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Biomedical subjects

R Krapf

Publications and source records attributed to R Krapf.

At least 55 records · Page 3Linked to original sources
PubMed1994

Analysis and pharmacokinetics of glycyrrhizic acid and glycyrrhetinic acid in humans and experimental animals.

Glycyrrhizic acid (GZA) and glycyrrhetinic acid (GRA) can be determined rapidly and precisely by high-performance liquid chromatography (HPLC) in biological fluids and tissues from experimental animals and humans. From plasma and tissues, GZA and GRA are extracted by organic solvents and the extracts can directly be used for HPLC. From bile or urine, extraction and determination of GZA and GRA are more difficult due to interfering endogenous compounds and conjugation of GRA with glucuronides or sulfates. Extraction of GZA and GRA from urine or bile can be performed by ion-pairing followed by extraction with organic solvents or by solid phase extraction. GRA conjugates can be determined by chromatographic separation or by pretreatment with beta-glucuronidase. The pharmacokinetics of GRA and GZA can be described by a biphasic elimination from the central compartment with a dose-dependent second elimination phase. Depending on the dose, the second elimination phase in humans has a half-life of 3.5 hours for GZA and between 10-30 hours for GRA. The major part of both GRA or GZA is eliminated by the bile. While GZA can be eliminated unmetabolized and undergoes enterohepatic cycling, GRA is conjugated to GRA glucuronide or sulfate prior to biliary excretion. Orally administered GZA is almost completely hydrolyzed by intestinal bacteria and reaches the systemic circulation as GRA.

Animals↗
PubMed1994

Azathioprine hypersensitivity mimicking Goodpasture's syndrome.

Side effects due to azathioprine (the nitroimidazole derivative of 6-mercaptopurine) can be classified as toxic (myelosuppression, hepatotoxicity) and idiosyncratic (fever, rigors, arthralgias, pneumonitis, and gastrointestinal symptoms). While the toxic effects are due to 6-mercaptopurine, the hypersensitivity reactions are believed to be caused by the nitroimidazole moiety. A 21-year-old male patient developed end-stage renal failure due to antiglomerular basement membrane (AGBM) disease (rapidly progressive glomerulonephritis with linear immunoglobulin G deposits and positive circulating AGBM antibodies). The patient became dependent on continuous ambulatory peritoneal dialysis and, later, hemodialysis, and received two renal allografts at the ages of 23 and 27 years. He received three courses of azathioprine treatment: one course for AGBM glomerulonephritis and two courses for rejection episodes. Each course was followed within 4 to 7 days by symptoms compatible with Goodpasture's syndrome, ie, high fever, rigors, arthralgias, diarrhea, myalgias, and pulmonary infiltrates with hemoptysis. All signs and symptoms always resolved completely on discontinuation of azathioprine. During the treatment for rejections, AGBM antibodies were not elevated, and during one episode AGBM disease in the lung (Goodpasture's syndrome) was excluded by open lung biopsy. Treatment of a subsequent rejection episode with 6-mercaptopurine was well tolerated. We conclude that azathioprine hypersensitivity can mimic the pulmonary manifestations of Goodpasture's syndrome. Hypersensitivity probably is due to the nitroimidazole moiety of azathioprine. Thus, differential diagnosis of Goodpasture's syndrome (and probably of any "pulmonary renal syndrome") should include azathioprine hypersensitivity.

Adult↗
PubMed1994

Kinetics and dynamics of orally administered 18 beta-glycyrrhetinic acid in humans.

18 beta-Glycyrrhetinic acid (GRA) represents a major metabolite of glycyrrhizic acid (glycyrrhizin), an important constituent of licorice and licorice root, and is a potent inhibitor of 11 beta-hydroxysteroid dehydrogenase (11 beta OHSD). Different oral doses of GRA (500, 1000, or 1500 mg) were administered to healthy volunteers in order to study its kinetics and dynamics. In agreement with the lipophilic nature of GRA, with a biphasic decay of the plasma concentration-time curve at doses greater than 500 mg. The mean (+/-SEM) half-life of the second elimination phase was 11.5 +/- 1.2 h after 1000 mg GRA and 38.7 +/- 10.5 h after 1500 mg GRA (P < 0.05). The peak plasma concentration and the area under the plasma concentration-time curve (AUC) increased with increasing GRA doses. Urinary elimination of GRA and GRA glucuronides over 24 h was less than 1% of the dose administered. The dynamics of GRA were assessed by measuring the activity of the 11 beta OHSD in vivo, as reflected by the cortisol and cortisone concentrations in plasma. With increasing doses of GRA, the cortisone concentration declined, and the cortisol/cortisone ratio increased. Both peak plasma concentration and AUCs of GRA correlated with changes in the AUC values of cortisone. Based on the single dose kinetics, the kinetic/dynamic analysis of the data revealed that after multiple doses of 1.5. g GRA/day, the 11 beta OHSD might be constantly inhibited, whereas at daily doses of 500 mg or less, such an inhibition might occur only transiently.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1994

[Vitamin D: clinical aspects and therapy].

This short review summarizes the metabolism and regulation of vitamin D3 with special emphasis on the regulation of renal 25-hydroxy-vitamin D3 1-alpha-hydroxylase. Vitamin D3 is of documented therapeutic utility in the following entities: Vitamin-D3 deficiency, involutional osteoporosis, glucocorticoid-induced osteoporosis and renal osteodystrophy. A therapeutic benefit of vitamin D3 is not yet established for hematological as well as for other neoplasias and for psoriasis. The introduction of noncalcemic vitamin-D3 analogs may lead to an increased use in these indications and will hopefully improve prevention and treatment of renal osteodystrophy.

Calcitriol↗
PubMed1993

Determination of 18 beta-glycyrrhetinic acid in biological fluids from humans and rats by solid-phase extraction and high-performance liquid chromatography.

Methods have been developed and characterized allowing rapid isolation and quantification of 18 beta-glycyrrhetinic acid (GRA) in biological fluids from both humans and rats. Sample preparation includes extraction with urea-methanol for plasma samples, and solid-phase extraction (SPE) for urine and bile samples. Hydrolysis of GRA glucuronides in urine and bile was performed by treatment with beta-glucuronidase. MGRA, the 3-O-methyl derivative of GRA was synthesized as an internal standard resistant to hydrolysis. High-performance liquid chromatography (HPLC) was performed with an isocratic system using methanol-water-acetic acid (83:16.8:0.2, v/v/v) as solvent on a Lichrocart RP-18 column at 30 degrees C with ultraviolet detection. The methods allowed base line separation of GRA and MGRA from all biological fluids tested, with a detection limit of 0.15 mg/l. Validation of the methods included determination of recovery, accuracy and precision in plasma, bile and urine from humans and rats. The methods were further evaluated by investigating the pharmacokinetics of GRA in normal rats and in rats with a bile fistula. Following an intravenous dose of 10 mg/kg, the plasma concentration-time curve of GRA could be fitted to a one compartment model both in control and bile fistula rats. The elimination half life averaged 15.0 +/- 2.2 versus 16.8 +/- 2.4 min in control and bile fistula rats (difference not significant). Within 90 min following administration of GRA, urinary elimination of GRA and GRA glucuronides was less than 1% in both groups whereas biliary elimination averaged 51.3 +/- 3.1%. The results show that the methods developed allow pharmacokinetic studies of GRA in humans and rats.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Primary structure of two P-type ATPases involved in copper homeostasis in Enterococcus hirae.

We cloned an operon, copAB, from Enterococcus hirae encoding two P-type ATPases of 727 and 745 amino acids, respectively. Both enzymes display heavy metal ion binding motifs in their polar N-terminal region. With an antibody against CopB, we showed on Western blots that expression of the operon is induced by either low or high ambient copper concentrations. Disruption of the copA gene renders the cells dependent, whereas copper disruption of copB results in a copper-sensitive phenotype. CopA exhibits 35% sequence similarity to CopB and 43% similarity to the ATPase encoded by the recently cloned human Mc1 gene, a gene responsible for the Menkes inborn error of copper metabolism. Our results imply that CopA and CopB are heavy metal ion ATPases that regulate the cytoplasmic copper activity, with CopA serving in the uptake and CopB in the extrusion of copper.

Adenosine Triphosphatases↗
PubMed1993

[3 dangerous electrolyte disturbances: hyponatremia, hyperkalemia and hypomagnesemia].

