Gary W. Barone

Drug Interaction between St. John's Wort and Cyclosporine

OBJECTIVE: To report a probable drug interaction between the herbal dietary supplement St. Johns wort and cyclosporine. CASE REPORT: A 29-year-old white woman who received a cadaveric kidney and pancreas transplant, with stable organ function and stable cyclosporine concentrations began self-medicating with St. Johns wort. After taking St. Johns wort supplements for four to eight weeks, her cyclosporine concentrations became subtherapeutic; this was associated with organ rejection. Four weeks after stopping St. Johns wort, her cyclosporine concentrations again became therapeutic. Subsequent to this rejection episode, she has developed chronic rejection and now has returned to dialysis. DISCUSSION: St. Johns wort is suspected to be a significant inducer of CYP3A4 isoenzyme activity and of P-glycoprotein (P-gp) expression, both of which are important in the metabolism and absorption of cyclosporine. Cyclosporine exhibits a relatively small therapeutic window and is sensitive to medications that can modulate the CYP3A4 isoenzyme and P-gp in both the liver and small intestines. CONCLUSIONS: Patients taking St. Johns wort concomitant with other prescription medications whose absorption and metabolism are mediated by the CYP3A4 isoenzyme and P-gp require close monitoring. Patient medication histories should include inquiries into the use of herbal dietary supplements.

Relationship of age, gender, race, and body size to infrarenal aortic diameter

PURPOSE To assess the effects of age, gender, race, and body size on infrarenal aortic diameter (IAD) and to determine expected values for IAD on the basis of these factors. METHODS Veterans aged 50 to 79 years at 15 Department of Veterans Affairs medical centers were invited to undergo ultrasound measurement of IAD and complete a pre-screening questionnaire. We report here on 69,905 subjects who had no previous history of abdominal aortic aneurysm (AAA) and no ultrasound evidence of AAA (defined as IAD > or = 3.0 cm). RESULTS Although age, gender, black race, height, weight, body mass index, and body surface area were associated with IAD by multivariate linear regression (all p < 0.001), the effects were small. Female sex was associated with a 0.14 cm reduction in IAD and black race with a 0.01 cm increase in IAD. A 0.1 cm change in IAD was associated with large changes in the independent variables: 29 years in age, 19 cm or 40 cm in height, 35 kg in weight, 11 kg/m2 in body mass index, and 0.35 m2 in body surface area. Nearly all height-weight groups were within 0.1 cm of the gender means, and the unadjusted gender means differed by only 0.23 cm. The variation among medical centers had more influence on IAD than did the combination of age, gender, race, and body size. CONCLUSIONS Age, gender, race, and body size have statistically significant but small effects on IAD. Use of these parameters to define AAA may not offer sufficient advantage over simpler definitions (such as an IAD > or = 3.0 cm) to be warranted.

Clinical assessment of CYP2D6-mediated herb–drug interactions in humans: Effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea

Cytochrome P450 2D6 (CYP2D6), an important CYP isoform with regard to drug-drug interactions, accounts for the metabolism of approximately 30% of all medications. To date, few studies have assessed the effects of botanical supplementation on human CYP2D6 activity in vivo. Six botanical extracts were evaluated in three separate studies (two extracts per study), each incorporating 16 healthy volunteers (eight females). Subjects were randomized to receive a standardized botanical extract for 14 days on separate occasions. A 30-day washout period was interposed between each supplementation phase. In study 1, subjects received milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa). In study 2, kava kava (Piper methysticum) and goldenseal (Hydrastis canadensis) extracts were administered, and in study 3 subjects received St. Johns wort (Hypericum perforatum) and Echinacea (Echinacea purpurea). The CYP2D6 substrate, debrisoquine (5 mg), was administered before and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP2D6 using 8-h debrisoquine urinary recovery ratios (DURR). Comparisons of pre- and post-supplementation DURR revealed significant inhibition (approximately 50%) of CYP2D6 activity for goldenseal, but not for the other extracts. Accordingly, adverse herb-drug interactions may result with concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 substrates.

Herbal supplements: a potential for drug interactions in transplant recipients.

