Ciclosporin Levels Research Articles

Retroperitoneal fibrosis as a postoperative complication following renal transplantation in cats.

The aim of this report was to describe the clinical signs, diagnostic imaging findings, surgical management, histopathological findings, outcome and possible risk factors for cats that developed retroperitoneal fibrosis (RPF) following renal transplantation. Medical records of cats that underwent renal transplantation and developed clinically significant RPF between 1995 and 2019 were reviewed. Eighty-one cats underwent 83 renal transplantations. Of these 81 cats, six developed clinically significant RPF. For all six cats, renal transplantation was performed using cold organ preservation solution and ureteral papilla implantation. Immunosuppression protocol included ciclosporin and prednisolone. All cats had at least one subtherapeutic trough ciclosporin level (<250 ng/ml) in the postoperative period. Cats presented with moderate-to-severe azotemia 39-210 days following renal transplantation. Abdominal ultrasonography and contrast pyelography revealed various degrees of hydroureter and hydronephrosis of the transplanted kidney. Surgical examination revealed a layer of dense fibrous tissue surrounding the transplanted kidney, ureter and bladder resulting in ureteral obstruction. Ureteral obstruction was managed by reimplantation of the proximal ureter or renal pelvis to the bladder. Histopathologic examination of the fibrous tissue and affected portion of the distal ureter revealed fibrous connective tissue with lymphoplasmacytic infiltration and perivascular inflammation suggestive of an autoimmune type reaction. Of the six cats, two died within 5 days after revision surgery, two developed signs consistent with recurrent partial ureteral obstruction (40 and 41 days after revision), one was euthanized 6 years later for an unrelated disease and one was lost to follow-up. The incidence of RPF in this population of cats was relatively low (7%), but still represents a significant cause of morbidity and mortality. The cause of RPF remains unknown, although investigation into suboptimal immunosuppression as a potential cause for local rejection reaction is warranted.

P55 Immunosuppression in the first six weeks following paediatric cardiac transplant

AimThe aim of this audit was to establish whether immunosuppression was being prescribed correctly and whether target levels were being reached during the first six weeks post-transplant.1 2MethodThe standards were discussed and agreed, due to an absence of standardised local or national written protocols, with the lead paediatric cardiothoracic transplant consultant and a specialist transplant liaison nurse. The paediatric transplant database provided a list of patients between October 2016 and July 2018, from which paediatric cardiac transplant patients were included in this audit. All data were collected retrospectively, for the first six weeks post-transplant, from patient’s electronic records.ResultsTwenty-three patients were included in the audit; fifteen males and eight females and the mean age was 6 years old. The standards for the timing and dosing of the first ciclosporin dose were met for 87% and 78% of patients respectively. Six patients (26%) had a ciclosporin level within the target range by day 4 post-transplant, for the remaining seventeen patients the average was day 9 post-transplant. The mean levels remained within this range or slightly above after day 9. Azathioprine or mycophenolate was started within 7 days of transplant in 6 patients (23%). Four patients (17%) had documented episodes of rejection; in one patient all other standards were met and in the other three only one additional standard was not met. Nineteen patients (83%) did not have a documented episode of rejection.ConclusionsPost-transplant management is individualised based on multiple factors such as clinical conditions e.g. renal/liver impairment and whether other agents such as ATG or steroids are being used.1 The lack of documentation around the treatment decisions made it difficult to explain deviations from standards in this audit. Ciclosporin standards were not met completely but were most likely unfeasible due to a narrow target range and the time between first dose and level monitoring. There did not appear to be a clear association between standards not being met and episodes of rejection. It would be beneficial to repeat this as a larger, prospective audit using revised standards.ReferencesCostanzo MR, Costanzo MR, Dipchand A, et al. The international society of heart and lung transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010;29:914–56.Sandimmun Concentrate for Solution for Infusion 50 mg/ml - Summary of Product Characteristics (SmPC) - (eMC) [Internet]. [cited 2018 Sep 2]. Available from: https://www.medicines.org.uk/emc/product/1036

Clinical Response and Complications are not Associated with Drug Levels in Patients with Severe Ulcerative Colitis on IV Cyclosporine Induction Therapy.

