Thermodynamic Perspective on Field-Induced Behavior of α-RuCl_{3}.

Measurements of the magnetic Grüneisen parameter (Γ_{B}) and specific heat on the Kitaev material candidate α-RuCl_{3} are used to access in-plane field and temperature dependence of the entropy up to 12 T and down to 1 K. No signatures corresponding to phase transitions are detected beyond the boundary of the magnetically ordered region, but only a shoulderlike anomaly in Γ_{B}, involving an entropy increment as small as 10^{-5}Rlog2. These observations put into question the presence of a phase transition between the purported quantum spin liquid and the field-polarized state of α-RuCl_{3}. We show theoretically that at low temperatures Γ_{B} is sensitive to crossings in the lowest excitations within gapped phases, and identify the measured shoulderlike anomaly as being of such origin. Exact diagonalization calculations demonstrate that the shoulderlike anomaly can be reproduced in extended Kitaev models that gain proximity to an additional phase at finite field without entering it. We discuss manifestations of this proximity in other measurements.

Understanding the clinical pharmacokinetics of a GABAA partial agonist by application of in vitro tools.

1. 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide (1), developed for general anxiety disorder, was discontinued from clinical development due to unsuitable oral pharmacokinetics. 2. In humans, (1) demonstrated an unacceptable high apparent oral clearance (Cl(p)/F) that also demonstrated a supraproportional dose-exposure relationship. Secondary peaks in the plasma concentration-time profile suggested possible enterohepatic recirculation of (1). A combination of in vitro mechanistic tools was applied to better understand the processes underlying these complex clinical pharmacokinetic profiles of (1). 3. In metabolism experiments, (1) was shown to be a substrate of monoamine oxidase A (MAO-A) as well as being metabolized by cytochrome P450. The former appeared to be a high K(M) process with a high capacity, while the latter showed saturation between 1 and 10 microM, consistent with the supraproportional dose-exposure relationship. 4. In a sandwich-cultured hepatocyte model, (1) was shown to be a substrate for both uptake and efflux into the canicular space, which is consistent with the observation of pharmacokinetics suggestive of enterohepatic recirculation. Finally, in human epithelial colon adenocarcinoma cell line (Caco-2) and Madin-Darby canine kidney cells transwell flux experiments, (1) was shown to have relatively low permeability and a basolateral-to-apical flux ratio consistent with the activity of P-glycoprotein. 5. In combination, a compounding of the contributions of MAO-A, hepatic uptake and efflux transporters, and P-glycoprotein to the disposition of (1) may underlie the low oral exposure, saturable clearance, and aberrant concentration versus time profiles observed for this compound in humans.

Pharmacokinetics, disposition and lipid-modulating activity of 5-{2-[4-(3,4-difluorophenoxy)-phenyl]-ethylsulfamoyl}-2-methyl-benzoic acid, a potent and subtype-selective peroxisome proliferator-activated receptor alpha agonist in preclinical species and human.

5-{2-[4-(3,4-Difluorophenoxy)-phenyl]-ethylsulfamoyl}-2-methyl-benzoic acid (1) is a novel, potent, and selective agonist of the peroxisome proliferator-activated receptor alpha (PPAR-alpha). In preclinical species, compound 1 demonstrated generally favourable pharmacokinetic properties. Systemic plasma clearance (CLp) after intravenous administration was low in Sprague-Dawley rats (3.2 +/- 1.4 ml min(-1) kg(-1)) and cynomolgus monkeys (6.1 +/- 1.6 ml min(-1) kg(-1)) resulting in plasma half-lives of 7.1 +/- 0.7 h and 9.4 +/- 0.8 h, respectively. Moderate bioavailability in rats (64%) and monkeys (55%) was observed after oral dosing. In rats, oral pharmacokinetics were dose-dependent over the dose range examined (10 and 50 mg kg(-1)). In vitro metabolism studies on 1 in cryopreserved rat, monkey, and human hepatocytes revealed that 1 was metabolized via oxidation and phase II glucuronidation pathways. In rats, a percentage of the dose (approximately 19%) was eliminated via biliary excretion in the unchanged form. Studies using recombinant human CYP isozymes established that the rate-limiting step in the oxidative metabolism of 1 to the major primary alcohol metabolite M1 was catalysed by CYP3A4. Compound 1 was greater than 99% bound to plasma proteins in rat, monkey, mouse, and human. No competitive inhibition of the five major cytochrome P450 enzymes, namely CYP1A2, P4502C9, P4502C19, P4502D6 and P4503A4 (IC50's > 30 microM) was discerned with 1. Because of insignificant turnover of 1 in human liver microsomes and hepatocytes, human clearance was predicted using rat single-species allometric scaling from in vivo data. The steady-state volume was also scaled from rat volume after normalization for protein-binding differences. As such, these estimates were used to predict an efficacious human dose required for 30% lowering of triglycerides. In order to aid human dose projections, pharmacokinetic/pharmacodynamic relationships for triglyceride lowering by 1 were first established in mice, which allowed an insight into the efficacious concentrations required for maximal triglyceride lowering. Assuming that the pharmacology translated in a quantitative fashion from mouse to human, dose projections were made for humans using mouse pharmacodynamic parameters and the predicted human pharmacokinetic estimates. First-in-human clinical studies on 1 following oral administration suggested that the human pharmacokinetics/dose predictions were in the range that yielded a favourable pharmacodynamic response.