Background. Herbal dietary supplements represent a potential and possibly an overlooked cause for drug interactions in transplant recipients. Methods. Two patients are reported which suggest that St. John’s Wort (SJW) may induce cytochrome P-450 3A4 activity and/or P-glycoprotein expression. Both of these mechanisms are significantly involved in the metabolism and absorption of cyclosporine (CSA) and other immunosuppressants. Results. After two renal transplant recipients started self-medicating with SJW, their CSA concentrations were consistently documented to be subtherapeutic. While on SJW, one patient developed acute graft rejection due to low CSA concentrations. In both patients, termination of SJW returned their CSA concentrations to therapeutic values. Conclusions. Patients taking SJW concomitantly with CSA or other medications whose absorption and metabolism are mediated by cytochrome P-450 and/or P-glycoprotein should require close monitoring. Potential herb-prescription drug interactions are not just limited to SJW. Inquiries regarding the usage of herbal supplements should be an integral component of a transplant recipient’s medication history.

UDP-GLUCURONOSYLTRANSFERASES IN HUMAN INTESTINAL MUCOSA

While UDP-glucuronosyltransferases (UGTs) are known to be expressed at high levels in human liver, relatively little is known about extrahepatic expression. In the present study, UGT2B family isoforms involved in the glucuronidation of steroid hormones and bile acids have been characterized in microsomes prepared from jejunum, ileum and colon from six human subjects. Glucuronidation of androsterone and testosterone was highly significant and increased from proximal to distal intestine. In contrast, hyodeoxycholic acid was glucuronidated at a low level in jejunum and ileum and activity was barely detectable in colon. No significant glucuronidation of lithocholic acid was found. Small phenols were glucuronidated with much lower activity than found in liver. High levels of UGT protein were detected with polyclonal anti-rat androsterone- and testosterone-UGT antibodies, whereas UGT2B4, a major hepatic hyodeoxycholic acid-specific UGT, was undetectable using a highly specific anti-human UGT2B4 antibody. Screening for RNA expression by RT-PCR confirmed the absence of UGT2B4 and UGT1A6 and showed expression of UGT2B7, a hepatic isoform shown to glucuronidate androsterone, in all intestinal segments. To our knowledge, the presence of functional androsterone and testosterone directed isoforms in human intestine is a novel finding which supports the idea that the intestinal tract functions as a steroid-metabolizing organ and plays a significant role in steroid hormone biotransformation.

Surgical complications from hemostatic puncture closure devices

BACKGROUND For securing immediate hemostasis following percutaneous arterial catheterization, the Food and Drug Administration has approved three hemostatic puncture closure devices. We reviewed our institutional experience with one device (Angio-Seal). METHODS A retrospective, single-center, nonrandomized observational study was made of all vascular complications following femoral cardiac catheterization. RESULTS An immediate mechanical failure of the device was experienced in 34 (8%) patients. Surgical repair was required in 1.6% (7 of 425) of patients following Angio-Seal versus 0.3% (5 of 1662) following routine manual compression (P = 0.004). In 5 patients, the device caused either complete occlusion or stenosis of the femoral artery. The polymer anchor embolized in 1 patient and was retrieved with a balloon catheter at surgery. CONCLUSION During the first year of utilization of a percutaneous hemostatic closure device following cardiac catheterization, we observed a marked increase in arterial occlusive complications requiring surgical repair. Surgeons must be familiar with the design of these devices to achieve precise repair of surgical complications.

Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may underlie many herb-drug interactions. Serial serum concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with milk thistle or black cohosh modified P-gp activity in vivo. Sixteen healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg daily) or black cohosh (40 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxicaps, 0.4 mg) was administered orally before and at the end of each supplementation and control period. Serial digoxin serum concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the serum concentration time curves from 0 to 3 h (AUC(0–3)), AUC(0–24), Cmax, apparent oral clearance of digoxin (CL/F), and elimination half-life were used to assess the effects of milk thistle, black cohosh, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC(0–3), AUC(0–24), and Cmax, whereas clarithromycin increased these parameters significantly (p < 0.01). Significant changes in digoxin half-life and CL/F were also observed with clarithromycin. No statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either milk thistle or black cohosh, although digoxin AUC(0–3) and AUC(0–24) approached significance (p = 0.06) following milk thistle administration. When compared with rifampin and clarithromycin, supplementation with these specific formulations of milk thistle or black cohosh did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.

Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: Comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics

Concomitant administration of botanical supplements with drugs that are P-glycoprotein (P-gp) substrates may produce clinically significant herb-drug interactions. This study evaluated the effects of St. Johns wort and Echinacea on the pharmacokinetics of digoxin, a recognized P-gp substrate. Eighteen healthy volunteers were randomly assigned to receive a standardized St. Johns wort (300 mg three times daily) or Echinacea (267 mg three times daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (300 mg twice daily, 7 days) and clarithromycin (500 mg twice daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin 0.25 mg) was administered orally before and after each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), elimination half-life, and maximum serum concentration were used to assess the effects of St. Johns wort, Echinacea, rifampin, and clarithromycin on digoxin disposition. St. Johns wort and rifampin both produced significant reductions (p < 0.05) in AUC((0-3)), AUC((0-24)), and C(max), while clarithromycin increased these parameters significantly (p < 0.05). Echinacea supplementation did not affect digoxin pharmacokinetics. Clinically significant P-gp-mediated herb-drug interactions are more likely to occur with St. Johns wort than with Echinacea.