IV ciclosporin therapy is effective in steroid-refractory ulcerative colitis. The optimal drug level to achieve response and minimize complications during induction therapy is not known. The primary aim was to evaluate if serum ciclosporin drug levels are associated with increased risk of colectomy within 90 days of hospitalization. Secondary aims were to determine if ciclosporin levels are associated with avoidance of colectomy at 7 and 30 days, if ciclosporin levels are associated with drug-related and postoperative complications, and if patient-specific factors are associated with response to ciclosporin. We conducted a retrospective analysis of 81 hospitalized patients with steroid-refractory ulcerative colitis treated with ciclosporin. Risk factors for colectomy within 7, 30, and 90 days, medication-specific and postoperative complications were compared by first, mean, and peak ciclosporin level during IV induction therapy. There were 47 patients (58%) who underwent surgery. There were no differences between initial, mean, and peak ciclosporin levels among responders and nonresponders and treatment-related or postoperative complications. Responders within 90 days had lower C-reactive-protein levels (20mg/L vs. 38mg/L, P = 0.01), lower serum albumin concentrations (3.4g/dL vs. 3.7g/dL, P = 0.03), and higher rates of kidney injury (50% vs 17%, P = 0.002). Initial, mean, and peak serum levels of ciclosporin did not correlate with response or toxicity. However, C-reactive-protein levels levels and kidney injury may be helpful in predicting clinical response to ciclosporin.

Increased incidence of adenoidectomy and tonsillectomy in children with renal transplantation

Previous studies have found that pediatric solid organ transplant recipients suffer from adenotonsillar hyperplasia. However, as this condition is also common in normal children, it remains unclear whether the incidence is truly increased. The aim of this study was to compare the incidences of surgery on the adenoids and tonsils of normal children with those receiving renal transplants and to define risk factors in the transplant population. Data on 49 consecutive children from a single renal transplant unit were compared to data from a large governmental survey of healthy German children (KiGGS). For analysis of 'survival without operation', controls were matched for gender, region and immigration status (n = 8,650), as well as for age to compare incidence rates (n = 637). The age-matched solid organ transplant recipients had a higher incidence of adenoidectomies [2.3-fold, [95 % confidence interval (CI) for relative risk 1.6-3.3) and a higher incidence of tonsillectomies/tonsillotomies (3.5-fold, 95 % CI 2.1-5.7). The normal peak of adenoidectomies was delayed by 2 years in the pre-school group, and transplanted teenagers showed an extra peak for both operations. Boys and those transplanted at a younger age were significantly more likely to need adenoidectomies. Ciclosporin levels, Epstein-Barr virus and cytomegalovirus infections did not influence the incidence of operations. Children receiving renal transplants are at markedly increased risk of adenotonsillar hyperplasia requiring surgery, especially males and young recipients.

Life-long diseases need life-long treatment: long-term safety of ciclosporin in canine atopic dermatitis

Ciclosporin (Atopica; Novartis Animal Health) has been licensed for canine atopic dermatitis (AD) since 2002. Adverse events (AEs) have been reported in 55 per cent of 759 dogs in 15...

Elevation of blood ciclosporin levels by voriconazole leading to leukoencephalopathy

We report that one 18-year-old female patient with no epilepsia history developed severe epileptiform seizures while she was receiving “ciclosporin A (CsA)-mycophenolate-methylprednisolone” antirejection therapy after combining one week's voriconazole administration following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndromes (MDS). Her blood concentration of CsA was 378 ng/ml (elevated ↑64%, contrasted with the level before the addition of voriconazole) on the second day of admission, and the MRI of head showed leukoencephalopathy in bilateral occipital and left frontal lobe on the 4th day of admission. The most likely mechanism is that because of voriconazole's enzyme inhibition and CsA as the substrate of hepatic enzymes, voriconazole elevated the blood concentration of CsA and enhanced its toxicity. This case highlights the importance of clinical pharmacists joining the medical team and optimizing the patients’ treatment protocols by performing a systematic literature research, accumulating the knowledge of the potential drug interaction and examining prescriptions.