Riboflavin treatment of antiretroviral induced lactic acidosis and hepatic steatosis.

BACKGROUND: Antiretroviral induced lactic acidosis and hepatic steatosis is a rare syndrome caused by inhibition of deoxyribonucleic acid (DNA) polymerase gamma by the Nucleoside Reverse Transcriptase Inhibitor (NRTI) class of antiretrovirals. There have been recent reports of NRTI-induced lactic acidosis treated with high-dose riboflavin. INTERVENTION AND RESULTS: We report a case of NRTI lactic acidosis reversed with high-dose riboflavin. Treatment with 50 mg of riboflavin per day was initiated on hospital day 10 after the patient developed respiratory failure. Arterial lactate decreased from 11.9 mmol/dL to 2.1 mmol/dL. Despite lactic acidosis reversal the patient developed acute respiratory distress syndrome (ARDS) and expired. Autopsy confirmed extensive hepatic steatosis with no infectious agents identified. CONCLUSION: Nucleoside Reverse Transcriptase Inhibitor lactic acidosis will likely become more prevalent with the trend toward aggressive antiretroviral treatment. This report provides additional support for the efficacy of riboflavin treatment to reverse this serious complication of antiretroviral therapy. Clinicians should have a high index of suspicion for lactic acidosis in a patient on NRTIs and the medications should be stopped at the earliest sign of toxicity.

Recessively inherited amyotrophic lateral sclerosis: a Germany family with the D90A CuZn-SOD mutation.

Mutations of the SOD1 gene encoding the free radical scavenging enzyme copper-zinc superoxide dismutase (CuZn-SOD) occur in patients with familial amyotrophic lateral sclerosis (ALS). Recent reports have shown homozygosity for a CuZn-SOD mutation in exon 4, the D90A (Asp90A1a) mutation. Other mutations described to date show an autosomal dominant pattern of inheritance. This is the first description of autosomal recessively inherited ALS in an out-bred population in central Europe. This study confirms the earlier described characteristic phenotype reported in D90A homozygous ALS patients in Scandinavia and supports the theory of the existence of a strong modifying factor in some cases of ALS associated with mutations in the CuZn-SOD gene.

Terminal nutrition: framing the debate for the withdrawal of nutritional support in terminally ill patients.

Nutrition and hydration have long been considered to be life-sustaining therapies that are associated with comfort and relief of suffering. This belief is largely based on our own experiences with the sensations of thirst and hunger, which have led physicians to question whether withdrawing or withholding nutritional support from a dying patient can be morally or ethically justified. When considered in light of the available evidence, the underlying premise of this question must be reevaluated. The evidence suggests an alternative formulation, namely, that unrequested nutritional support provided by either the enteral or parenteral route to a terminally ill patient may be both medically and ethically indefensible because it may increase suffering without improving outcome.

Hypoxemia after coronary bypass surgery modeled by resistance to oxygen diffusion.