Three cases of acute and potentially dangerous electrolyte disturbances provide a basis for discussion of selected aspects of pathogenesis, clinical manifestation and correction of certain electrolyte disorders (hyponatremia, hyperkalemia, hypomagnesemia). A case of diuretic-induced hyponatremia illustrates the controversy surrounding correction of this disorder. The regulatory mechanisms of transcellular potassium equilibrium are discussed with the help of a case of exercise-induced hyperkalemia. A separate case is dedicated to the discussion of the multiple causes and symptoms of magnesium depletion.

Acute Disease↗
PubMed1993

Determining peritoneal dialysis prescriptions by employing a patient-specific protocol.

OBJECTIVE: To develop a formula that would permit a rapid and simple calculation of required dialysate volume needed to provide a predetermined daily creatinine clearance. DESIGN: Prospective study of peritoneal dialysis patients followed for 6 months. SETTING: A primary care teaching hospital in New York. PATIENTS: Twenty-six patients beginning peritoneal dialysis entered and completed the study. INTERVENTION: By employing each patient's measured peritoneal equilibration test (PET) and a standard clearance formula, a patient-specific treatment protocol (PSP) was calculated. The PET 2-hour D/Pcreat was used for continuous cycling peritoneal dialysis (CCPD) and the 4-hour D/Pcreat was used for patients on continuous ambulatory peritoneal dialysis (CAPD) to determine a PSP that would provide a minimum of 6 L of creatinine clearance daily. MAIN OUTCOME MEASURES: Patients were followed for 6 months to assess the ability of this approach of maintaining acceptable levels of blood urea nitrogen, creatinine, albumin, and hematocrit over the 6-month period of observation. RESULTS: Our study of 26 patients revealed that only 6 patients (23%) could be treated with the standard prescription of 8 L/day on CAPD. The remaining 77% of our patients required 9-13 L/day for CAPD and 12-21 L/day for CCPD. All patients were free of uremic symptoms and demonstrated acceptable biochemical parameters over a 3-6 month period of observation. CONCLUSIONS: A patient-specific protocol utilizing individually derived PET data provides an acceptable and easy to calculate initial treatment prescription for each patient that avoids the necessity for trial and error that has heretofore been employed.

Adult↗
PubMed1992

Chronic respiratory alkalosis induces renal PTH-resistance, hyperphosphatemia and hypocalcemia in humans.

The effects of chronic respiratory alkalosis on divalent ion homeostasis have not been reported in any species. We studied four normal male subjects during a four-day control period (residence at 500 m), during six days of chronic respiratory alkalosis induced by hypobaric hypoxia (residence at 3450 m), followed by a six-day eucapnic recovery period (500 m) under metabolic balance conditions. Chronic respiratory alkalosis (delta PaCO2, -8.4 mm Hg, delta[H+] -3.2 nmol/liter) resulted in a sustained decrement in plasma ionized calcium concentration (delta[IoCa++]p, -0.10 mmol/liter, P less than 0.05) and a sustained increment in plasma phosphate concentration (delta[PO4]p, +0.14 mmol/liter, P less than 0.005) associated with increased fractional excretion of Ca++ (+0.5%, P less than 0.005), decreased phosphate clearance (-6.1 ml/min, P less than 0.025) and decreased excretion of nephrogenous cAMP (-1.5 nmol/100 ml GFR, P less than 0.0025). Urinary phosphate excretion decreased by 15.4 mmol/24 hr on day 1 of chronic respiratory alkalosis (P less than 0.0025), but returned to control values by day 6 despite hyperphosphatemia. Serum intact [PTH] did not change. Sustained hypomagnesuria (-0.8 mmol/24 hr, P less than 0.05) occurred during chronic respiratory alkalosis and was accounted for, at least in part, by decreased fractional excretion of Mg++ (-0.7%, P less than 0.05) in the absence of change in plasma magnesium concentration. Serum 1,25(OH)2D levels were unchanged by chronic respiratory alkalosis. In conclusion, the decrease in nephrogenous cAMP generation despite unchanged serum intact PTH concentration suggests that chronic respiratory alkalosis results in impaired renal responsiveness to PTH as manifested by alterations in PTH-dependent renal calcium and phosphate transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Abuse of germanium associated with fatal lactic acidosis.