Cutaneous nocardiosis in two dogs receiving ciclosporin therapy for the management of canine atopic dermatitis

Ciclosporin is a calcineurin inhibitor that is currently registered for the treatment of canine atopic dermatitis. The most common adverse effects include mild, transient gastrointestinal disturbances. Single case reports of opportunistic infections due to Nocardia spp., Neospora spp. and papillomaviruses have also been reported. Clinicians should be aware of the potential risk of systemic immunosuppression and subsequent infection with Nocardia spp. in dogs receiving ciclosporin. Cutaneous nocardiosis in two dogs receiving ciclosporin therapy for management of canine atopic dermatitis. Histopathology, PCR for Nocardia spp. and computed tomography. One dog developed disseminated nocardiosis due to Nocardia brasiliensis and a second dog developed localized cutaneous nocardiosis due to a novel Nocardia species subsequent to ciclosporin administration at the recommended dose rate for the management of canine atopic dermatitis. The second case was receiving a combination of ciclosporin and ketoconazole, and serum trough ciclosporin levels were elevated. Clinicians should be aware of the potential risk of systemic immunosuppression and subsequent infection with Nocardia spp. in dogs receiving ciclosporin. Measurement of serum ciclosporin levels may be useful in identifying those individuals which are at risk of opportunistic infections.

COLON TARGETED, LOW SYSTEMIC ABSORPTION SOLUBLE CICLOSPORIN IN ULCERATIVE COLITIS

IntroductionCiclosporin (CsA) is effective as rescue therapy in approximately 70–80% of patients with severe UC in whom surgery is contemplated. A recent study shows CsA to be as effective as...

Psoriatic arthritis: treatment strategies using anti-inflammatory drugs and classical DMARDs

Psoriatic Arthritis (PsA) is a chronic inflammatory disease typically characterized by arthritis and psoriasis variably associated with other extra-articular manifestations. PsA has been considered a milder and less disabling disease compared with rheumatoid arthritis (RA), even if some studies showed that PsA had joint erosions and damage. In addition, about 20-40% of PsA patients have axial skeleton involvement that may lead to functional limitation and deformity. The treatment of PsA ranged from initial treatment with non-steroidal anti-inflammatory drugs (NSAIDs) to one or more disease-modifying anti-rheumatic agents (DMARDs) for the suppression of inflammation in patients with recalcitrant peripheral joint disease. In clinical practice, the most widely used DMARDs are methotrexate (level of evidence B), sulfasalazine (level of evidence A), leflunomide (level of evidence A), and ciclosporin (level of evidence B). However, the efficacy of these agents in inhibiting joint erosions has not been assessed in controlled studies. Finally, the effectiveness of DMARDs in treating enthesitis and dactylitis is controversial. The present paper revised the evidence-based results on treatment with "conventional" therapy for PsA. The revision was based on all the subsets of the diseases, namely the various manifestations of the articular involvement (peripheral, axial, enthesitis, dactylitis) as well as the skin and nail involvement.