OBJECTIVE: To evaluate a model describing postoperative hypoxemia after cardiac surgery by using two variables, i.e., shunt and resistance to oxygen diffusion (Rdff). DESIGN: Estimation of these two variables in normal subjects and postoperative cardiac patients. SETTING: The pulmonary function laboratory for the normal subjects and the intensive care unit for the cardiac patients. PATIENTS/SUBJECTS: Nine postoperative cardiac patients and six healthy subjects. INTERVENTIONS: Inspired oxygen fraction was varied in normal subjects and in cardiac patients 3-6 hrs after surgery. This variation occurred in four to seven steps to achieve arterial oxygen saturations in the range 0.90-1.00. MEASUREMENTS AND MAIN RESULTS: Measurements were taken of arterial oxygen saturation, cardiac output, ventilation, and end-tidal gases at each inspired oxygen fraction. These measurements gave the following estimates for the normal subjects: shunt = 3.9+/-5.4% (mean +/- SD) and Rdiff = -5+/-16 torr/(L/min) [-0.7+/-2.2 kPa/(L/min)]; for the cardiac patients: shunt = 7.7+/-1.8% and Rdiff = 212+/-230 torr/(L/min) [28.2+/-30.6 kPa/(L/min)]. The increase in Rdiff (P = .01) was sufficient to explain the observed hypoxemia in these patients. The value for shunt was not significantly increased in the patients (p = .09). The two-variable model (shunt and Rdff) gave a better prediction of arterial oxygen saturation than a model with shunt as the only variable (p = .02). CONCLUSIONS: In cardiac patients requiring supplementary oxygen, the respiratory abnormality could, in our model, be best described by an increased Rdiff, not by an increased shunt value.

Synthesis and oral efficacy of a 4-(butylethylamino)pyrrolo[2,3-d]pyrimidine: a centrally active corticotropin-releasing factor1 receptor antagonist.

The syntheses of a centrally active nonpeptide CRF1 receptor antagonist 2, butylethyl[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP-154,526), and its analogs 11-14 and [3H]-2 are reported. The in vitro CRF1 receptor binding affinity in the series 2, the pharmacokinetic properties of 2 in rats, and the anxiolytic-like effects of orally administered 2 are presented.

Clinical non-invasive measurement of effective pulmonary capillary blood flow.

Since traditional pulmonary function testing is centered on measurements of air flow and lung volume, a method to assess the pulmonary circulation might improve our ability to evaluate diseases that impact upon pulmonary hemodynamics. We have developed a PC based application that rapidly calculates pulmonary blood flow. Subjects rebreath a mixture of 10% argon and 3.5% freon for 20 seconds. Gas concentrations at the mouth are monitored by a clinical mass spectrometer and signals are acquired and processed with off-the-shelf hardware. To test the accuracy and reproducibility of this technique, patients with pulmonary artery catheters were assessed by standard thermodilution methods and the rebreathing test. Measurements using this non-invasive technology closely corelate with invasive thermodilution methods (r = 0.980) and show equivalent reproducibility (average standard error = 2.5%). This application of signal processing technology can extend the role of pulmonary function testing to include routine evaluation of the pulmonary circulation.

Tissue distribution and elimination of indium in male Fischer 344 rats following oral and intratracheal administration of indium phosphide.

The use of indium phosphide (InP) in the semiconductor industry has raised concerns about potential occupational exposure. The tissue distribution and elimination of indium were investigated in adult male Fischer 344 rats following either a single or 14 consecutive daily oral doses, or following an intratracheal instillation of InP (10 mg/kg). The concentrations of indium ions in blood, urine, feces, and tissues were quantified either using direct acid digestion followed by electrothermal atomic absorption spectrophotometry (ET-AAS) or using an extraction method with methyltricapryl ammonium ions to remove indium from the matrix followed by ET-AAS. Indium was poorly absorbed from the gastrointestinal tract in both single and multiple oral dose studies. Upon its absorption, indium was relatively evenly distributed among the major organs such as liver, kidney, lung, spleen, and testes. By 96 h after oral dose treatment, less than 0.11% of the dose of indium was recovered from tissues in the single- or multiple-dose experiment. At 96 h, retention of indium in the body was about 0.36% of the dose (except for lung) following intratracheal instillation of InP. Following oral dose administration, the majority of indium was recovered from the gastrointestinal tract and its contents. The high recovery of indium (73% of the dose) in the feces after intratracheal instillation presumably reflects mucociliary clearance and/or biliary excretion of indium. Urinary indium accounted only for 0.08-0.23% of the dose during a 240-h collection period in both single- and multiple-dose studies. It seems that fecal excretion serves as the major route for indium elimination, and this results from poor absorption. Because of the poor absorption of indium following multiple oral doses or intratracheal instillation of InP, it seems unlikely that indium will accumulate in the body following InP exposure.

