Influence of Serum Protein Binding on the Pharmacokinetics of Quinidine in Normal and Anuric Rats

Abstract The pharmacokinetics of quinidine were investigated in normal and anuric rats after intravenous injection (25 mg per kg b. wt.). In normal rats only 2.6 percent of the injected dose was excreted as unchanged quinidine in the urine. Quinidine concentrations were determined in the blood and in different tissues after injection, and the serum protein binding was measured. Results were applied to a one compartment model. In normal rats a total body clearance of 18.5 ml/min. and a renal clearance of 0.5 ml/min. was found. The residual non-renal clearance (18.0 ml/min.), presumably taking place in the liver, exceeds the estimated liver blood flow (16.8 ml/min.), indicating efficient extraction of quinidine from plasma and blood cells (non-restrictive elimination). The apparent volume of distribution was greatly reduced, biological half-life slightly longer and the body clearance greatly reduced in anuric as compared to normal rats. The fraction of unbound quinidine in serum was 30.6 ± 0.6 (n=23) and 16.7 ± 0.5) (n=23) percent in normal and anuric rats. The reduction in the apparent volume of distribution is mainly explained by increased serum binding. The decline of body clearance of quinidine is most likely caused by a decreased liver blood flow in this complex state of renal insufficiency.     

The Inhibition of the Mitochondrial NADH Oxidase by Alprenolol and the Protective Effect of Cytochrome P-450

Abstract: The presence of the β-receptor blocking drug alprenolol at a low concentration was found to inhibit markedly the uptake of oxygen catalyzed by liver or heart mitochondria in the presence of β-hydroxybutyrate but not in the presence of succinate. The same was true for the endogenous oxygen uptake by heart slices but not by liver slices or isolated liver cells. In the latter two systems, the rate of oxygen uptake was inhibited only at considerably higher concentrations of the drug. However, in the presence of SKF 525-A — which prevents the binding of alprenolol to cytochrome P-450 — liver slices and isolated liver cells were as sensitive as isolated mitochondria to the inhibitory effect on oxygen uptake by alprenolol. Furthermore, liver homogenates or combinations of the liver mitochondrial and microsomal fractions, in the presence or absence of NADPH, exhibited almost the same sensitivity towards the inhibitory effect of alprenolol on oxygen consumption as the mitochondrial fraction. Thus, the results indicate that alprenolol is a rather potent inhibitor of NADH-linked mitochondrial oxidations, its site of action being localized between NADH and ubiquinone. In the intact liver cell, however, the mitochondria seem to be largely protected from this toxic effect by trapping of the drug by cytochrome P-450. This may in turn be of importance for decreasing the hepatic toxicity of the high concentrations of alprenolol resulting from the efficient liver extraction after oral administration of this drug.     

Intention to test for prostate cancer

The aim of this study was to assess intention among men to take a prostate-specific antigen (PSA) test, when this test was: (i) offered by a doctor or (ii) based on the men's own initiative. A further aim was to use the Theory of Planned Behaviour (TPB) to predict the most important determinants for taking a PSA test. In addition, the intention to take a PSA test among men who had the opportunity to read a PSA leaflet published by the Swedish Cancer Society was compared with men who had not read the leaflet. A total of 1000 men, age range 40-70 years, were selected randomly from a population database. The TPB model was used to measure attitudes about PSA testing. The constructed questionnaire was posted to the selected sample. Half of the sample received only the TPB questionnaire and the other half also received a PSA leaflet. The response rate was approximately 63%. The results showed that men would be less likely to request a PSA test if their doctor did not suggest the test (mean approximately 3.8 (range 1-7 from not likely to very likely)). However, if they were offered the test, most would take it (mean approximately 6.0 (range 1-7)). The positive "Attitude factor" towards the test was the most salient predictor of both behaviours. In addition, the probability of requesting a test was higher among those who had already taken a PSA test. The men who did not receive the PSA leaflet reported a higher intention to take the test than those who had received it. Overall, 47% of the variance was explained concerning men's intention to take a PSA test when offered by a doctor and 25% of men's intention to request the PSA test themselves. In conclusion, the majority of men in this study had a positive attitude towards PSA testing. The results indicate that most men could be expected to accept screening. The intention to take the PSA test was lower among the men who had received the PSA leaflet.     

