Lack of effect of the calcium antagonist isradipine on cyclosporine pharmacokinetics in renal transplant patients.

Hypertension has emerged as a frequent side effect in transplant recipients on effective doses of cyclosporine (CsA). To control hypertension in renal transplant patients, calcium channel blockers have been used; some of these, however, have been shown to cause significant increases in CsA levels. These findings point out that possible interactions of each calcium antagonist with CsA deserve investigation. We performed an open, placebo-controlled study in 12 stable renal transplant recipients to determine whether short-term isradipine influences CsA pharmacokinetics. All patients had mild to moderate hypertension and received triple immunosuppressive therapy with CsA, azathioprine, and prednisolone. Throughout a 4-week period of isradipine treatment, blood CsA levels (specific and nonspecific monoclonal antibodies) remained stable. The mean trough specific level was 121 +/- 14 micrograms/L following placebo, compared to 120 +/- 14 micrograms/L during isradipine. Corresponding non-specific values were 465 +/- 68 and 474 +/- 63 micrograms/L. Also, values for Cmax, AUC, and t1/2 were not significantly changed following 4 weeks of isradipine. Mean arterial pressure was significantly reduced at the end of the study. This study implies that isradipine does not influence CsA metabolism. Further studies should be carried out to determine its long-term effects on CsA pharmacokinetics and renal function in transplanted patients.     

Efficacy of cefcanel on staphylocci

The minimum inhibitory concentration (MIC) of cefcanel, a new oral cephalosporin, has been tested against 153 staphylococci subdivided into the species Staphylococcus aureus. S. epidermidis sensu lato and S. saprophyticus, with and without beta-lactamase production. The concentration inhibiting 50% of the strains was 0.5 mg/l for all three species while the corresponding values for 90% of the strains were 1, 2 and 1 mg/l, respectively. These values apply to all the strains. The MICs of the non-beta-lactamase-producing strains were identical to the MICs of the beta-lactamase-producing strains for S. aureus, three twofold steps lower for S. epidermidis and one step higher for S. saprophyticus. Consequently, beta-lactamase production had no consistent consequences for the activity of cefcanel against S. aureus and S. saprophyticus. In contrast, the beta-lactamase production of S. epidermidis did influence the activity of cefcanel. Among the tested cephalosporins, cefcanel had the highest antistaphylococcal activity, and no strain was resistant to this new cephalosporin.     

Percutaneous technique for venovenous bypass including a heat exchanger is safe and reliable in liver transplantation

We have introduced and evaluated several modifications of the conventional venovenous bypass (VVBP) in 29 adult patients undergoing liver transplantation (OLT). A percutaneous technique for insertion of a jugular venous return cannula and a femoral vein cannula was applied. The inferior mesenteric vein (IMV) was used for splanchnic decompression, which facilitated dissection of the recipient liver and allowed portal anastomosis to be performed without disconnecting the portal bypass. A heat exchanger was introduced into the bypass circuit to prevent heat loss. The percutaneous technique prevented complications related to dissection in the axilla and groin. Hemodynamic characteristics corresponded to those found using the traditional technique. Complications related to the VVBP were seen in only one patient in whom the femoral catheter was accidentally introduced into the femoral artery. We conclude that percutaneous cannulas, use of the IMV for splanchnic decompression and the introduction of a heat exchanger offer significant benefits and that they are safe and reliable. Received: 23 August 1996 Received after revision: 14 January 1997 Accepted: 27 January 1997     

Tolerance of intravenously administered ciprofloxacin

Twelve healthy volunteers received single doses of 200, 300, and 400 mg ciprofloxacin intravenously (30-min infusion). Crystals appeared in the urine of only 1 subject after the 400 mg dose. The crystals appeared in the 0-2 h urine specimen only and were observed immediately upon voiding while the urine was maintained at 37 degrees C. The pH of the urine was 7.3. The event was without untoward consequences to the person as evidenced by urinalysis and blood chemistry. Local skin reactions occurred on the arm of the infusion (cutaneous erythema, itching and burning sensation). The reactions were less after the lowest dose. The reactions started within minutes after the beginning of the infusion and disappeared either during the infusions or immediately after the end of administration. These local reactions were of moderate degree and did not necessitate termination of the infusion.     

Multiple aneurysms in Beh?et's disease

Beh?et's disease is characterized by recurrent ulcers of the mouth and genitalia and relapsing iritis. It is now recognized as a chronic multisystem disease affecting the skin, mucous membranes, eye, joints, central nervous system, and blood vessels. One of the known vascular complications of Beh?et's disease is aneurysm formation or venous thrombosis. The two patients with Beh?et's disease in this report developed multiple aneurysms over a short time span. Vascular surgeons dealing with young adults with peripheral aneurysms must be aware of this uncommon yet challenging clinical entity.     