Noninvasive estimation of pulmonary vascular resistance by stroke index measurement with an inert gas rebreathing technique.

Patients with pulmonary hypertension (PH) have a cardiac limitation characterized by a decreased resting stroke index (SI) and an inability to augment stroke volume with exercise. We tested the hypothesis that a noninvasive estimation of SI, either at rest or with exercise, could be used to identify the presence and severity of PH. We used the inert gas rebreathing technique for measuring cardiac output and SI in nine subjects with PH and seven control subjects without pulmonary vascular disease. Noninvasive measurement of SI was compared with invasive measurement of pulmonary artery pressure (PAP), pulmonary vascular resistance index (PVRI), and SI. Inert gas estimation of cardiac output correlated well with invasive measurements (r = 0.94). All PH subjects had a depressed resting SI while all control subjects had a normal resting SI. An inverse correlation between the SI measured by inert gas technique and mean PAP was seen with both rest (r = 0.86) and exercise (r = 0.79). Because the resting SI differentiated subjects with PH from controls and correlated with disease severity, exercise measurements were not required. Multiple serial measurements performed in two PH subjects while receiving prostacyclin infusion produced a high level of correlation between the inert gas SI and mean pulmonary artery pressure. We conclude that inert gas measurement of SI may serve a useful role in the diagnosis and management of patients with PH.

Toxicokinetics of sulfasalazine (salicylazosulfapyridine) and its metabolites in B6C3F1 mice.

The toxicokinetics of salicylazosulfapyridine (SASP) and its metabolites were investigated in male and female B6C3F1 mice either following single intravenous (5 mg/kg) or oral (67.5, 675, 1350, and 2700 mg/kg) doses, or following three consecutive daily oral doses (675, 1350, and 2700 mg/kg). Plasma concentrations of SASP and its metabolites were quantified by HPLC. Upon intravenous administration, SASP rapidly disappeared from blood with a mean residence time of 0.45-0.78 hr. The only metabolite of SASP found in plasma after an intravenous dose was sulfapyridine (SP). In both sexes, the absolute oral bioavailability of SASP ranged between 16.6-18.2% at a dose of 67.5 mg/kg, and between 2.6-8.7% at doses of 675-2700 mg/kg. Following oral administration of SASP, both SP and AcSP were identified in plasma. The area under the plasma concentration-time curves (AUC) of SP at all four oral doses were approximately 21- to 32-fold or 5- to 25-fold greater than those of SASP in male or female mice, respectively. The acetylated form of SP and AcSP, produced AUC values higher than SASP but much less than SP. Multiple oral doses with SASP did not alter the temporal patterns of SASP absorption and elimination in comparison to a single dose. However, SP accumulated in both sexes following multiple oral doses. A gender-dependent difference in toxicokinetic profiles for SASP and SP was also observed. Female mice displayed a higher Cmax of SASP and SP than did male mice. Although the volume of distribution of SASP was similar in both sexes, the systemic clearance of SASP in males was about twice that observed in females.(ABSTRACT TRUNCATED AT 250 WORDS)

The disposition of acrylic acid in the male Sprague-Dawley rat following oral or topical administration.

The disposition of [1-14C] acrylic acid (AA) was characterized in the male Sprague-Dawley rat following oral administration, by gavage in water, at 400 mg/kg and topical application, in acetone, at 501 micrograms/cm2. The oral dose was well absorbed, rapidly and extensively metabolized, and excreted primarily (approx. 80%) as 14CO2 within 24 hr of administration. The rate and extent of 14CO2 evolution from [14C]AA was greater for [1-14CAA] while a significantly lower proportion of the dosed radioactivity remained in the tissue of animals than that reported for [2,3-14C]AA (Winter et al., Drug Metabolism and Disposition 1992, 20, 665). This is consistent with incorporation of AA into a minor beta-oxidation pathway of mitochondrial propionate metabolism by which AA may be metabolized to CO2 or incorporated into cellular constituents. Approximately 5% of the dosed radioactivity was excreted in the urine. The disposition of [1-14C]AA following dermal application was studied using charcoal-containing traps attached to the back of the rats to trap volatilized AA from the dosing sites. Following application of 100 microliters AA [4% (v/v) in acetone] to an area of 8.4 cm2 of the skin of a rat (501 micrograms/cm2), the majority (about 73%) of the dose volatilized and was recovered in the charcoal trap. Percutaneous absorption of AA that did not volatilize was rapid and appeared to have the same metabolic fate as AA administered orally with about 75% of the absorbed dose excreted as 14CO2 within 24 hr.