Methotrexate dose delivery is more important than ciclosporin level in graft-versus-host disease prophylaxis following T-replete reduced-intensity sibling allogeneic stem cell transplant

We investigated the contributions of methotrexate (MTX) and ciclosporin (CsA) prophylaxis to acute/chronic graft-versus-host disease (a/cGvHD) prevention following reduced-intensity conditioned allogeneic haematopoietic stem cell transplant (HSCT). Ninety-two fludarabine-melphalan sibling allo-SCT received CsA. Nine, 30 and 47 patients received no MTX, 2-3 doses and 4 doses, respectively. Cumulative CsA blood level to day 21 (CsA(21)) was calculated. Grades II-IV aGvHD incidence was 37.2%. In multivariate analysis, MTX omission and increasing donor age significantly associated with aGvHD incidence whilst MTX reduction and CsA(21) did not. Median duration of first immunosuppressive therapy (IST) for aGvHD was 68 days; duration of first IST was significantly longer in older patients but was not associated with MTX or CsA(21). Extensive cGvHD incidence was 60.6% at 1 year. Reduction of MTX to 2-3 doses, but not MTX omission or CsA(21), was associated with greater incidence of cGvHD affecting ≥3 organs. Median IST duration was 22 months; neither MTX nor CsA(21) influenced this. IST duration was significantly greater in patients receiving a CD34 dose below median. Neither MTX nor CsA(21) altered survival or relapse outcomes. MTX influences GvHD following T-replete RIC sibling HSCT.

Interchangeability of ciclosporin formulations in stable adult renal transplant recipients: comparison of Equoral and Neoral capsules in an international, multicenter, randomized, open-label trial

The cost of immunosuppression following transplantation can be reduced by using generic ciclosporin (for example, Equoral) rather than innovator ciclosporin drugs such as Neoral. Thus, this study aims to evaluate the interchangeability, safety, and tolerability of Equoral, a generic ciclosporin, with Neoral in stable adult renal transplant recipients. This was a multicenter, randomized, open-label, parallel-group clinical trial in stable renal transplant patients, comparing 6 months of treatment with Equoral with the same treatment period on Neoral. The primary end point was the between-treatment comparison of the total daily ciclosporin dose at the end of the study. A total of 99 patients were enrolled and constituted the full analysis/safety population, and 78 patients forming the per-protocol population were assessed for efficacy. Equoral was found to be equivalent to Neoral with regard to the primary end point of daily dose at the end of the study. This was supported by comparable serum ciclosporin levels at the end of the study. There were no renal transplant rejection incidents, but there was one death (in the Neoral group). Drug tolerability and incidence of adverse events were comparable between the treatment groups. In conclusion, Equoral and Neoral are interchangeable in stable renal transplant patients, and both drugs are associated with a similar safety and tolerability profile.

Urinary Monocyte Chemoattractant Protein-1 (MCP-1) in Renal Transplant Recipients: Implications in Proteinuric Patients

Background: After the first year of transplantation chronic allograft nephropathy is the most important cause of renal graft loss and hypertension and proteinuria occur commonly. In native nephropathies, proteinuria and progression to renal failure are linked and renal tubulo-interstitial fibrosis determines prognosis. Monocyte chemoattractant protein-1 (MCP-1) is a powerful chemokine promoting tubulo-interstitial fibrosis but data are limited in a transplant context. Hence this observational cross-sectional study. Methods: The MAP, 24h urinary creatinine clearance, proteinuria and MCP-1 were measured in 81 renal transplant pa- tients (43 with chronic allograft nephropathy). Most patients were on calcineurin-inhibitor based immunosuppression. Re- gression analysis was applied and comparisons made with 64 patients with native nephropathies and comparable function. Results: One fifth (18/81) of all renal transplant patients had less than optimally controlled hypertension. Proteinuria was heaviest in non-transplanted patients (average 3.0 g/24h, 0.1-12.2) and the ciclosporin-treated transplant patients (1.2 g/24h, 0.02-6.4). Proteinuria and MCP-1 were positively correlated in all patients (r 0.54, p<0.0001) and r 0.84, p<0.0001 in 19 transplant patients receiving angiotensin-converting enzyme inhibitors. MCP-1 levels were highest in non-transplant and ciclosporin-treated patients; geometric mean (SE), 412.4(1.16) and 314.5(1.21) pg/24h respectively. MCP-1 levels were unrelated to age, MAP, creatinine clearance, or blood ciclosporin or tacrolimus levels. Conclusions: Urinary MCP-1 may be a useful non-invasive marker of chronic graft dysfunction in transplant patients fa- cilitating monitoring of progression and response to treatment even in proteinuric patients.