Therapeutic efficacy by recombinant human granulocyte/monocyte-colony stimulating factor on mucositis occurring in patients with oral and oropharynx tumors treated with curative radiotherapy

BACKGROUND: Previous studies suggested granulocyte-macrophage-colony stimulating factor (GM-CSF) might be beneficial for radiotherapy-induced mucositis. This trial examined the efficacy of GM-CSF in reducing mucositis of the oral cavity and/or oropharynx compared with conventional treatment. METHODS: Mucositis, documented by a five-grade scale, was defined in patients with tumors of the head-neck. Centers were allowed to use their own preferred fractionation regimen. Randomization to treatment was decided before radiotherapy. Treatment with GM-CSF 4 microg/kg/d subcutaneous, started when patients displayed a mucositis score > or = 1.5. RESULTS: Ninety-two patients entered the study according to intention-to-treat principle. Twenty did not reach a mucositis index of 1.5. Sixty-one patients were included in the statistical analysis. Forty-five percent of the patients randomized to receive GM-CSF had a significant reduction of the mucositis more than one grade compared to 9% of the conventional treated. CONCLUSIONS: In severe mucositis, GM-CSF is more effective than conventional treatment.     

A novel molecule (frakefamide) with peripheral opioid properties: the effects on resting ventilation compared with morphine and placebo

In animal models frakefamide (FF) is a potent analgesic that acts as a peripheral active mu-selective receptor agonist. In this double-blind, randomized, double dummy four-way crossover study in 12 healthy male subjects, we investigated the effects on resting ventilation of FF and 2 dose levels of morphine compared with placebo. Each drug was infused for 6 h. The subjects received 1.22 mg/kg FF, 0.43 mg/kg morphine (M-large), and 0.11 mg/kg morphine (M-small). Sodium chloride 9 mg/mL was used as placebo. Ventilation was measured by pneumotachography and inline capnography. Blood was collected and plasma concentrations of FF and morphine and its metabolites were analyzed. Within 15 min after administration of FF all subjects complained of a transient myalgia, which disappeared within 30 min. At target measurement (335 min), there were no differences in tidal volume among the groups. Respiratory rates were, however, slower in the two M-groups (P < 0.05 in M-small and P < 0.001 in M-large) compared with FF and placebo. Minute volume was significantly less in the M-large group compared with the FF (P < 0.01) and placebo (P < 0.01) groups. This difference was reflected by an elevated ETco(2) in the M-large group (P < 0.01). We conclude that, during resting ventilation, FF, unlike morphine, did not cause central respiratory depression. This suggests that FF has only peripheral mu-opioid agonist activity in humans.     

Tumours of the ureter and renal pelvis treated with resection and renal autotransplantation: a study with up to 20 years of follow-up

OBJECTIVE: To report long-term follow-up data from patients treated with resection of urothelial neoplasms of the upper urinary tract combined with autotransplantation of the kidney. PATIENTS AND METHODS: In a clinical and histopathological review of 23 patients who had 25 autotransplantations, they were followed for 7-20 years or until death. Nine patients had either a solitary kidney or bilateral renal pelvic tumours (group A) and 14 had a normal contralateral kidney (group B). RESULTS: Seven operations were unsuccessful, ending in nephrectomy. Of the nine patients in group A two with high-grade renal pelvic tumours survived with no dialysis and recurrences for 127 and 238 months, respectively. Three patients required haemodialysis 0-3 times weekly for 27, 85 and 108 months, respectively. Three patients with low-grade disease developed invasive recurrences in the autotransplanted kidney after 16, 27 and 90 months, respectively, and later died from the disease. One patient died in an accident after 14 months. Of the 14 patients in group B, one developed a deeply invasive recurrence in the autotransplanted kidney after 86 months, despite frequent controls. CONCLUSIONS: In patients with a normal contralateral kidney resection and renal autotransplantation is not indicated and might even be harmful, compared to standard nephroureterectomy. The operation might be beneficial in patients with solitary kidneys but other treatments should first be considered, including open or endoscopic resection, and nephroureterectomy and haemodialysis.     

