Potent inhibition of cytochrome P450IID6 (debrisoquin 4-hydroxylase) by flecainide in vitro and in vivo.

Flecainide acetate, a class Ic antiarrhythmic agent, is eliminated to a larger extent by renal excretion and to a minor extent by the liver. In patients with impaired renal function or with elevated urinary pH, however, its elimination is dominated by hepatic metabolism. Recent evidence suggests that the in vivo metabolism of flecainide is controlled by the genetic polymorphism of the debrisoquin/sparteine type; i.e., it is a substrate of cytochrome P450IID6. We investigated the inhibitory effect of flecainide on bufuralol 1'-hydroxylation in human liver microsomes in vitro and on the metabolic dextromethorphan urinary ratio in eight healthy male volunteers. Both bufuralol and dextromethorphan are well-known substrates of cytochrome P450IID6. Microsomal bufuralol 1-hydroxylation was competitively inhibited by flecainide with an apparent Ki of 0.954 mumol/L. Moreover, a statistically significant increase in the urinary metabolic ratio (MR) of dextromethorphan/dextrorphan after 1 week of administration of oral flecainide was observed (p = 0.013) in all subjects. One individual increased the urinary MR to a value consistent with the poor metabolizer phenotype. We conclude that flecainide is a potent inhibitor of cytochrome P450IID6 in vitro and in vivo and that careful drug monitoring is required with respect to renal function, debrisoquine phenotype, and concomitant drug administration.     

Influence of different pressure gradients on late clinical outcome after aortic valve replacement.

Late outcome vs. hemodynamic parameters were assessed and compared in a series of 44 patients followed for 10-17 years after aortic valve replacement either with a Starr-Edwards A 1260 (SE) or a Bjork-Shiley 60 degrees (BS) prosthesis. The two groups, 22 patients each, were selected by computer from the data base SG as to be matched for age, sex, underlying lesion, date of implantation, valve size, left ventricular function, and concomitant coronary artery disease. There was no significant difference in mortality and complication rates. Clinical evaluation at a mean of 12.5 +/- 2.2 years postoperatively revealed identical findings of heart size on chest X-rays (CTR 0.50 +/- 0.04 SE vs. 0.50 +/- 0.05 BS) and nearly identical incidence of left ventricular hypertrophy on the ECG (2/22 SE and 1/22 BS). There was a statistically significant difference in Doppler ultrasonic peak pressure gradients between the two valve types (SE 32 +/- 15 mmHg, BS 23 +/- 9 mmHg; p = 0.047), and of fractional shortening on M-mode echocardiograms (SE 30 +/- 9%, BS 37 +/- 8%, p = 0.038), but this was not reflected by a difference in the symptomatic status of the two groups. It is concluded, that in two groups of patients surviving 10-17 years after isolated aortic valve replacement with SE or BS valves, the statistically significant nine mmHg difference in gradient across the two valve types had no effect on long-term clinical outcome.     

The results of combined cataract extraction and trabeculectomy using separate incisions

A method of combined cataract extraction with posterior chamber intraocular lens and trabeculectomy using separate incisions was tested in 44 operations on 38 patients. The mean preoperative intraocular pressure (IOP) of 28.1 ± 11.7 (range 12 to 56) mmHg on maximum medication was lowered to 13.9 ± 3.4 (9 to 23) mmHg at one year, with half the eyes still requiring topical medication. The IOP was 40 mmHg or more preoperatively in eight eyes and 20 mmHg or more in only two patients at one year. There were no rises in IOP above 20 mmHg in the early postoperative period (days 1 and 2). Visual acuity was 6/9 or better in 27 and 6/12 in three eyes. There was an expulsive haemorrhage in one case, rupture of the posterior capsule in two eyes and a choroidal detachment in one eye, but no flat anterior chambers. The two-incision method allowed placement of an intraocular lens with good postoperative pressure control.     

FK506 in combination with methotrexate for the prevention of graft- versus-host disease after marrow transplantation from matched unrelated donors

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus- host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno- occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan- Meier estimates of disease-free survival at 2 years for good-risk, poor- risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.     

Percutaneous transluminal angioplasty: the treatment of choice for renovascular hypertension due to fibromuscular dysplasia

Twenty-three renal artery stenoses in 21 hypertensive patients, caused by fibromuscular dysplasia, were treated with percutaneous transluminal angioplasty (PTA). Follow-up over a period of 1 to 30 months, including angiography, renal vein renin assay, and radionuclide flow studies, was performed in 8 patients, each with one stenosis. Dilatation was initially successful in all cases and was successfully repeated in 1 case. The mean systolic pressure decreased by 61.81 mm Hg and the mean diastolic pressure by 36.28 mm Hg in response to treatment. Thirteen patients were cured, 8 were felt to have better control of blood pressure on medication, and there was no failures. This study demonstrates that PTA is a clinically effective method of treating renovascular hypertension due to fibromuscular dysplasia.