Correlation between finger-prick and venous ciclosporin levels: association with gingival overgrowth and hypertrichosis

The aims of this study were (1) to ascertain ciclosporin C(2) levels currently being achieved in children with steroid-sensitive nephrotic syndrome (SSNS) and renal transplants (RTs), (2) to determine the feasibility of the use of finger-prick samples for the measurement of ciclosporin levels, and (3) to identify any correlation between hypertrichosis or gingival overgrowth (GO) and level of ciclosporin 2 h post-dose (C(2)). Seventy-two children (39 with SSNS, 33 with RT) participated. Ciclosporin 12 h trough (C(12)) and C(2) levels were measured in venous and finger-prick samples by high-performance liquid chromatography tandem mass spectroscopy. Photographs of the teeth and back were taken for assessment of GO and hypertrichosis. Mean (+/-SD) C(2) levels in the SSNS and RT groups were 512 (+/-181) microg/l and 471 (+/-229) microg/l. There was a highly significant relationship between venous and finger-prick ciclosporin levels (r(2) = 0.96, P < 0.0001). Fourteen children had severe GO. There was a small, though statistically significant, impact of ciclosporin level on GO (C(2) r(2) = 0.12, P = 0.003 and C(12) r(2) = 0.06, P = 0.038) but no correlation with dose (milligrammes per kilogramme per day or milligrammes per square metre per day) or duration. Seventeen children had moderate or severe hypertrichosis, this being more common in children of South Asian ethnicity (P < 0.0001). There was no correlation between ciclosporin exposure or duration and hypertrichosis. Finger-prick blood sampling may serve as a practical alternative to venepuncture in children receiving ciclosporin.

Ciclosporin use in multi‐drug therapy for meningoencephalomyelitis of unknown aetiology in dogs

To evaluate the efficacy and safety of ciclosporin therapy alone or in combination with corticosteroids and/or ketoconazole in dogs with diagnosis of meningoencephalomyelitis of unknown aetiology. Medical records of 10 dogs diagnosed with meningoencephalomyelitis of unknown aetiology and treated with ciclosporin therapy alone or in combination with corticosteroids and/or ketoconazole were reviewed at the Veterinary Medical Teaching Hospital, University of Wisconsin-Madison. Laboratory abnormalities, side effects, clinical and cerebrospinal fluid responses to treatment and association between blood ciclosporin level and response to treatment were evaluated. Histopathological diagnosis was available in three patients. No significant abnormalities were detected on serial complete blood count and serum chemistry panel in any of the dogs. Side effects of ciclosporin therapy included excessive shedding, gingival hyperplasia and hypertrichosis. Overall median survival time for all dogs in the study was 930 days (range, 60 to more than 1290 days). In all dogs, serial cerebrospinal fluid analysis showed a marked improvement in the inflammation. Results suggest that ciclosporin either alone or in combination with ketoconazole may be a safe and effective treatment for meningoencephalomyelitis of unknown aetiology in dogs.

Early assessment of renal resistance index after kidney transplant can help predict long-term renal function

Color Doppler ultrasonography of intrarenal arterial resistance index (RI), performed early after kidney transplant, has proven to reliably predict short-term allograft function. The aim of this study was to assess whether it could also predict long-term renal function. We retrospectively analysed 76 kidney transplant patients who underwent RI assessment within 1 month after the transplant, subdivided into two groups according to RI values, lower (group A) or higher (group B) than its median value (0.635). Compared with group A subjects, the patients of group B were older at the time of transplant (42 +/- 9 vs 35 +/- 8 years; P = 0.001), the donor age was also older (41 +/- 16 vs 33 +/- 13 years; P = 0.02) and had a slightly higher proteinuria (0.54 +/- 0.5 vs 0.32 +/- 0.2 g/24 h; P = 0.02). Serum creatinine, ciclosporin or tacrolimus trough level, arterial blood pressure, number of human leukocyte antigen (HLA) mismatches, anti-hypertensive medications and incidence of delayed graft function were not significantly different between the two groups. By univariate analysis, RI turned out to directly correlate with the recipient age, donor age and daily proteinuria (P = 0.007, P = 0.0007 and P = 0.02, respectively). Multivariate analysis showed that only donor and recipient age maintained their independent predictive value on RI. Kaplan-Meier analysis, considering a serum creatinine increase >50% as the endpoint of the study, showed a statistically significant different graft survival in the two groups (log-rank test = 5.489; P = 0.01). The univariate relative risk of deterioration of graft function among patients with higher RI was 3.77. Proteinuria and recipient age increased the risk as well. Our data seem to suggest that early determination of RI can help predict long-term graft function in kidney transplant recipients.

Impact of citrus soft drinks relative to grapefruit juice on ciclosporin disposition

A recent case report had suggested a citrus soft drink (Sun Drop) may have caused clinically relevant elevations in ciclosporin levels through a grapefruit juice-like mechanism via inactivation of intestinal cytochrome P450 3A4 (CYP3A4). This study was conducted to investigate the effect of grapefruit juice and citrus sodas Sun Drop and Fresca, the latter soda containing 83-fold higher concentration of the proposed CYP3A4 inhibitor bergamottin than Sun Drop, relative to water on oral ciclosporin pharmacokinetics. In a randomized four-way crossover study with a washout of at least 1 week, 12 healthy volunteers received a single oral dose of ciclosporin (Neoral) with Sun Drop, Fresca, grapefruit juice and water (control). Each drink (591 ml) was consumed twice on the prior day and three times on the study day. Whole blood concentrations of ciclosporin were measured up to 24 h with a fluorescence polarization immunoassay. Grapefruit juice increased area under the concentration-time curve by 186% (P < 0.0001; 95% confidence interval of mean difference 3302-6240 ng ml h(-1)) and peak concentration by 150% (P < 0.0001) of ciclosporin with a significant decrease in oral clearance of 43% (P < 0.0001) when compared with water. Neither citrus soda altered significantly ciclosporin pharmacokinetic variables; changes in mean values ranged from +/- 3 to 11% of the corresponding water value. Although our results do not support a clinically relevant grapefruit juice-like interaction between oral ciclosporin and citrus constituent containing sodas Sun Drop or Fresca, an effect in the setting of chronic ciclosporin therapy cannot be ruled out.

