat, and the effect of tolerance development.

The present study compares the tissue distribution of glyceryl trinitrate (GTN) in plasma, heart, brain, aortic tissue, and adipose tissue from GTN tolerant and GTN nontolerant rats at various time points. Furthermore, the cGMP levels in brain, heart, and aortic tissue were studied at various time points as well as the concentration-effect relationship for GTN in aorta isolated at different time points after the last exposure to GTN. Concentrations of GTN were found to be higher in all tissues studied as compared with plasma, and the concentrations of GTN were higher in tissues from tolerant rats as compared with nontolerant rats, except for aortic tissue. Concentration-effect curves obtained in vitro showed that aortic smooth muscle was still tolerant 24 h after the last dose of GTN. The cGMP level in brain was significantly increased by 40% 2 h after a single dose of GTN (50 mg/kg) and in aortic tissue by 50% at 15 min and at 2 h after a single dose of GTN (50 mg/kg). There was no effect on cGMP in brain, while an increase was seen in aortic tissue 15 min after the last dose in tolerant animals. No change in cGMP level was seen in heart neither in nontolerant nor in tolerant animals at 15 min and at 2 h. No effect on cGMP levels in brain, heart, and aortic tissue was seen 8, 16, and 24 h after exposure to GTN in either tolerant or nontolerant rats. In conclusion, GTN does not involve the cGMP system in heart, and tolerance development caused a less pronounced GTN-induced cGMP increase in aortic tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue distribution of glyceryl trinitrate and the effect on cGMP levels in rat.

In order to study distribution in tissue, rats were treated subcutaneously with glyceryl trinitrate, GTN, (50 mg/kg). The concentrations of GTN were measured in plasma, brain, heart, adipose tissue and aortic tissue at different sampling times by a gas chromatographic method with electron-capture detection. The peak GTN-concentration was reached after 2 hours in all tissues examined. The highest concentration of GTN was found in adipose tissue, where the level was approximately forty times higher than in plasma. The concentration of GTN in brain, heart and aortic tissue was about 2-3 times as high as in plasma. The cGMP level was measured in heart and brain. An increase of the cGMP level was found in brain 2 hours after GTN administration. No cGMP increase was found in heart tissue. The results indicate a substantial distribution of GTN to tissue, and an increase of cGMP in brain. The distribution of the substance in the tissues as shown, might have both pharmacokinetic and pharmacodynamic implications.

The 24 hour variation of salivary carbamazepine and carbamazepine-10,11-epoxide concentrations in children with epilepsy.

Variations in carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-EP) concentrations were measured in saliva over 24 hours in 33 children with complex partial seizures and/or generalized tonic-clonic seizures; all patients received CBZ as monotherapy. CBZ varied between 37-104% and CBZ-EP varied between 26-119%. One venous blood sample was obtained simultaneously with the first saliva sample before the morning dose of CBZ. The free fraction of plasma CBZ was 25.5%. Medication side effects are most likely to appear within 3-4 hours of drug intake; therefore, it is advisable to take another sample in children demonstrating time-related side effects. A controlled release formulation of CBZ should minimize the fluctuations of salivary drug levels of CBZ and CBZ-EP.

Sensitive assay of methadone in plasma by using capillary gas chromatography with photoionization detection.

A new gas chromatographic assay for methadone, utilizing a fused-silica capillary column, is presented. Extreme sensitivity was reached, compared to nitrogen-phosphorus and mass spectrometry detection, by employing a photoionization detector. Plasma concentrations of methadone as low as 1 ng/ml can easily be detected and, by further optimization, 0.1 ng/ml was reached. The minimum detectable amount of methadone reaching the detector was 70 fg. The results indicate that the photoionization detector has potential as a tool in drug monitoring.

Intramuscular bioavailability of chlorazepate as compared to diazepam.

Dipotassium chlorazepate (DPC) and diazepam (DZM) were given i.m. and i.v. to 6 healthy volunteers in doses of 20 mg (48.9 mumol) DPC and 15 mg (52.0 mumol) DZM. The interval between the injections was at least 1 week. Plasma samples were analyzed for DPC and DZM by HPLC. The bioavailability of DPC and DZM after i.m. administration, determined from computer calculated AUCs, was 1.04 and 0.85, respectively.

Pharmacokinetics of chlorazepate after intravenous and intramuscular administration.

Dichlorazepate (DPC) was given to eight healthy volunteers aged 22-38 years (five males and three females). The dose was 20 mg (48.9 mumol) given either as an IV or an IM injection. The interval between the injections was at least 1 week. Plasma samples were analysed for desmethyldiazepam (DMD) by HPLC before and after acid hydrolysis. The kinetics after both IV and IM administration could be explained by a one or two compartment open model. By comparing values before and after hydrolysis an estimate of di- and/or monopotassiumchlorazepate (MPC) could be made. The bioavailability was almost 100% after IM administration. The plasma half lives of DPC and DMD were independent of the form of administration (2.42 and 46.0 h respectively after IV and 2.29 and 45.1 h respectively after IM injection).

