Nivolumab-induced pneumonitis and cardiopathy in a patient with relapsed Hodgkin's lymphoma.

INTRODUCTION: Nivolumab, the monoclonal antibody inhibitor of programmed cell death protein 1, enhances the T-cell response, including anti-tumour responses, by blocking the attachment of programmed death-ligand 1 and programmed death-ligand 2 ligands to the programmed cell death protein 1 receptor, which in turn leads to a reduction in tumour growth. Nivolumab has been approved in relapsed or refractory classic Hodgkin's lymphoma after autologous transplantation of haematopoietic stem cell and treatment with brentuximab as monotherapy. CASE REPORT: We herewith report a case of 65-year-old woman who developed an interstitial pneumonitis and a global cardiac hypokinesis following a treatment with Nivolumab for a refractory Hodgkin's Lymphoma. Nivolumab was administered as the fifth line of therapy. Some concomitant patient treatments include drug with known autoimmune toxicities. Although the patient had a persistent complete remission following the sixth infusion, it was discontinued as she developed dyspnea of NYHA stage IV and orthopnea. The chest tomography revealed a bilateral micronodular pattern of organizing pneumonia with bilateral pleural effusion. The forced expiratory volume was decreased to 50%. In parallel her transthoracic echocardiography revealed a global hypokinesis with a left ventricular ejection fraction of 20%. MANAGEMENT AND OUTCOME: The patient was treated with empiric antibiotics although the microbial assessments were negative. She was also treated with beta-blocker and angiotensin-converting enzyme inhibitors. The cardiac magnetic resonance imaging performed after 4 months confirmed the hypokinetic cardiopathy with an ejection fraction of 48%. The patient had a significant clinical improvement. The tomography emission positron scan conducted 8 months after interruption of Nivolumab showed complete remission with some moderate activation of residual lesion basal posterior lobe of left lung field. DISCUSSION: Early and effective diagnosis of immune-related adverse events through the search for predictive biomarkers like drug factors and individual risk factors will allow targeted surveillance leading to a better tolerance.

Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence.

Hepatitis C virus (HCV) recurrence is the most important complication in HCV liver transplant patients. Boceprevir with pegylated interferon and ribavirin (PegIFN/RBV) enabled improvement in sustained virological response rates of patients with genotype 1 HCV. Boceprevir interacts with immunosuppressive therapy (IT) by inhibiting the cytochrome P450 3A enzyme. Our aim was to study interactions and assess the safety of boceprevir in the context of HCV recurrence. Boceprevir (800 mg three times a day) initiated after a 4-week lead-in phase was associated with cyclosporine (three patients), tacrolimus (two patients), and everolimus (one patient) in five liver transplant patients with genotype 1 HCV infection who experienced HCV recurrence. The mean follow-up period after HCV therapy was 14.8 ± 3.1 weeks. Estimated oral clearances of IT decreased on average by 50%, requiring reduced dosing regimens. Anemia occurred in all patients, with a mean fall in hemoglobin levels between baseline and week 12 of 3.12 ± 2.27 g/dl. All patients required administration of ß-erythropoietin (n = 5), three needed ribavirin dose reduction, and one needed a blood transfusion. A virological response was observed in all patients (mean HCV viral load [HVL] decrease at week 12, 6.64 ± 0.35 log(10) IU/ml). These preliminary results in liver transplant patients with HCV recurrence demonstrate the feasibility and safety of coadministration of boceprevir and IT.

Significance of isolated hepatic veno-occlusive disease/sinusoidal obstruction syndrome after liver transplantation.