Imbalanced chordal force distribution causes acute ischemic mitral regurgitation: mechanistic insights from chordae tendineae force measurements in pigs

BACKGROUND: Ischemic mitral regurgitation is caused by an imbalance of the entire mitral-ventricular complex. This interaction is mediated through the chordae tendineae force distribution, which may perturb several elements of the mitral valve apparatus. Our objective was to investigate the association between the mitral valvular 3-dimensional geometric perturbations and chordae tendineae force redistribution in a porcine model of acute ischemic mitral regurgitation. METHODS: In 9 pigs, acute ischemic mitral regurgitation was induced by repeated microembolization of the left circumflex coronary artery. Mitral leaflet coaptation geometry was determined by 2-dimensional echocardiography and reconstructed 3-dimensionally. Leading edge chordal forces were measured by dedicated miniature force transducers at control and during ischemic mitral regurgitation. RESULTS: During acute ischemic mitral regurgitation, there was a decreased tension of the primary chorda from the ischemic posterior left ventricular wall to the anterior leaflet (0.295 +/- 0.063 N vs 0.336 +/- 0.071 N [control]; P < .05). The tension of the chorda from the nonischemic anterior left ventricular wall to the anterior leaflet increased (0.375 +/- 0.066 N vs 0.333 +/- 0.071 N [control]; P < .05). In accordance, relative leaflet prolapse was observed at the ischemic commissural side, whereas there was an increase in the leaflet surface area at the nonischemic commissural side, indicating localized leaflet tethering. CONCLUSIONS: Acute ischemic mitral regurgitation due to posterior left ventricular wall ischemia was associated with focal chordal and leaflet tethering at the nonischemic commissural portion of the mitral valve and a paradoxical decrease of the chordal forces and relative prolapse at the ischemic site of the anterior mitral valve leaflet.     

Intravesical bacillus Calmette-Guèrin therapy: experience with a reduced dwell-time in patients with pronounced side-effects

OBJECTIVE: To report the side-effects after a reduction in the dwell-time in patients who had pronounced symptoms after intravesical bacillus Calmette-Guèrin (BCG) treatment, as side-effects such as fever, haematuria, and frequency are common and sometimes severe after BCG treatment in patients with bladder cancer. PATIENTS AND METHODS: The dwell-time was reduced to < or = 30 min in 51 patients who had pronounced side-effects after the preceding BCG instillation. All patients self-reported side-effects after each instillation in a questionnaire. RESULTS: After reducing the BCG dwell-time, fever, chills, dysuria and the overall time-to-recovery were significantly reduced but frequency and haematuria were not influenced. Patients with carcinoma in situ had significantly less dysuria than patients with papillary tumours. There was no difference in the treatment results between patients who had a normal dwell-time and a reduced dwell-time, determined at the first and second follow-up cystoscopy. CONCLUSION: Reducing the BCG dwell-time to < or = 30 min could be an alternative to a dose reduction in patients who experience pronounced side-effects after BCG instillations. The long-term outcome after reducing dwell-time and after dose reduction has not been studied and warrants further investigation.     

Glucose stimulates glucagon release in single rat alpha-cells by mechanisms that mirror the stimulus-secretion coupling in beta-cells

In isolated rat pancreatic alpha-cells, glucose, arginine, and the sulfonylurea tolbutamide stimulated glucagon release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P<0.05; n=5) and doubled the free cytoplasmic Ca2+ concentration. In cell-attached recordings, azide opened KATP channels. The N-type Ca2+-channel blocker omega-conotoxin and the Na+-channel blocker tetrodotoxin inhibited glucose-induced glucagon release whereas tetraethylammonium, a blocker of delayed rectifying K+ channels, increased secretion. Glucagon release increased monotonically with increasing K+ concentrations. omega-Conotoxin suppressed glucagon release to 15 mM K+, whereas a combination of omega-conotoxin and an L-type Ca2+-channel inhibitor was required to abrogate secretion in 50 mM K+. Recordings of cell capacitance revealed that glucose increased the exocytotic response evoked by membrane depolarization 3-fold. This correlated with a doubling of glucagon secretion by glucose in intact rat islets exposed to diazoxide and high K+. In whole-cell experiments, exocytosis was stimulated by reducing the cytoplasmic ADP concentration, whereas changes of the ATP concentration in the physiological range had little effect. We conclude that glucose stimulates glucagon release from isolated rat alpha-cells by KATP-channel closure and stimulation of Ca2+ influx through N-type Ca2+ channels. Glucose also stimulated exocytosis by an amplifying mechanism, probably involving changes in adenine nucleotides. The stimulatory action of glucose in isolated alpha-cells contrasts with the suppressive effect of the sugar in intact islets and highlights the primary importance of islet paracrine signaling in the regulation of glucagon release.