Studies on hydralazine

Summary The bioavailability of orally administered hydralazine was assessed in 4 healthy subjects after separate administration of a single oral or intravenous dose (0.3 mg·kg^–1). Comparison of the areas under the serum concentration-time curves showed that 26 – 55 % of the oral dose was available to the systemic circulation as unchanged drug. The O - 24 h excretion of the drug in urine was rapid: 11.4 – 14.1 % of the dose after intravenous administration, and 2.0 – 3.6 % after an oral dose. Acetylation of hydralazine leads to formation of 3-methyl-s-triazolo-3,4,a-phthalazine (MTP) and a gas-liquid-chromatographic method for its measurement in urine was developed. After oral and intravenous administration, 0.8 – 1.2 % and 1.4 – 2.3 % of the dose, respectively, were recovered within 24 hours from urine as MTP. After oral administration there was a relative increase in the amount of MTP in every subject, which indicates route-dependent metabolism. The lower bioavailability of oral hydralazine could be explained in terms of first-pass metabolism.     

The Metabolism of Biphenyl. III. Phenolic Metabolites in the Pig

Abstract The phenolic metabolites of biphenyl in both male and female pigs were qualitatively and quantitatively analysed as trimethylsilyl (TMS) ethers by combined gas chromatography/mass spectrometry and gas chromatography, respectively. This xenobiotic was metabolized mainly to mono–hydroxylated biphenyl, and in small amounts to di– and tri–hydroxylated biphenyls. Urinary excretion was the only route of elimination of these compounds from the body. The total urinary recovery in male pigs was 44.8 % of the dose 96 hrs after administration of the drug, and the corresponding value in female pigs was 27.6%. The main part of the urinary metabolites was excreted during the first 24 hrs after dosing in both sexes.     

A respiration-metabolism chamber system and a GC-MS method developed for studying exhalation of perfluorobutane in rats after intravenous injection of the ultrasound contrast agent Sonazoid

Sonazoid is a new contrast agent for ultrasound imaging comprising an aqueous suspension of lipid-stabilised perfluorobutane (PFB) gas microbubbles. A respiration-metabolism chamber system was developed to collect exhaled air following intravenous administration of Sonazoid to rats. Analysis of PFB in the exhaled rat air was performed using a modified version of an earlier published method for blood samples, i.e. an automatic headspace gas chromatographic mass spectrometric (GC-MS) method using electron impact ionisation. The calibration standards were PFB diluted in air (2.5-1800 pg/ml). Perfluoropentane (PFP) was used as an internal standard and the MS detector was set to single ion monitoring of the base fragment ions of PFB (m/z 69 and 119) and PFP (m/z 69). The calibration curve, made by plotting the peak area ratios of PFB (m/z 69) to PFP (m/z 69) against the theoretical concentration of PFB, was fitted to a linear equation with weighting 1/y2 and found to be reproducible. The lower limit of quantification (LLOQ) was 2.5 pg PFB/ml. The between-day variation of the method was below 2.6% relative standard deviation (R.S.D.) and the within-day variation of the method was below 6.4% R.S.D. The accuracy of the method was evaluated and showed a relative error less than 5.2%. PFB was found to be stable for 14 days when stored in Tedlar sample bags at room temperature. An even lower detection limit may be obtained by using the more time-consuming process of solid-phase micro extraction; thus, by concentrating PFB on carboxen-PDMS fibres an LLOQ of 0.5 pg PFB/ml was obtained. When five rats were given an i.v. bolus injection of Sonazoid at a dose of 8 microl microbubbles/kg a mean recovery of 96% (range, 81-110%) was found during 24 h; more than 50% was exhaled during the first 30 min after injection.     

Gastric accommodation assessed by ultrasonography

Gastric accommodation is important for the understanding of the pathophysiology in functional dyspepsia and is also relevant for symptom generation in other disorders. The term gastric accommodation has at least three different meanings: The accommodation process, the accommodation reflex, and the accommodation response. The gastric accommodation process is a complex phenomenon that describes how the size of the gastric compartment changes in response to a meal. The electronic barostat is considered the gold standard in assessing gastric accommodation. Imaging methods, including MRI, SPECT, and ultrasonography may also be used, particularly in patients who are stressresponsive, e.g. functional dyspepsia patients, as a noninvasive and less stress-inducing method is favourable. Ultrasonography satisfies these criteria as it does not by itself distort the physiological response in stressresponsive individuals.     

High Heart Rate as Predictor of Essential Hypertension:: The Hyperkinetic State, Evidence of Prediction of Hypertension, and Hemodynamic Transition to Full Hypertension

Although essential hypertension seems to have a strong hereditary component, the triggering mechanism is unclear. It is likely that the central nervous system via autonomic sympathetic overactivation plays a key role in the development of hypertension. High heart rate has proven to be a strong predictor for cardiovascular disease and a predictor of the development of essential hypertension. Because heart rate is highly influenced by many factors such as anxiety and physical activity, it is sometimes difficult to interpret the value of heart rate measurement in individual persons. Whether heart rate itself is a risk factor for development of hypertension or just a marker for sympathetic overactivation is still a matter of debate, but the presence of elevated heart rate in both hyperkinetic and hypertensive subjects makes it an interesting and easy measurable prognostic marker.     

