The influence of CYP3A,PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients

Purpose

Tacrolimus (Tac) and cyclosporine (CsA) are mainly metabolized by CYP3A4 and CYP3A5. Several studies have demonstrated an association between the CYP3A5 genotype and Tac dose requirements. Recently, CYP3A4, PPARA, and POR gene variants have been shown to influence CYP3A metabolism. The present study investigated potential associations between CYP3A5*3, CYP3A4*22, PPARA c.209-1003G>A and c.208?+?3819A>G, and POR*28 alleles and dose-adjusted concentrations (C/D) of Tac and CsA in 177 renal transplant patients early post-transplant.

Methods

All patients (n?=?177) were genotyped for CYP3A4*22, CYP3A5*3, POR*28, PPARA c.209-1003G>A, and PPARA c.208?+?3819A>G using real-time polymerase chain reaction (PCR) and melting curve analysis with allele-specific hybridization probes or PCR restriction fragment length polymorphisms (RFLP) methods. Drug concentrations and administered doses were retrospectively collected from patient charts at Oslo University Hospital, Rikshospitalet, Norway. One steady-state concentration was collected for each patient.

Results

We confirmed a significant impact of the CYP3A5*3 allele on Tac exposure. Patients with POR*28 and PPARA variant alleles demonstrated 15 % lower (P?=?0.04) and 19 % higher (P?=?0.01) Tac C₀/D respectively. CsA C₂/D was 53 % higher among CYP3A4*22 carriers (P?=?0.03).

Conclusion

The results support the use of pre-transplant CYP3A5 genotyping to improve initial dosing of Tac, and suggest that Tac dosing may be further individualized by additional POR and PPARA genotyping. Furthermore, initial CsA dosing may be improved by pre-transplant CYP3A4*22 determination.     

Posterior cranial fossa dimensions in the Chiari I malformation: Relation to pathogenesis and clinical presentation

Summary Skull dimensions were measured on lateral skull radiographs in 33 adult patients with MRI-verified Chiari I malformations and in 40 controls. The posterior cranial fossa was significantly smaller and shallower in patients than in controls. In the patients, there was a positive correlation between posterior fossa size and the degree of the cerebellar ectopia, which might indicate that a posterior cranial fossa which was originally too small had been expanded by the herniation of hindbrain structures at an early stage. Pyramidal signs and cerebellar symptoms and signs, which may be due to compression of neural structures, were associated with a large degree of ectopia and a relatively large posterior cranial fossa. Syringomyelia and headache, which may be due to the valve action of the herniated cerebellar tissue, were not associated with a particularly large posterior fossa or herniation. No special clinical presentation was associated with a very small posterior cranial fossa, which may indicate that a small posterior cranial fossa per se has little or no clinical significance, although it may be the primary developmental anomaly.     

Femoral venous reflux abolished by greater saphenous vein stripping

Preoperative venous duplex scanning has revealed unexpected deep venous incompetence in patients with apparently only varicose veins. Acting on the hypothesis that the deep vein reflux was secondary to deep vein dilation caused by reflux volume, the following was done. Between July 1990 and April 1993, 29 limbs in 21 patients (16 females) were examined by color-flow duplex imaging to determine valve closure by the method of van Bemmelen. Instrumentation included high-resolution ATL-9 venous interrogation using a pneumatic cuff deflation stimulus of reflux in the standing, nonweight-bearing limb. All limbs showed greater saphenous vein reflux. Twenty-nine showed superficial femoral vein reflux and of these three showed popliteal vein reflux. Duplex testing was performed by a certified vascular technologist whose interpretation was blinded as to the results of clinical examination and grading of the severity of venous insufficiency. Surgery was performed on an outpatient basis under general anesthesia using groin-to-knee removal of the greater saphenous vein by the vein inversion technique of Van Der Strict. Stab avulsion of varicose tributary veins was accomplished during the same period of anesthesia. In 27 of 29 limbs with preoperative femoral reflux, that reflux was abolished by greater saphenous stripping. In patients with popliteal reflux both femoral and popliteal reflux was abolished. Improvement of deep venous hemodynamics by ablation of superficial reflux supports the reflux circuit theory of venous overload. Furthermore, preoperative evaluation of venous hemodynamics by duplex scanning appears to provide useful pre- and postoperative information regarding venous insufficiency in individual patients.Presented at the Twelfth Annual Meeting of the Southern California Vascular Surgical Society, Coronado, Calif, September 17–19, 1993.     

Revascularization in treatment of mesenteric infarction.

This study compares results of primary revascularization with primary intestinal resection in treatment of acute mesenteric artery occlusion in 48 surgical patients. All cases were verified by surgical exploration, angiography or autopsy. Fifteen occlusions were caused by mesenteric thrombosis and 33 by superior mesenteric artery embolization. Primary revascularization was done in 6 of 15 patients with arteriosclerotic mesenteric thrombosis. Total bowel salvage was achieved in 4 patients but no patient with mesenteric thrombosis treated by any method survived long term. Primary embolectomy was done in 11 patients with superior mesenteric artery embolization. Ttoal bowel salvage was achieved in 8 patients. Three of 11 patients died. Primary exploration and/or resection was done in 11 patients; 9 died. All 11 umoperated patients died. A continuation of attempts at mesenteric revascularization is advocated.     