After liver transplantation (LT), hepatic veno-occlusive disease (VOD), which is also known as sinusoidal obstruction syndrome (SOS), has been reported initially in relation to azathioprine use and subsequently in relation to acute rejection (AR). Isolated veno-occlusive disease (iVOD)/SOS raises some questions about its significance and especially its treatment. From the post-LT biopsy samples of 1364 patients (2000-2008), 31 patients with index biopsy samples showing VOD/SOS (2.3%) were identified. After a review of the index biopsy samples and previous biopsy samples, those patients not exposed to azathioprine therapy were subdivided into 2 groups according to the absence or presence of AR. Fifteen of the 31 patients had no previous evidence of AR, whereas 16 experienced episodes of AR (before or concurrently with VOD). The 2 groups were similar in terms of demographic and clinical data and the range of histological centrilobular changes. AR episodes were characterized by an endothelial predilection. iVOD/SOS occurred later than acute rejection-related veno-occlusive disease (AR-VOD)/SOS (mean times of 65 and 4.4 months, respectively, P = 0.0098). There was a tendency for iVOD/SOS to progress less frequently to chronic rejection in comparison with AR-VOD/SOS (3/15 versus 9/15, P = 0.06). The histological resolution of iVOD/SOS was significantly more frequent in patients who benefited from increased immunosuppression in comparison with those who did not (5/7 versus 2/8, P = 0.05). When the groups were considered together, the same result was obtained (14/18 versus 4/12, P = 0.024). In conclusion, despite a constant overall prevalence of VOD/SOS, the proportion of iVOD/SOS has increased. The histological resolution of iVOD/SOS after increase in immunosuppression suggests an immune-mediated origin. Better optimization of immunosuppression may be a curative treatment.

Cytotoxics compounded sterile preparation control by HPLC during a 16-month assessment in a French university hospital: importance of the mixing bags step.

The Centralized Chemotherapy Reconstitution Unit (CCRU) of Paul Brousse Hospital Pharmacy Department assessed the reliability of its Cytotoxics Compounded Sterile Products (CCSP) preparation method in order to improve its CCSP quality assurance system. Five cytotoxic drugs - gemcitabine, 5-fluorouracil, docetaxel, paclitaxel, and oxaliplatin - were assayed by high performance liquid chromatography (HPLC) to determine CCSP concentration. During the observation period, 23,892 CCSP were prepared. Overall, 12,964 preparations contained one of the five analyzed drugs; 7382 (56.9%) out of 12,964 CCSP were analyzed by HPLC; 646 (8.8%) out of 7382 concentrations were outside ± 20% of the prescribed dose; 544 (84.2%) out of 646 were post-administration results and could not be verified. Out of 102 (15.8%) pre-administration results that were re-tested after re-shaking, 94 (92.2%) were found to be acceptable upon re-testing, and 8 (7.8%) were confirmed to be unacceptable and needed to be re-compounded. The 8.8% of tested CCSP were outside ± 20% of the prescribed dose, but extrapolating the results on re-tested CCSP, we can say that our CCSP preparation is reliable with an estimation of only 0.7% of 7382 CCSP analyzed, confirmed as being ± 20% outside the prescribed dose. Nevertheless, this ± 20% magnitude of error should be reduced. Based on pre-administration results, the primary cause of concentration errors appeared to be insufficient mixing of the finished product. Most CCSP dosages occurred after it had been administered, the organization should, therefore, be improved to include testing all CCSP prior to administration. Pharmaceutical companies should endeavor to manufacture compounded injectible drugs in a 'ready to use' form and provide vehicles in accurate volumes in order to improve compounding precision.

Interleukin-2 treatment effect on imatinib pharmacokinetic, P-gp and BCRP expression in mice.

The aim of this study was to investigate the effect that recombinant interleukin-2 (rIL-2) (0.16 MUI/injection) had on the pharmacokinetics of imatinib (IM) in plasma. In this study, IM was given orally to mice at a dose of 150 mg/kg once a day for 11 days (from day 1 to 11) either alone or in combination with intraperitoneal injections of rIL-2 twice a day from day 8 to 11. Pharmacokinetic parameters were determined using WinNonLin software. Areas under the curve were compared using Bailer's method. The repeated administration of the rIL-2+IM combination was shown to have two pharmacokinetic advantages compared with repeated IM doses alone. In addition to the pharmacodynamic interest of this treatment, we found that the combined treatment significantly increased the IM Cmax (P<0.05) and significantly increased the IM trough concentration (C(24 h)) (P<0.01), which was always above the minimum therapeutic IM concentration (1 mumol/l) in plasma. Those pharmacokinetic modifications may be explained, in part, by a decrease in the P-glycoprotein expression in the three intestinal segments of the mice (duodenum, P<0.01; jejunum, P<0.05; and ileum, P<0.05) and a decrease in BCRP expression in the duodenum segment (P<0.05) due to rIL-2. In another experiment, we found a significant induction of intestinal P-glycoprotein expression in mice that had been given IM orally (150 mg/kg) twice a day for 11 days. It would be interesting to further investigate the IM disposition associated with rIL-2 treatment for clinical applications.

Enfuvirtide: a safe and effective antiretroviral agent for human immunodeficiency virus-infected patients shortly after liver transplantation.

The aim of this study was to evaluate the impact of an enfuvirtide-based antiretroviral (ARV) regimen on the management of immunosuppression and follow-up in hepatitis C virus (HCV)/hepatitis B virus (HBV)/human immunodeficiency virus (HIV)-coinfected liver transplant patients in comparison with a lopinavir/ritonavir-based ARV regimen. Tacrolimus and cyclosporine trough concentrations were determined at a steady state during 3 periods: after liver transplantation without ARV treatment (period 1), at the time of ARV reintroduction (period 2), and 2 to 3 months after liver transplantation (period 3). The findings for 22 HIV-coinfected patients were compared (18 with HCV and 4 with HBV); 11 patients were treated with enfuvirtide and were matched with 11 lopinavir/ritonavir-exposed patients. During period 1, tacrolimus and cyclosporine A doses were 8 and 600 mg/day, respectively, and the trough concentrations were within the therapeutic range in both groups. In period 2, the addition of lopinavir/ritonavir to the immunosuppressant regimen enabled a reduction in the dose of immunosuppressants required to maintain trough concentrations within the therapeutic range (to 0.3 mg/day for tacrolimus and 75 mg/day for cyclosporine). Immunosuppressant doses were not modified by the reintroduction of enfuvirtide, there being no change in the mean trough concentrations over the 3 periods. CD4 cell counts remained at about 200 cells/mm3. The HIV RNA viral load remained undetectable. Both groups displayed signs of mild cytolysis and cholestasis due to the recurrence of HCV, whereas no renal insufficiency was observed. Enfuvirtide is an attractive alternative to standard ARV therapy, facilitating the management of drug-drug interactions shortly after liver transplantation. Moreover, the lack of liver toxicity renders this drug valuable in the event of a severe HCV recurrence.

Effect of interleukin-2 pretreatment on paclitaxel absorption and tissue disposition after oral and intravenous administration in mice.

The aim of the present study was to investigate the effects of recombinant interleukin (rIL)-2 treatment on paclitaxel (PLX) pharmacokinetics in the plasma and tissue of Lewis lung carcinoma-bearing mice (lung tissues and s.c. tumors). PLX pharmacokinetics studies were conducted after oral and i.v. administration of 15 and 4 mg/kg, respectively, either alone or after 3 days of rIL-2 pretreatment. The noncompartmental approach was used to determine the mean pharmacokinetic parameters using WinNonlin software (Pharsight, Mountain View, CA). The influence of rIL-2 pretreatment on physiological P-glycoprotein (P-gp) expression in lung and intestine was investigated by Western blot analysis. After oral administration of PLX, areas under the curve (AUC) in plasma, lung, and s.c. tumors were significantly higher (2.98, 2.66, and 3.41-fold, respectively) in the rIL-2 + PLX group as compared with the PLX group. However, no significant effect of rIL-2 pretreatment was observed in plasma or lung following i.v. administration of PLX. PLX AUC in s.c. tumors was significantly higher (1.37-fold) with rIL-2 pretreatment as compared with the PLX-alone group after i.v. injection. Pretreatment with rIL-2 appeared to have no effect on PLX plasma terminal half-life when PLX was administered orally or i.v. However, prolongation of PLX terminal half-life estimated from lung and s.c. tumors data had been observed. Increased PLX tissue absorption in the rIL-2-pretreated group may be explained by a decrease of P-gp expression in the intestines and lung or decreased functionality due to rIL-2. Oral administration allowed the targeted tissues a much higher PLX exposure as compared with i.v. administration.

Disposition of Delta tetrahydrocannabinol in CF1 mice deficient in mdr1a P-glycoprotein.

P-glycoprotein (P-gp) plays a major role in drug efflux. All the transported substrates are more or less hydrophobic and amphiphatic in nature. Being lipophilic, Delta(9) tetrahydrocannabinol (THC), the main cannabis component, could be a potential P-gp substrate. The aim of this project was to determine the contribution of the mdr1a gene product to THC disposition. Therefore, oral THC and digoxin (substrate test for P-gp) pharmacokinetics have been investigated in the intestinal epithelium and in the brain capillary endothelium of CF1 mdr1a-/- mice (mice naturally deficient in P-gp). These pharmacokinetics were compared to THC and digoxin oral pharmacokinetics in wild type mice mdr1a+/+ (not P-gp deficient). The application of Bailer's method showed that THC total exposure measured by the area under the plasma concentration time curve was 2.17-fold higher in CF1 mice naturally deficient in P-gp than in wild type mice after oral administration of 25 mg/kg of THC, and 2.4-fold higher after oral administration of 33 microg/kg of digoxin. As a consequence, the oral bioavailability of THC and digoxin was higher in naturally P-gp-deficient mice. We concluded that P-gp limits THC oral uptake and mediates direct drug excretion from the systemic circulation into the intestinal lumen.