Thoracic impedance changes measured via defibrillator pads can monitor ventilation in critically ill patients and during cardiopulmonary resuscitation

OBJECTIVE: Monitoring of ventilation performance during cardiopulmonary resuscitation would be desirable to improve the quality of cardiopulmonary resuscitation. To investigate the potential for measuring ventilation rate and inspiration time, we calculated the correlation in waveform between transthoracic impedance measured via defibrillator pads and tidal volume given by a ventilator. DESIGN: Clinical study. SETTING: Emergency department of a tertiary care university hospital. PATIENTS: A convenience sample of mechanical ventilated patients (n = 32), cardiac arrest patients (n = 20), and patients after restoration of spontaneous circulation (n = 31) older than 18 were eligible. INTERVENTIONS: The Heartstart 4000SP defibrillator (Laerdal Medical Cooperation, Stavanger, Norway) with additional capabilities of recording thoracic impedance changes was used. MEASUREMENTS AND MAIN RESULTS: The relationship between impedance change and tidal volume (impedance coefficient) was calculated. The mean (sd) correlations between the impedance waveform and the tidal volume waveform in the patient groups studied were .971 (.027), .969 (.032), and .967 (.035), respectively. The mean (sd) impedance coefficient for all patients in the study was .00194 (.0078) Omega/mL, and the mean (sd) specific (weight-corrected) impedance coefficient was .152 (.048) Omega/kg/mL. The measured thorax impedance change for different tidal volumes (400-1000 mL) was approximately linear. CONCLUSIONS: The impedance sensor of a defibrillator is accurate in identifying tidal volumes, when chest compressions are interrupted. This also allows quantifying ventilation rates and inspiration times. However this technology, at its present state, provides only limited practical means for exact tidal volume estimation.     

Expression mapping of tetracycline-responsive prion protein promoter: digital atlasing for generating cell-specific disease models

We present a digital atlas system that allows mapping of molecular expression patterns at cellular resolution through large series of histological sections. Using this system, we have mapped the distribution of a distinct marker, encoded by the LacZ reporter gene driven by the tetracycline-responsive prion protein promoter in double transgenic mice. The purpose is to evaluate the suitability of this promoter mouse line for targeting genes of interest to specific brain regions, essential for construction of inducible transgenic disease models. Following processing to visualize the promoter expression, sections were counterstained to simultaneously display cytoarchitectonics. High-resolution mosaic images covering entire coronal sections were collected through the mouse brain at intervals of 200 microm. A web-based application provides access to a customized virtual microscopy tool for viewing and navigation within and across the section images. For each section image, the nearest section in a standard atlas is defined, and annotations of key structures and regions inserted. Putative categorization of labeled cells was performed with use of distribution patterns, followed by cell size and shape, as parameters that were compared to legacy data. Among the ensuing results were expression of this promoter in putative glial cells in the cerebellum (and not in Purkinje cells), in putative glial cells in the substantia nigra, in pallidal glial cells or interneurons, and in distinct cell layers and regions of the hippocampus. The study serves as a precursor for a database resource allowing evaluation of the suitability of different promoter mouse lines for generating disease models.     

Pain attacks in non-complicated and complicated gallstone disease have a characteristic pattern and are accompanied by dyspepsia in most patients: the results of a prospective study

OBJECTIVE: The cardinal indication for surgical treatment of gallstones is pain attacks. However, following cholecystectomy, 20% of patients remain symptomatic. It is unclear to what extent post-cholecystectomy symptoms can be ascribed to persistence of preoperative symptoms or to new pathology. The pain and digestive pattern in gallstone patients has not been defined in a recent setting with ultrasonography as the diagnostic method. The aim of this study was to characterize a pain pattern that is typical for gallstone disease and to describe the extent of associated dyspepsia. MATERIAL AND METHODS: A total of 220 patients with symptomatic gallstone disease including complicated disease (acute cholecystitis and common bile duct stones) were interviewed using detailed questionnaires to disclose pain patterns and symptoms of indigestion. RESULTS: All patients had pain in the right upper quadrant (RUQ) including the upper midline epigastrium. The pain was localized to the right subcostal area in 20% and to the upper epigastrium in 14%, and in the rest (66%) it was more evenly distributed. An area of maximal pain could be defined in 90%. Maximal pain was located under the costal arch in 51% of patients and in the epigastrium in 41%, but in 3% behind the sternum and in 5% in the back. The pain was referred to the back in 63% of the patients. The mean visual analogue scale (VAS) score was very high: 90 mm on a 0-100 scale. A pattern of incipient or low-grade warning pain with a subsequent relatively steady state until subsiding in the same fashion was present in 90% of the patients. An urge to walk around was experienced by 71%. Pain attacks usually occurred in the late evening or at night (77%), with 85% of the attacks lasting for more than one hour and almost never less than half an hour. Sixty-six percent of the patients were intolerant to at least one kind of food, but only 48% to fatty foods. Symptoms of functional indigestion (gastroesophageal reflux, dyspepsia or irritable bowel symptoms) were seen in the vast majority in association with attacks. CONCLUSIONS: Gallstone-associated pain follows a certain pattern in the majority of patients. The pain is located in a defined area with a point of maximum intensity, is usually referred, and occurs mainly at night with duration of more than one hour. The majority of patients experience functional indigestion, mainly of the reflux type or dyspepsia.