Germanium compounds are marketed as nonprescription drugs in Europe and are recommended by the suppliers for AIDS and metastatic cancer disease. We observed a patient with nonmetastatic breast cancer who died because of severe lactic acidosis (plasma lactate concentration = 27 mmol/l) after ingestion of 25 g of elemental germanium over a 2-months period. Renal failure and hepatotoxicity had newly developed during germanium intake. Postmortem examination revealed severe hydropic vacuolation of tubule cells and the presence of inclusion bodies predominantly in straight proximal tubule cells with normal appearance of renal interstitium and glomeruli. The liver showed panlobular steatosis. Urine, blood and tissue (kidney, liver, muscle, pancreas) levels of germanium were high. Lactic acidosis may have been caused by the combined, germanium-induced renal and hepatic failure (underutilization), but it remains to be seen whether germanium can affect lactate production and/or metabolism directly.

Acidosis↗
PubMed1992

Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia.

Chronic metabolic acidosis results in metabolic bone disease, calcium nephrolithiasis, and growth retardation. The pathogenesis of each of these sequelae is poorly understood in humans. We therefore investigated the effects of chronic extrarenal metabolic acidosis on the regulation of 1,25-(OH)2D, parathyroid hormone, calcium, and phosphate metabolism in normal humans. Chronic extrarenal metabolic acidosis was induced by administering two different doses of NH4Cl [2.1 (low dose) and 4.2 (high dose) mmol/kg body wt per d, respectively] to four male volunteers each during metabolic balance conditions. Plasma [HCO3-] decreased by 4.5 +/- 0.4 mmol/liter in the low dose and by 9.1 +/- 0.3 mmol/liter (P < 0.001) in the high dose group. Metabolic acidosis induced renal hypophosphatemia, which strongly correlated with the severity of acidosis (Plasma [PO4] on plasma [HCO3-]; r = 0.721, P < 0.001). Both metabolic clearance and production rates of 1,25-(OH)2D increased in both groups. In the high dose group, the percentage increase in production rate was much greater than the percentage increase in metabolic clearance rate, resulting in a significantly increased serum 1,25-(OH)2D concentration. A strong inverse correlation was observed for serum 1,25-(OH)2D concentration on both plasma [PO4] (r = -0.711, P < 0.001) and plasma [HCO3-] (r = -0.725, P < 0.001). Plasma ionized calcium concentration did not change in either group whereas intact serum parathyroid hormone concentration decreased significantly in the high dose group. In conclusion, metabolic acidosis results in graded increases in serum 1,25-(OH)2D concentration by stimulating its production rate in humans. The increased production rate is explained by acidosis-induced hypophosphatemia/cellular phosphate depletion resulting at least in part from decreased renal tubular phosphate reabsorption. The decreased serum intact parathyroid hormone levels in more severe acidosis may be the consequence of hypophosphatemia and/or increased serum 1,25-(OH)2D concentrations.

Acidosis↗
PubMed1992

Ventilatory support during magnetic resonance imaging.

Ventilatory support during magnetic resonance imaging is difficult because metallic objects on ventilatory support devices can interfere with the imaging field and/or become magnetized and move inside the patient or become flying projectiles. We report the successful MRI examination of an intubated respirator-dependent pediatric patient. Ventilatory support was carried out with a plastic ambu bag, exhalation valve circuit, and tubing.

Equipment Design↗
PubMed1991

[Hypo- and hyperventilation: consequences for acid-base balance].

Deviations of the alveolar ventilation rate from normality induce respiratory acid-base disturbances. Alveolar hyperventilation leads to hypocapnia and thus respiratory alkalosis whereas alveolar hypoventilation induces hypercapnia leading to respiratory acidosis. The changes in CO2 induce compensatory alterations of renal bicarbonate transport: Hypercapnia stimulates renal reabsorption of bicarbonate whereas hypocapnia enhances urinary bicarbonates. The plasma bicarbonate concentration rises in response to hypercapnia and falls following hypocapnia. Renal regulation of plasma bicarbonate results in a characteristic dependence on systemic PCO2 permitting the formation of diagnostic criteria for respiratory imbalance of acid-base homeostasis. In chronic respiratory acidosis plasma bicarbonate should rise by 0.35 mmol/l per mmHg increase in PCO2. In chronic respiratory alkalosis, on the other hand, plasma bicarbonate should fall by 0.4 mmol/l for every mmHg decrease in PCO2. If the measured bicarbonate values do not fall into this expected range, acute respiratory or mixed (respiratory and metabolic) acid-base disturbances should be suspected. The clinical significance and application of these diagnostic criteria are illustrated by examples.

Acid-Base Equilibrium↗