Polyoma viral infection in renal transplantation: the role of immunosuppressive therapy

Background: Polyoma virus infection in renal transplant recipients has been observed with increasing frequency in recent years. Renal allograft involvement in this condition may occur as a result of primary infection or secondary to reactivation of the latent virus. Interstitial nephritis, ureteric stenosis, rise in serum creatinine and allograft function loss have been attributed to this viral infection. 
Methods: In this study we reviewed our experience with 8 patients who developed polyoma viral infection confirmed by allograft biopsy. All patients were receiving mycophenolate mofetil as part of the immunosuppression and 7 of the 8 patients were on tacrolimus. All patients have biopsy proven polyoma viral infection. The following therapeutic maneuvers were carried out following the diagnosis of polyoma viral infection: 1) stopping mycophenolate and 2) switching tacrolimus to cyclosporine or reducing the tacrolimus dose to adjust it at a lower therapeutic trough level. The clinical course and outcome of our patients were reviewed in relation to manipulation of immunosuppressive medications. 
Results: The incidence of this infection in our transplant program in the last 3 yr was 5.3%. Seventy‐five percent of the patients had at least one rejection episode and 63% had more than one rejection episode. The main risk factor for the development of polyoma viral infection was related to the intensity of immunosuppression. The use of antirejection therapy after histological diagnosis of polyoma virus infection was not associated with improvement of renal function despite the histological appearance of acute rejection. Thus, the interstitial nephritis associated with polyoma viral infection appears to be an inflammatory response to the virus rather than acute rejection. Six out of the 8 patients stabilized renal function with reduction in immunosuppression. 
Conclusions: Reduction in immunosuppression was associated with the stabilization of renal function when instituted early. However, these patients were left with a degree of allograft dysfunction and their outcome may be significantly compromised. The lack of effective antiviral therapy for polyoma virus may limit the use of newer and more potent immunosuppressive medications.

Carotid-subclavian bypass: A twenty-two–year experience

PURPOSE A retrospective review of 124 patients who underwent carotid-subclavian bypass from 1968 to 1990 was done to assess primary patency and symptom resolution. METHODS Preoperative data included age, atherosclerosis risk factors, and indications for surgery. Perioperative data included mortality and morbidity rates and graft conduit. Postoperative follow-up assessed graft patency, resolution of symptoms, and late survival. RESULTS Age ranged from 42 to 78 years (mean 57.9). Indications for surgery were vertebrobasilar insufficiency in 24 (19%), extremity ischemia (EI) in 33 (27%), transient ischemic attacks (TIAs) in 13 (11%), both vertebrobasilar insufficiency and EI in 31 (25%), and both TIAs and EI in 23 (18%) patients. Graft conduits were polytetrafluoroethylene in 44 (35%) and Dacron in 80 (65%) cases. Concomitant ipsilateral carotid endarterectomy was done in 32 (26%) patients. During operation, death occurred in one patient (0.8%), and complications occurred in 10 (8%) patients. Thirty-day primary patency and symptom-free survival rates were 100%. Long-term follow-up ranging from 5 to 164 months was available for the 60 cases done between 1975 and 1990. Three grafts occluded at 30, 36, and 51 months after surgery for a primary patency rate of 95% at 5 and 10 years. Twenty-two patients died, yielding survival rates of 83% at 5 years and 59% at 10 years. Symptom recurrence occurred in six (10%) patients from 9 to 66 months after surgery. The symptom-free survival rate was 98% at 1 year, 90% at 5 years, and 87% at 10 years. Symptoms recurred in three patients with occluded grafts and three with patent grafts. The preoperative symptoms of drop attacks and TIAs did not recur. EI recurred in 5% and was noted only in the presence of graft occlusion. Dizziness recurred in 17% of patients admitted with this symptom and was observed despite graft patency. CONCLUSION Carotid-subclavian bypass was a safe and durable procedure for relief of symptomatic occlusive disease of the subclavian artery. Long-term symptomatic relief appeared particularly likely in patients with drop attacks or upper extremity ischemia.