Adherence to continuous positive airway pressure treatment in patients with Alzheimer's disease and obstructive sleep apnea.

OBJECTIVE: This analysis examined whether patients with Alzheimer disease (AD) tolerate continuous positive airway pressure (CPAP). METHOD: Thirty patients with AD were randomized to CPAP or sham CPAP and completed sleep, depression, and quality-of-life questionnaires. Participants could choose to continue treatment after the trial. RESULTS: Patients wore CPAP for 4.8 hours per night. More depressive symptoms were associated with worse adherence (rS=-0.37; N=30, p<0.04). Patients who continued using CPAP had fewer depressive symptoms (t [19]=2.45, p=0.02) and better adherence (t [19]=2.32, p=0.03) during the trial. CONCLUSION: Patients with AD with obstructive sleep apnea can tolerate CPAP. Adherence and long-term use may be more difficult among those patients with more depressive symptoms.     

Reproducibility of angiotensin converting enzyme inhibitor induced cough: A double-blind randomised study

1 The reproducibility of angiotensin converting enzyme inhibitor induced cough was examined in a double-blind cross over study in patients previously shown to have exhibited this side effect.

2 Ninety-seven patients who had experienced angiotensin converting enzyme inhibitor cough within the last 2 years were challenged with enalapril 20 mg daily for 4 weeks to establish eligibility. Eighty-eight of 97 (91%) patients experienced a repeat of their cough symptoms. Sixty-four patients entered the double-blind part of the study where they were treated with enalapril 20 mg and a renin inhibitor for up to 4 weeks in random order. These periods were separated by a minimum 4 week placebo wash out.

3 Of 59 evaluable patients who received enalapril a second time, 37 (62.7%) experienced cough again. Of 62 patients on the renin inhibitor 16 (25.8%) experienced cough, however as it was not equi-efficacious to enalapril no valid comparison could be made.

4 Angiotensin converting enzyme inhibitor cough is not reproducible within patients, as other factors are involved in the aetiology. Objective testing with blinded assessment together with symptom reporting, would give a more accurate measure of the incidence, and mechanism of this side effect.

     

Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans

The calcium channel blocker verapamil [2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] undergoes extensive biotransformation in man. We have previously demonstrated cytochrome P450 (CYP) 3A4 and 1A2 to be the enzymes responsible for verapamil N-dealkylation (formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile]), and verapamil N-demethylation (formation of norverapamil [2,8-bis(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]), while there was no involvement of CYP3A4 and CYP1A2 in the third initial metabolic step of verapamil, which is verapamil O-demethylation. This pathway yields formation of D-703 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] and D-702 [2-(3,4-dimethoxyphenyl)-8-(4-hydroxy-3-methoxyphenyl)6-methyl-2-isopropyl-6-azaoctanitrile]. The enzymes catalyzing verapamil O-demethylation have not been characterized so far. We have therefore identified and characterized the enzymes involved in verapamil O-demethylation in humans by using the following in vitro approaches: (I) characterization of O-demethylation kinetics in the presence of the microsomal fraction of human liver, (II) inhibition of verapamil O-demethylation by specific antibodies and selective inhibitors and (111) investigation of metabolite formation in microsomes obtained from yeast strain Saccharomyces cerevisiae W(R), that was genetically engineered for stable expression of human CYP2C8, 2C9 and 2C18.In human liver microsomes (n=4), the intrinsic clearance (CL_int), as derived from the ratio of V _max/K_m, was significantly higher for O-demethylation to D-703 compared to formation of D-702 following incubation with racemic verapamil (13.9±1.0 vs 2.4±0.6 ml^*min^{-1 *}g^-1 mean±SD; p<0.05), S-Verapamil (16.8±3.3 vs 2.2±1.2 ml^* mini^*g^-1, p<0.05) and R-verapamil (12.1±2.9 vs 3.6 ±1.3 ml^*min^{-1 *} g^-1; p<0.05), thus indicating regioselectivity of verapamil O-demethylation process. The CL_int of D-703 formation in human liver microsomes showed a modest but significant degree of stereo selectivity (p<0.05) with a S/R-ratio of 1.41±0.17. Anti-LKM2 (anti-liver/kidney microsome) autoantibodies (which inhibit CYP2C9 and 2C19) and sulfaphenazole (a specific CYP2C9 inhibitor) reduced the maximum rate of formation of D-703 by 81.5±4.5% and 45%, that of D-702 by 52.7±7.5% and 72.5%, respectively. Both D-703 and D-702 were formed by stably expressed CYP2C9 and CYP2C18, whereas incubation with CYP2C8 selectively yielded D-703.In conclusion, our results show that enzymes of the CYP2C subfamily are mainly involved in verapamil O-demethylation. Verapamil therefore has the potential to interact with other drugs which inhibit or induce these enzymes.     