Dynamics of the Circadian Blood Pressure Profiles after Renal Transplantation

Abnormalities of diurnal blood pressure (BP) rhythm ("nondipping") are well-described in dialysis patients, and have prognostic importance. It is controversial whether successful renal transplantation (RTx) improves diurnal BP rhythm. To date, no study has attempted to define and model the evolution of diurnal BP rhythm profiles from dialysis to engraftment, focusing on the immediate (4-6 weeks) and medium-term (>1 year) postengraftment periods. To test if kidney transplantation normalizes the BP profile, ambulatory blood pressure monitoring (ABPM) was performed in 20 living related transplants (age, 30.3+/-5.1 years; 11 males, on dialysis for 25.6 months) 1 month preRTx and repeated 1 month and >1 year (ABPM3) after successful RTx. Dipping was defined as a sleep-to-awake ratio>0.92 (for systolic BP) and >0.90 (for diastolic BP). PreRTx only 15% patients were dippers. At 1 month postRTx (creatinine clearance, 65.8 ml/min), all patients were complete nondippers. However, after >1 year postRTx (creatinine clearance, 70.4 ml/min), 40% were now dippers. Most importantly, overall, 30% of the patients improved significantly their circadian rhythm (35.3% of the initial preRTx nondippers). Despite successful renal transplantation, 55% patients maintained unchanged their nondipping profile throughout all three ABPM recordings. The only determinants of "long-term" postRTx circadian rhythm are the contemporary level of the renal function and the baseline, dialysis dipping profile: SBP3 sleep-to-awake ratio is related with serum creatinine3 (r=0.58, P=0.001), creatinine clearance (r=-0.41, P=0.036) and SBP1 sleep-to-awake ratio (r=0.48, P=0.034); similarly DBP3 sleep-to-awake ratio is related with serum creatinine3 (r=0.63, P=0.001), creatinine clearance (r=-0.471, P=0.036) and SBP1 sleep-to-awake ratio (r=0.53, P=0.016). In all, 57% of the variance in dipping status can be attributed and explained by the contribution of renal function and initial circadian variability. Half of the nondipper dialysis patients maintain a permanently abnormal circadian rhythm, despite successful RTx. In the short term, RTx is associated with a highly abnormal diurnal profile, exclusively related to ciclosporin dose and levels. However, in the longer term, renal transplantation leads to a significant improvement of the circadian blood pressure profile, influenced by the renal function level and by the pretransplantation dipping profile.

Ezetimibe

Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Following oral administration, ezetimibe is rapidly absorbed and extensively metabolised (>80%) to the pharmacologically active ezetimibe-glucuronide. Total ezetimibe (sum of 'parent' ezetimibe plus ezetimibe-glucuronide) concentrations reach a maximum 1-2 hours post-administration, followed by enterohepatic recycling and slow elimination. The estimated terminal half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours. Consistent with the elimination half-life of ezetimibe, an approximate 2-fold accumulation is observed upon repeated once-daily administration. The recommended dose of ezetimibe 10 mg/day can be administered in the morning or evening without regard to food. There are no clinically significant effects of age, sex or race on ezetimibe pharmacokinetics and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. The major metabolic pathway for ezetimibe consists of glucuronidation of the 4-hydroxyphenyl group by uridine 5'-diphosphate-glucuronosyltransferase isoenzymes to form ezetimibe-glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the faeces predominantly as ezetimibe, with the balance found in the urine mainly as ezetimibe-glucuronide. Overall, ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between ezetimibe and a variety of drugs commonly used in patients with hypercholesterolaemia. Ezetimibe does not have significant effects on plasma levels of HMG-CoA reductase inhibitors commonly known as statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibric acid derivatives (gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and triphasic oral contraceptives (ethinylestradiol and levonorgestrel). Concomitant administration of food, antacids, cimetidine or statins had no significant effect on ezetimibe bioavailability. Although coadministration with gemfibrozil and fenofibrate increased the bioavailability of ezetimibe, the clinical significance is thought to be minor considering the relatively flat dose-response curve of ezetimibe and the lack of dose-related increase in adverse events. In contrast, coadministration with the bile acid binding agent colestyramine significantly decreased ezetimibe oral bioavailability (based on area under the plasma concentration-time curve of total ezetimibe). Hence, ezetimibe and colestyramine should be administered several hours apart to avoid attenuating the efficacy of ezetimibe. Finally, higher ezetimibe exposures were observed in patients receiving concomitant ciclosporin, and ezetimibe caused a small but statistically significant effect on plasma levels of ciclosporin. Because treatment experience in patients receiving ciclosporin is limited, physicians are advised to exercise caution when initiating ezetimibe in the setting of ciclosporin coadministration, and to carefully monitor ciclosporin levels.

Terbinafine in the treatment of onychomycosis: a review of its efficacy in high-risk populations and in patients with nondermatophyte infections.