The pharmacokinetics of cimetidine and its sulphoxide metabolite in patients with normal and impaired renal function.

1 The pharmacokinetics of cimetidine and its sulphoxide metabolite was studied after a single intravenous dose of 200 mg cimetidine in nine patients with normal renal function and ten patients with severe renal failure on regular haemodialysis and during continuous oral cimetidine treatment in ten patients with normal renal function and 31 patients with different degrees of renal failure. 2 In normal renal function a mean of 47.3% of the single intravenous dose was excreted as unchanged drug and 12.8% as cimetidine sulphoxide. The mean plasma elimination half-life (T1/2) of cimetidine was 2.0 h and of cimetidine sulphoxide 1.7 h. 3 In severe renal failure a mean of 2.2% of the single intravenous dose was excreted as unchanged drug and 0.5% as cimetidine sulphoxide. The mean plasma T1/2 of cimetidine was 3.9 h. The plasma concentrations of the sulphoxide metabolite increased successively with time after dosing and no elimination phase was observed still 9 h after dose. The mean non-renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients g and no elimination phase was observed still 9 h after dose. The mean non-renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients g and no elimination phase was observed still 9 h after dose. The mean non-renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients with different degrees of renal failure given reduced doses of cimetidine the plasma concentrations of the sulphoxide metabolite were higher with decreasing renal function. The mean plasma T1/2 of cimetidine was 3.1 h in mild renal dysfunction (creatinine clearance 50-75 ml/min) and 4.5 h in severe renal failure (creatinine clearance 5-15 ml/min) and of cimetidine sulphoxide 5.3 and 14.4 h respectively. 5 Toxicity studies of cimetidine sulphoxide may be needed to assess if high plasma concentrations of the sulphoxide metabolite in severe renal failure are of clinical significance.

Pharmacokinetics of dipotassium chlorazepate in patients after repeated 50 mg oral doses.

Dipotassium chlorazepate (DPC) was administered to ten patients (five males and five females), ages 18-37 years (mean 27.4), as a once daily dose of 50 mg until a steady state was reached. Plasma concentrations of the main metabolite N-desmethyldiazepam (DMD) were monitored by a high pressure liquid chromatographic (HPLC) method during the medication period and for 5 days after withdrawal of the drug. The plasma half life (t1/2), the elimination coefficient (K beta), the steady state concentration (Css), and the apparent volume of distribution (V beta), were calculated at steady state and the mean values +/- SEM were 44 +/- 5 h. 0.0184 +/- 0.0026 h(-1), 1590 +/- 163 ng/ml and 1.41 +/- 0.17 l/kg, respectively. A moderate inter-individual variability was observed. There was no tendency towards dose dependent elimination.

Inter and intra laboratory variation of digoxin radioimmunoassay in Sweden.

Samples from two pools were sent 10 times to 27 laboratories for assay of digoxin. One pool contained digoxin 2.60 nmol/l in normal plasma (SP); the other was pooled plasma from patients treated with digoxin (PP). Ten radioimmunoassay (RIA) methods were used. The mean of SP assays was 2.59 nmol/l, not significantly different from 2.60 nmol/l. The mean of PP determinations was 2.46 nmol/l. Within each of the 10 assay rounds, the concentrations showed an almost twofold variation and S.D. averaged 0.33 nmol/l and 0.31 nmol/l for SP and PP respectively. Significant differences (P less than 0.001) were found between mean concentrations obtained for the pools at various laboratories (SP range 2.15-2.85 nmol/l; PP range 2.12-2.72 nmol/l). The laboratory means obtained for SP and PP correlated significantly (P less than 0.001). Nevertheless, significant (P less than 0.01) variations between laboratories were found also concerning the mean difference between SP and PP concentrations. The interassay SD of the assays differed significantly between laboratories (range 0.05-0.61 nmol/l. Between and within groups of laboratories using the same RIA method and between various types of laboratories, differences were also found concerning both accuracy and precision of the assays. It is concluded that a better control of digoxin assay is needed.

The influence of trichloroethylene and related drugs on the vestibular system.

A previously described experimental model for studying the effect of industrial solvents on the vestibular system of rabbits has been applied to trichloroethylene. Estimation of trichloroethylene and its metabolites in blood and cerebrospinal fluid was performed by gas chromatography. Vestibular function was studied by recording nystagmus, induced by positional changes or accelerated rotation. At blood levels of trichloroethylene above 30 p.p.m. "positional nystagmus" develops. Two metabolites of trichloroethylene, chloral hydrate and trichloroethanol, which are known as central nervous system (CNS) depressants, did not induce this abnormal nystagmus. However, alpha-chloralose, a derivative of chloral hydrate, induced positional nystagmus and also a markedly exaggerated nystagmus developed during rotatory acceleration. It is suggested that solvents like trichloroethylene elicit vestibular disturbances by stimulation of central subcortical vestibulo-oculomotor connections. The stimulation may be caused by a blockage of inhibitory systems.