Prospective assessment of biofeedback for the treatment of paradoxical puborectalis contraction

Eighteen patients with chronic constipation were diagnosed as having paradoxical puborectalis contraction (PPC) as the cause for their constipation. The diagnosis of PPC was made after office evaluation, colonic transit study, manometry, cinedefecography, and electromyography (EMG). These 18 patients had a mean duration of symptoms of 26.9 years; none of these patients had unassisted bowel movements. Fourteen patients had a mean of 4.6 laxative-induced bowel evacuations per week, and 11 patients had a mean of 4.4 enema-induced bowel evacuations per week. Patients underwent a mean of 8.9 one-hour EMG-based biofeedback sessions. At a mean follow-up of 9.1 (range, 0.5–12) months, these 18 patients had a mean of 7.3 unassisted bowel actions per week ( P <0.0001). In addition, persistent laxative use was reported by only two patients, and, in both cases, this was once a week or less ( P <0.001). Similarly, enema use was reported by only three patients, one once weekly and the other two thrice weekly ( P <0.002). No biofeedback-related complications were identified. EMG-based biofeedback is a valuable technique associated with an 89 percent success rate in the treatment of PPC.Read at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, May 12 to 17, 1991.     

Reversibility of calcitriol-induced medial artery calcification in rats with intact renal function.

VC is an important clinical entity; however, very little information is available on its resolution. Induction and regression of calcitriol-induced VC was studied in 47 rats. After calcitriol withdrawal, there was a relatively rapid regression of VC mediated by an active cellular process. INTRODUCTION: Vascular calcifications (VCs) represent an important risk factor for cardiovascular death. Although VCs are prevalent in relevant diseases (e.g., chronic kidney disease, osteoporosis, diabetes), the reversibility of extraskeletal calcifications is an unresolved issue. This study was conducted to investigate (1) the in vivo effect of calcitriol on VC and (2) whether calcitriol-induced VC would regress after suppression of calcitriol treatment. MATERIALS AND METHODS: The calcifying effect of calcitriol was studied in four groups of rats (n = 8) that received calcitriol (1 mug/kg, IP) for 2, 4, 6, and 8 days. The reversibility of VC was studied in three additional groups (n = 5) treated with 1 mug/kg of calcitriol for 8 days that were subsequently killed 1, 2, and 9 weeks after the last calcitriol dose. Aortic VC was assessed by histology and by quantification of aortic calcium and phosphorus content. The aortic wall was studied by histology and immunohistochemistry. Statistical analysis was performed by ANOVA and t-tests. RESULTS: Calcitriol administration resulted in a time-dependent induction of VC, with aortic calcium and phosphorus being significantly increased at 6 and 8 days. Treatment with calcitriol for 8 days resulted in massive medial calcification of the aorta with a 10- to 30-fold increase in the aortic Ca and P content. After suppressing calcitriol administration, a progressive decrease in von Kossa staining and aortic Ca (from 32.8 +/- 2.5 to 9.3 +/- 1.8 mg/g of tissue, p < 0.001) and P (from 11.9 +/- 1.2 to 2.7 +/- 1.8 mg/g of tissue, p = 0.001) content was evidenced. Histology of the aortic wall showed monocytes adhered to the aortic endothelium and macrophages involved in the reabsorption of calcium deposits. CONCLUSIONS: Our results show that calcitriol treatment induces time-dependent VC. After calcitriol withdrawal, VC regress rapidly with aortic calcium and phosphorus decreasing by 75% in the course of 9 weeks. An active cellular process seems to be involved in regression of VC.     

Arteriovenous hemangioma: a clinicopathological and immunohistochemical study

The clinicopathological and immunohistochemical properties of 6 examples of arteriovenous hemangioma, including 2 intraoral lesions, were reviewed. This distinct benign, acquired vascular lesion, infrequently encountered in the literature, is characterized by multiple thick- and thin-walled vascular spaces resembling arteries and veins, respectively. In our study, we performed elastic stains that revealed a prominent venular component, whereas the arterial aspect was inconspicuous to absent. Our aim was also lo elucidate the possible histogenesis of this lesion. Previous reports suggest as pathogenetic mechanisms hamartomatous proliferation either of the subpapillaiy vascular plexus or of the Suquet-Hoyer canal of the true glomus. Our immunohistochemical studies failed to identify typical glooms cells. In addition, we investigated the mast cell count in all lesions and it was found increased. These findings, as well as recent evidence directly implicating mast cells in angiogenesis, can support the theory of hamartomatous proliferation of the subpapillary plexus. One should also not exclude the possibility of a reactive process resulting in the characteristic features of arteriovenous hemangioma.     

Fixation of cementless acetabular cups: A radiographic 4-8-year study of 102 porous-coated components

We studied fixation changes over time in 113 porous-coated Howmedica (PCA) cementless acetabular cups inserted in 90 patients 1984-1988. The mean follow-up was 5 years. Radiographic fixation was classified as stable, fibrous-stable, or unstable. 9 cups, 3 in neutral position and 6 vertical, were revised. At follow-up, 40/75 neutral cups were stable versus 7/27 vertical cups. Most stable cups and two thirds of the unstable cups were clinically good. After the first 2 years, 28/75 neutral cups and 10/27 vertical cups changed their fixation: 12 had improved fixation and 26 had a worse one.