Flow cytometric DNA ploidy pattern in dysplastic mucosa, and in primary and metastatic carcinomas in patients with longstanding ulcerative colitis

Eighty-nine fresh tissue samples from flat colonic mucosa, polypoid lesions, macroscopically evident carcinomas, and metastatic carcinomas from ten patients with longstanding ulcerative colitis (greater than or equal to 8 years duration) were analysed by DNA flow cytometry and light microscopy. Of a total of ten carcinomas found in six patients, six showed DNA aneuploidy. Three patients developed metastatic carcinomas, all with aneuploid cell populations with similar DNA indices as in the primary carcinoma. Furthermore, aneuploid cell populations with similar DNA indices often occurred, both in separate mucosa samples, as well as in mucosa and carcinoma samples, from the same patient. DNA aneuploidy was found in flat mucosa in five of the six patients with carcinoma, and in one of the four patients without carcinoma (P greater than 0.1). High grade dysplasia was found in only four of the six cases with carcinoma, indicating that high grade dysplasia is insufficient as marker for malignant development. DNA aneuploidy was found in 24% of the dysplastic mucosa samples, and in 18% of the non-dysplastic mucosa samples (n.s., both with regard to high and low grade dysplasia). Since abnormal DNA ploidy pattern was not confined to dysplastic epithelium only, DNA aneuploidy in flat mucosa may constitute an additional marker in the identification of patients at increased cancer risk who could benefit from a closer surveillance.     

Failure of Nonoperative Management of Isolated Superior Mesenteric Artery Dissection

A case of isolated dissection of the superior mesenteric artery is presented here. This rare condition was confirmed angiographically in a 46-year-old man with persistent abdominal pain. He was treated initially with anticoagulation alone. One year later, he developed recurrent symptoms and had radiologic documentation of progression of the condition. Operative repair was performed and recovery was uneventful. This case demonstrates a failure of the nonoperative approach to this rare condition and suggests that disease progression may be inevitable. Early surgical correction may ease operative management.     

Expression of Adhesion Molecules and Cytokines on Saphenous Veins in Chronic Venous Insufficiency

The objective of this study was to assess the relationship of signaling molecules to monocyte/ macrophages as a precursor to venous valve and venous wall dysfunction in patients with varicose veins. One of the hallmarks of venous dysfunction is destruction of venous valves with subsequent reflux and elevation of distal venous pressure. We recently observed that monocytes/macrophages migrate into the venous walls and valves of patients with venous insufficiency. There, they may play a role in the pathogenesis of primary venous insufficiency. If so, an important element in their performance would be the interaction between the monocytes and the endothelium as a precursor of damage to venous valves and the venous wall. To explore this interaction, immunohistochemistry was carried out to detect adhesion molecules and cytokines in surgical specimens removed during surgical therapy. Twenty-four surgical specimens consisting of proximal saphenous vein and subterminal valve were obtained using minimally traumatic technique in 6 males and 18 females who ranged in age from 31 to 79 years. Reflux was confirmed preoperatively by duplex technique, and severity was classified by the CEAP classification of the American Venous Forum. Ten patient limbs were class 2, eight were class 3, four were class 4, and two were class 6. The venous specimens were labeled using monoclonal antibody against ICAM-1, E-selectin, IL-1alpha, and TNF-alpha. CD68 was used for detection of monocytes/macrophages. Our results indicate that not only luminal venous endothelium but also endothelium in the vasa vasora of refluxing saphenous veins is activated, as indicated by the up-regulation of ICAM-1. However, IL-1alpha and TNF-alpha were increased in only selected specimens and are mainly detected in the vein wall. The factors that serve as trigger mechanisms to activate cells in the pathogenesis of primary venous dysfunction remain to be explored.     

Effect of norfloxacin on human oropharyngeal and colonic microflora and multiple-dose pharmacokinetics

10 healthy volunteers received 200 mg norfloxacin orally every 12 h for 7 days. Saliva, throat and faecal specimens were collected days 0, 3, 5, 7, 14 and 21 to study the effect of norfloxacin on the normal microflora. The concentrations of norfloxacin in serum, urine, saliva and faeces were determined by a microbiological method and all samples except faeces were also assayed by high-pressure liquid chromatography (HPLC). The pharmacokinetics of norfloxacin were studied on day 3. The mean peak serum concentration (+/- SD) attained after 0.75-1.0 h was 0.75 +/- 0.15 mg/l measured by HPLC, and the mean terminal serum half-life was 4.2 +/- 0.6 h. The mean cumulative urinary elimination was 29% during 12 h after dosing. There was no significant difference between values obtained by microbiological assay and by HPLC. The saliva concentration was approximately 30% of the serum levels 1.0-1.5 h after administration. No accumulation in faeces was found during the administration period, and mean concentrations were 940 mg/kg. The changes in the oropharyngeal flora were minor and only branhamella were affected. In the colonic flora, the number of enterobacteria was strongly depressed while the anaerobic microflora was only slightly affected. Two weeks after the administration period, both the oropharyngeal and colonic microflora had returned to normal.     

Inclusion of CYP3A5 genotyping in a nonparametric population model improves dosing of tacrolimus early after transplantation

Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C₀ concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking. A nonparametric population model was developed for tacrolimus in renal transplant recipients. Data from 99 patients were used for model development and validation. A three‐compartment model with first‐order absorption and lag time from the dosing compartment described the data well. Clearances and volumes of distribution were allometrically scaled to body size. The final model included fat‐free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP3A5 genotype provided an initial advantage, but only until 3‐4 tacrolimus concentrations were known. After this, a model without CYP3A5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation.