The effect on paracetamol absorption of stimulation and blockade of beta-adrenoceptors.

1 The effect of drugs acting on beta-adrenoceptors on the absorption and excretion of paracetamol was studied in 26 volunteers and nine patients with mild hypertension, each subject acting as his/her own control. 2 Isoprenaline given 30 min before paracetamol significantly slowed absorption, the effect being dose related, and blocked by prior administration of propranolol. 3 When isoprenaline was given immediately before the paracetamol, absorption was not altered, although a cardiovascular response was seen. 4 Oral salbutamol also delayed paracetamol absorption. 5 Propranolol given alone increased the rate of paracetamol absorption. 6 These results with the changes in the rate of gastric emptying produced by these agents.     

Emphysema in the renal allograft

Two diabetic patients in whom emphysematous pyelonephritis developed after renal transplantation are described. Clinical recognition of this unusual and serious infection is masked by the effects of immunosuppression. Abdominal radiographic, ultrasound, and computed tomography findings are discussed. The clinical presentation includes urinary tract infection, sepsis, and acute tubular malfunction of the allograft in insulin-dependent diabetics.     

Measuring Outcome in Psychogenic Nonepileptic Seizures: How Relevant Is Seizure Remission?

PURPOSE: To examine whether seizure remission is a comprehensive marker of outcome in psychogenic nonepileptic seizures (PNESs). METHODS: A postal questionnaire was returned by 147 patients with PNESs a mean of 4.2 years after diagnosis (mean age at follow-up, 38.1 years). The proportion of patients who were "unproductive" (receiving health-related state benefits) at follow-up was determined, with a comparison of markers of ongoing psychopathology (Global Severity Index, anxiety and depression scores of the Symptom Checklist 90, Somatization Index DSM of the SOMS-2) in three outcome groups: group 1, continuing seizures; group 2, seizures stopped but patients "unproductive;" and group 3, seizures stopped, patients "productive." RESULTS: Of the patients, 71.4% continued to have seizures, and 28.6% had achieved seizure remission; 60.0% of patients with continuing seizures and 42.7% of patients in remission were "unproductive" (difference, NS). Ongoing psychopathology was related to the factor "group membership" with higher values in groups 2 and 3 than in group 1 (GSI, p < 0.001; anxiety, p = 0.01; depression, p = 0.02; Somatization Index DSM, p < 0.001). Across all patients and in the subgroup with PNESs and additional epilepsy, differences were significant only between groups 2 and 3, not between groups 1 and 2. In patients with PNESs alone, differences were significant only between groups 1 and 2. CONCLUSIONS: Seizure remission is not a comprehensive measure of good medical or psychosocial outcome in PNESs. Nearly half the patients who become seizure free remain unproductive. Many of these patients continue to report symptoms of psychopathology. Seizure control should not be the only focus of treatment in clinical practice or outcome observation in research studies.     

Extracranial internal carotid artery aneurysm presenting as symptomatic hypoglossal and glossopharyngeal nerve paralysis

Aneurysms of the extracranial portion of the internal carotid artery are rare, particularly in young patients. They usually develop following trauma, or secondary to infection involving the parapharyngeal space that extends to the vessel wall. This is a case of an internal carotid artery aneurysm presenting acutely following chiropractic neck manipulation with hypoglossal and glossopharyngeal nerve palsy. The imaging findings and subsequent operative management are described.     

SU11752 inhibits the DNA-dependent protein kinase and DNA double-strand break repair resulting in ionizing radiation sensitization

Loss of the DNA-dependent protein kinase (DNA-PK) results in increased sensitivity to ionizing radiation due to inefficient repair of DNA double-strand breaks. Overexpression of DNA-PK in tumor cells conversely results in resistance to ionizing radiation. It is therefore possible that inhibition of DNA-PK will enhance the preferential killing of tumor cells by radiotherapy. Available inhibitors of DNA-PK, like wortmannin, are cytotoxic and stop the cell cycle because they inhibit phoshatidylinositol-3-kinases at 100-fold lower concentrations required to inhibit DNA-PK. In an effort to develop a specific DNA-PK inhibitor, we have characterized SU11752, from a three-substituted indolin-2-ones library. SU11752 and wortmannin were equally potent inhibitors of DNA-PK. In contrast, inhibition of the phoshatidylinositol-3-kinase p110gamma required 500-fold higher concentration of SU11752. Thus, SU11752 was a more selective inhibitor of DNA-PK than wortmannin. Inhibition kinetics and a direct assay for ATP binding showed that SU11752 inhibited DNA-PK by competing with ATP. SU11752 inhibited DNA double-strand break repair in cells and gave rise to a five-fold sensitization to ionizing radiation. At concentrations of SU11752 that inhibited DNA repair, cell cycle progression was still normal and ATM kinase activity was not inhibited. We conclude that SU11752 defines a new class of drugs that may serve as a starting point for the development of specific DNA-PK inhibitors.     

The development of an oral antidiabetic combination tablet: design,evaluation and clinical benefits for patients with type 2 diabetes

Type 2 diabetes is a chronic and progressive disease. Oral antidiabetic monotherapies directly address only one defect as their primary mechanism of action, and do not control blood glucose sufficiently well to meet current glycaemic targets. In consequence, most patients need combination therapy within a few years. However, the co-administration of two or more oral antidiabetic drugs may render treatment regimens difficult to follow. Combining oral antidiabetic agents into a single tablet provides a means of intensifying antidiabetic therapy while supporting good patient compliance. An insulin sensitiser and an insulin secretagogue represent a rational oral antidiabetic combination, as they address the dual endocrine defects of insulin resistance and impaired beta-cell function in type 2 diabetes. Nevertheless, the components of a combination tablet must be carefully chosen. Metformin (an insulin sensitiser) and glibenclamide (an insulin secretagogue) are well supported by decades of clinical evidence, and the pharmacokinetics of these agents support twice-daily co-administration. The final technical challenge is to optimise their delivery within a single-tablet combination. A recently-introduced metformin-glibenclamide combination tablet (Glucovance) has been extensively studied in well-designed clinical trials, where it has been shown to be more effective than its component monotherapies in controlling fasting and postprandial glycaemia. This treatment provides a case study in the development of a single-tablet oral antidiabetic combination, in terms of the pharmacokinetic issues facing the development of this preparation, and the implications of the pharmacokinetic properties of the components of the combination tablet on their pharmacodynamic actions and risk-benefit profile.