The prevalence of onychomycosis is higher in certain high-risk populations, such as the immunocompromised, diabetics and human immunodeficiency virus (HIV)-positive patients. These patients can also develop onychomycosis due to nondermatophyte fungi. Although the efficacy of terbinafine is well demonstrated in the treatment of conventional dermatophyte nail infection, there are few data on the efficacy of terbinafine in high-risk patient groups or in nondermatophyte fungi, which can be difficult to treat. To review previously published data regarding the safety and efficacy of terbinafine in special patient populations, such as those with diabetes mellitus or HIV infection, those receiving immunosuppressive therapy, and patients with onychomycosis due to nondermatophyte fungi. A Medline literature search up to October 2002 was performed in order to identify relevant studies. Pertinent abstracts presented at international meetings were also included. Cure rates (per-protocol and intention-to-treat) were extracted or calculated. All available safety data were also collated. Terbinafine was highly effective and well tolerated in patients with diabetes mellitus. Mycological cure rates of 62-78% were achieved in three studies, which is comparable with the efficacy in nondiabetic populations. Mycological cure rates of 64-91% were achieved in subsets of diabetic patients with Candida-positive nail cultures. The efficacy of terbinafine in patients receiving immunosuppressive therapy was also similar to that reported in immunocompetent patients. Levels of ciclosporin in the blood clearly decreased, with little clinical consequence; however, consideration should be given to the monitoring of ciclosporin levels in patients concomitantly receiving immunosuppressive therapy and terbinafine. Two small studies reported that terbinafine was also effective in treating onychomycosis in HIV-positive patients. Terbinafine was also effective and well tolerated in the treatment of nondermatophyte onychomycosis. This review suggests that terbinafine is a safe and effective treatment for onychomycosis in high-risk populations. However, the majority of these studies only included small numbers of patients and larger clinical trials are needed, especially in patients with HIV infection.

P-glycoprotein-170 inhibition significantly reduces cortisol and ciclosporin efflux from human intestinal epithelial cells and T lymphocytes.

To assess the role of P-glycoprotein-170 (P-gp) in transporting cortisol and ciclosporin from human intestinal epithelium and T lymphocytes. The effect of P-gp inhibitors (verapamil, 0-100 microM; PSC 833, 0-20 microM) on the intracellular accumulation of 3H-cortisol and 3H-ciclosporin was studied in confluent layers of human Caco-2 cells (n=6), a P-gp-dependent absorptive intestinal epithelial cell phenotype, and moderately resistant MDRhigh CEM/VBL 100 T cells (n=6). The transport of 3H-vinblastine, a strong multidrug resistance (MDR) substrate, and 3H-progesterone, a poor MDR substrate, was also studied. Caco-2 cells had a 2.4-, 6.6-, 6.7- and 1.03-fold higher net basal to apical transport (efflux) of 3H-cortisol, 3H-ciclosporin, 3H-vinblastine and 3H-progesterone, respectively. PSC 833 (20 microM) reduced cortisol efflux by 69% (0.23 +/- 0.04 to 0.07 +/- 0.01 pmol/cm2/h, P < 0.05) and ciclosporin efflux by 76% (11.1 +/- 1.4 to 2.7 +/- 0.6 pmol/cm2/h, P < 0.001). MDRlow CEM T cells had a 1.4-, 1.9-, 3.2- and 1.02-fold higher intracellular accumulation of cortisol, ciclosporin, vinblastine and progesterone than MDRhigh CEM/VBL 100 T cells. Increasing concentrations of PSC 833 (> 0.1 microM) and verapamil (> 1 microM) restored the intracellular level of 3H-cortisol and 3H-ciclosporin in MDRhigh CEM/VBL 100 T cells to that of MDRlow CEM cells with little change in accumulation in the MDRlow parental cell line. P-gp inhibitors significantly increase intracellular cortisol and ciclosporin levels in human intestinal epithelium and T lymphocytes in a dose-dependent manner, demonstrating a potential mechanism for overcoming poor response to immunosuppressant therapy in refractory inflammatory bowel disease.