Four kits for plasma digoxin radioimmunoassay compared.

We evaluated four commercial radioimmunoassay kits for digoxin. We assayed a standard plasma containing digoxin, 2.0 microgram/L, and samples from patients receiving digoxin, with use of the kits and of a bioassay, the 86Rb-uptake inhibition technique. Intra-assay precisions differed significantly. Computer-calculated 95% confidence intervals for the radioimmunoassays averaged 0.4 to 0.6 microgram/L at the proposed toxic threshold of 2.0 microgram/L; the corresponding value of the 86Rb assay was 0.75 microgram/L. Digoxin in the standard plasma was overestimated with three of the kits (means: 2.40, 2.56, and 2.59 microgram/L) but was assayed accurately by the 86Rb technique and by one kit. This same kit gave a significantly lower mean (1.07 microgram/L) for the patients' samples then did the other three kits (1.32, 1.49, and 1.29 microgram/L), two of which also differed significantly in accuracy. The 86Rb assay measured glycoside activity corresponding to a mean digoxin concentration of 1.35 microgram/L. We conclude that the relatively low precision of digoxin assay and the variations in accuracy between kits from various vendors apparently deserve continual attention.

In vivo lung uptake of lidocaine in pigs.

A mixture of 14C-labelled lidocaine and indocyanine green dye (IG) (Cardiogreen) was injected as a bolus into the pulmonary artery in pigs (15-25 kg). Time-concentration curves for both substances were constructed from 20s blood samples taken from the common carotid artery for approximately 20s. The extraction of lidocaine in each sample and the 95% first passage uptake (FPU) were calculated, assuming that IG is inert with respect to the lung and that it remains within the vascular compartment. The IG curves were also used to calculate cardiac output. The acid-base status and arterial blood pressure or ECG were also followed. Each animal was given two injections. When 0.5 mg/kg b.w. lidocaine was injected, FPU was 41 +/- 3%; at a dose of 2 mg/kg b.w., FPU was 28 +/- 3% (P less than 0.05). The initial extraction during the first 2 s after appearance of the substances was approximately 80%. This level declined with subsequent samples, and the decline was equally rapid at both dose levels.

Pharmacokinetics of N-desmethyldiazepam in healthy volunteers after single daily doses of dipotassium chlorazepate.

Dipotassium chlorazepate was administered to 12 healthy volunteers (8 males and 4 females), aged 22-38 years, as a single daily dose of 20 mg for 14 days. Plasma concentrations of N-desmethyldiazepam were monitored with a gas-chromatographic method during the medication period and for 5 days after withdrawal of the drug. The plasma half-life (t1/2), the elimination coefficient (Kbeta), the concentration (Css), and the apparent volume of distribution (Vbeta) were calculated at steady state, and the mean values +/- SEM were 53 +/- 6 h, 0.0147 +/- 0.0013 h-1, 884 +/- 73 ng/ml, and 1.13 +/- 0.08 1/kg, respectively. A moderate interindividual variability was observed regarding these parameters. There was no tendency toward a biexponential elimination. A significant difference in the apparent volume of distribution was found when males and females were compared.

On the absorption of proscillaridin A after single oral doses to normal and achlorhydric subjects.

Proscillaridin A was given in single oral doses (1.5-2.5 mg) to normal and achlorhydric subjects. Plasma activities of the glycoside were analysed by 86Rb-technique. The absorption pattern was similar in both groups. A marked first peak of proscillaridin activity was seen after about 30 min. After a first minimum, a second peak of activity was registered within 6-12 hrs. An estimate of the amount of active glycoside absorbed during the first 12 hrs after the administration was obtained by calculating the areas under the plasma activity curves (AUC). When corrected for differences in dose per kg body weight, the mean AUC in the achlorhydric group was about 60 per cent greater than in the normal group. The results suggest that proscillaridin is rapidly absorbed; gastric acidity seems to contribute to inter-individual differences in the bio-availability of the glycoside.

On the pharmacokinetics of proscillaridin A in man.

The plasma concentration of proscillaridin was measured by a modified 86Rb method during treatment with multiple doses of a commercial preparation of proscillaridin. Despite high doses, very low plasma levels were found, and there were only minute amounts of glycoside activity in urine and faeces. Administration of an enteric-coated proscillaridin preparation gave higher plasma levels, which raises the possibility of inactivation of the glycoside by acid gastric juice. The results suggest that proscillaridin has low biological availability when given orally, and that it is extensively metabolised in the body.