Reduced Serum Theophylline Concentrations after Discontinuation of Azithromycin: Evidence for an Unusual Interaction

A 68-year-old man receiving long-term therapy with oral sustained-release theophylline 450 mg twice/day was admitted to the hospital after failing treatment with azithromycin for an acute exacerbation of obstructive lung disease. Peak serum theophylline concentration was 20 μg/ml (normal 10–20 μg/ml). Azithromycin was discontinued and the theophylline dosage reduced by 33%. The subsequent 80% decrease in serum theophylline to 4.6 μg/ml was unexpectedly large. Two rechallenges produced similar transient depressions of serum theophylline concentrations after withdrawal of azithromycin, suggesting an interaction. Withdrawal of azithromycin may leave an increased number of active enzyme sites available as the drug is cleared from the system. In some circumstances, it may be useful for pharmacokinetic interaction studies to continue measuring concentrations after the suspected interacting agent is stopped.     

Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson's disease (PD). Opposite changes in mood, such as mania or depression, have been reported after surgery, but it is not known whether these side effects are specifically related to STN DBS. To learn whether STN DBS also influences the limbic loop, we investigated acute subjective psychotropic effects related to levodopa or bilateral STN DBS. After a median postoperative follow-up of 12 months, 50 PD patients completed the Addiction Research Center Inventory (ARCI), assessing subjective psychotropic effects in four conditions: off-drug/on-stimulation; off-drug/off-stimulation; on-drug/off-stimulation; and on-drug/on-stimulation. Both levodopa and STN DBS improved all the ARCI subscales, indicating subjective feelings of well being, euphoria, increase in motivation, and decrease in fatigue, anxiety, and tension. A suprathreshold dose of levodopa was significantly more effective than STN DBS, using the same electrical parameters as for chronic stimulation, on four of the five ARCI subscales. We concluded that 1) both STN DBS and levodopa have synergistic acute beneficial psychotropic effects in PD, 2) the psychotropic effects of both treatments need to be considered in the long-term management of chronic STN DBS, and 3) the results indicate an involvement of the limbic STN in mood disorders of PD.     

Racial differences in the incidence of end-stage renal disease in types I and II diabetes mellitus

An increased risk of end-stage renal disease (ESRD) among blacks has been previously shown for most causes of chronic renal failure, including diabetes. Most previous studies have not considered the higher prevalence of diabetes in the black population and have not analyzed relative risk by type of diabetes. We found that the incidence of ESRD among blacks with diabetes was 3.6 times the rate in whites with diabetes. The relative risk for blacks increases progressively with age, reaching a maximum of 6.9 in persons over the age of 65. The incidence of ESRD due to diabetes is higher in the population with type I diabetes (492 per 100,000) than in the population with type II diabetes (71 per 100,000). Blacks have a higher incidence of ESRD in both type I diabetes (odds ratio, 2.96; 95% confidence interval, 1.8 to 4.9) and type II diabetes (odds ratio, 4.9; 95% confidence interval, 3.6 to 6.5). The incidence of ESRD in patients with diabetes varies with age, race, and type of diabetes.     

Pyrosequencing for detection of mutations in the connexin 26 (GJB2) and mitochondrial 12S RNA (MTRNR1) genes associated with hereditary hearing loss

Hereditary hearing loss (HHL) is one of the most common congenital disorders and is highly heterogeneous. Mutations in the connexin 26 (CX26) gene (GJB2) account for about 20% of all cases of childhood deafness, and approach 50% in documented recessive cases of non-syndromic hearing loss. In addition, a single mitochondrial DNA mutation, mt1555A>G, in the 12S rRNA gene (MTRNR1), is associated with familial cases of progressive deafness. Effective screening of populations for HHL necessitates rapid assessment of several of these potential mutation sites. Pyrosequencing links a DNA synthesis protocol for determining sequence to an enzyme cascade that generates light whenever pyrophosphate is released during primer strand elongation. We assessed the ability of Pyrosequencing to detect common mutations causing HHL. Detection of the most common CX26 mutations in individuals of Caucasian (35delG), Ashkenazi (167delT), and Asian (235delC, V37I) descent was confirmed by Pyrosequencing. A total of 41 different mutations in the CX26 gene and the mitochondrial mt1555A>G mutation were confirmed. Genotyping of up to six different adjacent mutations was achieved, including simultaneous detection of 35delG and 167delT. Accurate and reproducible results were achieved taking advantage of assay flexibility and experimental conditions easily optimized for a high degree of standardization and cost-effectiveness. The standardized sample preparation steps, including target amplification by PCR and preparation of single-stranded template combined with automated sequence reaction and automated genotype scoring, positions this approach as a potentially high throughput platform for SNP/mutation genotyping in a clinical laboratory setting. .     

Lymphocytotoxins in epileptic patients receiving phenytoin.

The present study was undertaken to determine the prevalence and nature of lymphocytotoxic antibodies in patients receiving phenytoin. Of forty-six sera examined, lymphocytotoxins and antinuclear antibodies were detected in fourteen and eleven samples respectively. Antibodies to double-stranded RNA (poly-A-poly-U) were found in six out of thirty-eight sera studied. A highly significant correlation was found between the presence of lymphocytotoxins and antinuclear antibodies (chi2 = 9.72; P less than 0.01). Lymphocytotoxins were found to be of the IgM class, to have activity against T and B cells, and to be dependent on the presence of Ca and Mg ions for activity. These findings may have pathogenetic importance in the genesis of the altered immune state of patients reveiving phenytoin.     

Antibodies to β2 microglobulin in the sera of patients with systemic lupus erythematosus

The present study reports the detection of antibodies to β₂ microglobulin in the sera of patients with systemic lupus erythematosus (SLE). Using a Farr-type ammonium sulphate precipitation assay, test sera were reacted with ¹²⁵Iβ₂ microglobulin, and immunoglobulins precipitated by 50% saturated ammonium sulphate. Increased β₂ microglobulin binding activity (normal values: mean±2 sd = 35.5 ±7.8) was detected in 18 of 42 SLE sera. Anti-HLA sera did not reveal increased binding activity, suggesting that the antibody in SLE serum was directed toward free β₂ microglobulin. Direct validation was done by reacting ¹²⁵Iβ₂ microglobulin with 4 SLE sera having increased ¹²⁵Iβ₂ microglobulin binding activity, and subjecting the reactants to sucrose density gradient ultracentrifugation. Two peaks were obtained, one corresponding to free β₂ microglobulin, and the other to 7S material complexed to β₂ microglobulin. Normal sera demonstrated only one peak corresponding to unbound β₂ microglobulin. Assays of β₂ microglobulin binding activity on protein fractions obtained by Sephadex G200 column chromatography also showed the presence of increased binding activity with 7S fractions. Using a double antibody assay, the 7S material reactive to β₂ microglobulin was demonstrated to be IgG. It was also shown that sera with abnormal β₂ microglobulin binding activity had higher titres of antinuclear antibody compared to those lacking such activity (t = 3.18; P<0.01), indicating the pathogenetic relationship of this antibody to increased disease activity. This antibody may be responsible for some of the abnormalities of cell-mediated function previously described in SLE patients.