[Professional concept of physicians in child and adolescent psychiatry in former East Germany (1990)]. / Zum Berufsverständnis der Arztinnen/Arzte für Kinder- und Jugendpsychiatrie in den alten Bundesländern (1990).

For this study the authors prepared a questionnaire for 662 child and youth psychiatrists with a return quota of 45%. Careerwise most medical doctors--working as psychiatrists and psychotherapists with an equal distribution in hospitals and offices--acquired further special training and education, particularly in Pediatrics, Psychotherapy and Autogenous Training. Work performance meets general agreement: a noticeable lack of corresponding doctors offices, mainly due to the economic situation. Unequivocal agreement exists concerning the necessity of diagnosis, the necessity of out-patient and in-patient therapy, as well the necessity of interdisciplinary cooperation. The views, however, on the quality of cooperation and the hierarchy within the team show differences. Views on self-concept almost equally determined an identification as doctor and as psychotherapist. The main professional motivations were enjoyment, success and ability. The professional concept was unvocally agreed upon. The survey revealed a poor reputation of child and adolescent psychiatrists. Professional basics include preserving the complexity in the field of child and adolescent psychiatry including medical assignments onesidedness rejected. Conflicts arise concerning the "professional self concept", resulting from the thin line between the required separation of child and adolescent psychiatry and associated professions and the required cooperation with associated professions.

Identification and comparison of the urinary metabolites of [1,2,3-13C3]acrylic acid and [1,2,3-13C3]propionic acid in the rat by homonuclear 13C nuclear magnetic resonance spectroscopy.

Acrylic acid (AA) and its esters are used extensively for the production of a variety of polymers. Despite their ubiquitous nature, little has been reported on the metabolism of the parent acid. The metabolites of AA may be volatile, unstable, polar, and thus difficult to isolate. Therefore, 13C NMR was used to help identify and compare directly the urinary metabolites of both 99% 13C-enriched AA and propionic acid (PA). Male Sprague-Dawley rats received [1,2,3-13C]AA (400 mg/kg in water p.o.) or an equimolar dose of [1,2,3-13C]propionate together with a radioactive tracer, [2,3-14C]AA, or [1-14C]propionate, respectively, and excreta were collected for 72 hr. For both acids, expiration of 14CO2 was the major route of elimination of radiolabel (approximately 80%). Approximately 6% of the dose was excreted in the urine. Urine was analyzed directly using proton-decoupled 13C and two-dimensional 13C homonuclear correlated NMR spectroscopy. The urine from AA-treated rats revealed major signals, the intensity of which was time-dependent, from at least five 13C-enriched metabolites of AA. Signals have been assigned to 3-hydroxypropionic acid, N-acetyl-S-(2-carboxyethyl)cysteine, and N-acetyl-S-(2-carboxyethyl)cysteine-S-oxide by comparison with spectra of authentic standards. No unchanged AA was detected. In contrast, the spectra of urine from a propionate-treated rat revealed only a few minor 13C-enriched signals that were assigned to methylmalonic acid. No unchanged PA was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereoselective aliphatic hydroxylation of 6-n-propylchromone-2-carboxylic acid by female Dutch rabbits.

6-n-Alkylchromone-2-carboxylic acids are metabolized solely by aliphatic oxidation. In the rabbit, the 6-n-propyl congener (PCCA) undergoes omega-1 hydroxylation exclusively. Following administration of PCCA to female Dutch rabbits (500 mumol/kg), some 77% of the dose was excreted in the urine, 41% as PCCA and 36% as 6-(2'-hydroxy-n-propyl)chromone-2-carboxylic acid. Since this metabolite is chiral, we have examined the stereochemistry of the excreted material. Diastereoisomeric (as camphanate and alpha-methoxy-alpha-(trifluoro-methyl)phenylacetate esters) and direct chiral HPLC and chiral lanthanide shift NMR have each shown the S:R ratio of the excreted metabolite to be 76:24. When rabbits were dosed with the racemic metabolite, excretion of the compound was not stereoselective. The regio- and stereo-selectivity of the aliphatic hydroxylation of PCCA are thus reflections of the selectivities of the enzyme systems responsible for its formation and suggest PCCA to be an appropriate probe compound for the study of prochiral-chiral hydroxylations.