Internal to External Carotid Artery Transposition to Repair Recurrent Stenosis after Carotid Artery Stenting

Recently, carotid artery stenting (CAS) has emerged as a treatment option for carotid artery stenosis. Since the procedure is new, management of its complications is not standardized. This case report describes one method of arterial reconstruction after failed CAS. A 64-year-old male underwent CAS of his right internal carotid artery (ICA) for an asymptomatic 65% stenosis. Seven months later the stented area had narrowed to 95%. Arteriography revealed that the common and external carotid arteries (ECA) were free of disease so we elected to perform a transposition of the distal ICA onto the proximal ECA. The ECA and its branches were completely mobilized and the ascending pharyngeal and lingual arteries divided. The ICA was divided distal to the stent. Transection of the occipital artery provided an arteriotomy for an end ICA to side ECA anastamosis, thus preserving ECA flow. Postoperative surveillance after 8 months has revealed no recurrent stenosis. Operative repair of restenosis after CAS may be challenging if standard endarterectomy is not possible. Other options for reconstruction are feasible but if the common and external carotid arteries are disease-free, an ICA to ECA transposition provides a simple all-arterial repair that avoids bypass and prosthetic material.     

Use of yeast-secreted in vivo biotinylated recombinant antibodies (Biobodies) in bead-based ELISA.

PURPOSE: To measure circulating antigens, sandwich ELISA assays require two complementary affinity reagents. Mouse monoclonal antibodies (mAb) and polyclonal antibodies (pAb) are commonly used, but because their production is lengthy and costly, recombinant antibodies are emerging as an attractive alternative. EXPERIMENTAL DESIGN: We developed a new class of recombinant antibodies called biobodies (Bb) and compared them to mAb for use in serodiagnosis. Bbs were secreted biotinylated in vivo by diploid yeast and used as affinity reagents after Ni purification. Bead-based assays for HE4 and mesothelin were developed using Bbs in combination with pAbs (Bb/pAb assays). To assess precision, reproducibility studies were done using four runs of 16 replicates at six analyte levels for each marker. Pearson correlations and receiver-operator characteristic analyses were done in 214 patient serum samples to directly compare the Bb/pAb assays to mAb assays. Diagnostic performance of the Bb/pAb assay was further assessed in an expanded set of 336 ovarian cancer cases and controls. RESULTS: On average across analyte levels, Bb/pAb assays yielded within-run and between-run coefficients of variations of 11.7 and 23.8, respectively, for HE4 and 14.0 and 14.5, respectively, for mesothelin. In the subset (n = 214), Pearson correlations of 0.95 for HE4 and 0.92 for mesothelin were observed between mAb and Bb/pAb assays. The area under the curves for the mAb and Bb/pAb assays were not significantly different for HE4 (0.88 and 0.84, respectively; P = 0.20) or mesothelin (0.74 and 0.72, respectively; P = 0.38). CONCLUSION: Yeast-secreted Bbs can be used reliably in cost-effective yet highly sensitive bead-based assays for use in large validation studies.     

A comparison of single-dose oral fluconazole with 3-day intravaginal clotrimazole in the treatment of vaginal candidiasis

Summary. A total of 369 women with clinical and mycological evidence of vaginal candidiasis received treatment, after random allocation, with either a single oral 150-mg dose of fluconazole (188 women) or 200 mg of intravaginal clotrimazole given daily for 3 consecutive days (181 women). They were assessed at 5–16 days and again at 27–62 days after treatment. Candida species were completely eradicated from the vagina in 72% of the fluconazole group and in 62% of the clotrimazole group at the long-term assessment (P=0·07). Favourable clinical responses were obtained in 99% of the fluconazole group and in 97% of the clotrimazole group at the short-term assessment and in 93% and 84% respectively at the long-term assessment when there was a significant advantage for fluconazole treatment (P=0·02). Symptoms in patients receiving fluconazole were relieved more rapidly (P<0·001). Treatment-related side-effects were few and minor in both groups. It is concluded that treatment of vaginal candidiasis with fluconazole, as a single oral dose, was more effective in the long term, relieved symptoms more rapidly, and was as safe as treatment with intravaginal clotrimazole.     

The saphenous vein: derivation of its name and its relevant anatomy.

Generally, when the origin of the word saphenous is discussed, most affirm that the term derives from the Greek word safaina, which means "evident." The ancient Greeks knew only the caudal portion of the vein, and neither the Greeks nor the Romans used the term saphena. In fact, the term first appeared in the writings of Avicenna. In contrast, the term saphenous is derived from the Arabic el safin, which means "hidden" or "concealed." Ancient Arabic physicians knew the anatomy of superficial veins of the human body and its extremities because they performed therapeutic bleeding. Arabic physicians phlebotomized the distal portion of the greater saphenous vein (GSV) at the ankle. Such phlebotomies were never performed on the proximal portions of the GSV because they were not superficial enough to be clearly evident. As a consequence, the proximal GSV was called el safin, or "the concealed." The modern reader will recognize that based on duplex examination, the GSV is correctly identified on the basis of its deep position with the superficial fascia covering it. This information may be useful in modern saphenous vein surgery in identifying the proximal portion of the GSV.     

Varicose veins: hooks, clamps, and suction. Application of new techniques to enhance varicose vein surgery

Surgical principles that guided varicose vein surgery for nearly 75 years have been time honored and taught to generations of surgeons. Each of these principles has been challenged successfully, and, as a result, varicose vein surgery has changed markedly. The fundamental principle of totally removing varicose clusters from the circulation remains firmly established. However, methods of accomplishing this have changed and continue to change. Hook phlebectomy and clamp phlebectomy have replaced open dissection and tributary ligation. The place of tumescent anesthesia, transilluminated-powered phlebectomy, and sclerotherapy remain unsettled. However, there now are a number of alternatives in planning patient care.