Human-cell-derived organoids as a new ex vivo model for drug assays in oncology.

In oncology, a 2D in vitro model of cancer cell lines is still widely used for large-scale drug screening. However, most promising candidates firstly identified by in vitro analysis tend to fail during the next steps of drug development. The generation of an ex vivo approach termed 'organoid' is emerging as a promising preclinical model to mimic human tumors more accurately. In this review, we focus on human-derived organoid use for anticancer drug screening. We describe the development of this new in vitro model, its use for anticancer agent assays and the advantages compared with the currently used 2D models. Finally, we discuss organoid limitations in the common use of this technology during preclinical studies.

Effect of highly active antiretroviral therapy on tacrolimus pharmacokinetics in hepatitis C virus and HIV co-infected liver transplant recipients in the ANRS HC-08 study.

OBJECTIVE: To characterise the interactions between tacrolimus and antiretroviral drug combinations in hepatitis C virus-HIV co-infected patients who had received a liver transplant. DESIGN: An observational, open-label, multiple-dose, two-period, one-sequence design clinical trial in which patients received tacrolimus as an immunosuppressive therapy during the postoperative period and then had an antiretroviral drug regimen added. Tacrolimus pharmacokinetics were evaluated at steady state during these two periods. METHODS: Fourteen patients participated in the study and seven participated in the intensified pharmacokinetic protocol. Patients were included if they had undergone liver transplantation for end-stage chronic hepatitis C, absence of opportunistic infection, a CD4 cell count of >150 cells/microL and an undetectable HIV plasma viral load (<50 copies/mL) under highly active antiretroviral therapy. During the posttransplantation period, the tacrolimus dose was adjusted according to blood concentrations. When liver function and the tacrolimus dose were stable, antiretroviral therapy was reintroduced. RESULTS: When lopinavir/ritonavir were added to the tacrolimus regimen (seven patients), the tacrolimus dose was reduced by 99% to maintain the tacrolimus concentration within the therapeutic range. Only two patients were treated with nelfinavir, which led to a wide variation in inhibition of tacrolimus metabolism. When efavirenz (four patients) or a nucleoside analogue combination (one patient) was added, very little change in tacrolimus dosing was required. CONCLUSION: The lopinavir/ritonavir combination markedly inhibited tacrolimus metabolism, whereas the effect of efavirenz was small. Tacrolimus dosing must be optimised according to therapeutic drug monitoring and the antiretroviral drug combination.

Bioavailability and tissular distribution of docetaxel, a P-glycoprotein substrate, are modified by interferon-alpha in rats.

Interferon-alpha (IFN-alpha) inhibits intestinal P-glycoprotein (P-gp) expression in rats. In the present study, the effects of repeated pre-treatment with recombinant human INF-alpha (rhIFN-alpha) on oral and intravenous pharmacokinetics of a P-gp substrate, docetaxel (DTX; Taxotere) were investigated in a rat model. The bioavailability and distribution in different organs were also studied. Sprague-Dawley rats were subcutaneously pre-treated with either rhIFN-alpha for 8 days (4MIU kg(-1), once daily) or with pegylated-IFN-alpha (ViraferonPeg; 60 microg kg(-1), Days 1, 4 and 7). The rats were then distributed into sub-groups (n = 5-6) according to the pre-treatment type, and received one dose of [(14)C]DTX (20 mgkg(-1)) either orally or intravenously. Pharmacokinetics studies were then performed over 240 min, at the end of which tissues (intestine, liver, kidneys, lung, heart and brain) were immediately removed for radioactivity quantitation. Non-pegylated and pegylated IFN-alpha both increased DTX oral bioavailability parameters: C(max) (17.0+/-4.0 microg L(-1) (P < 0.02) and 18+/-5.5 microg L(-1) (P < 0.05), respectively, vs 7.4+/-2.5 microg L(-1) for the control) and AUC (0.036+/-0.010 microg h mL(-1) (P < 0.01) and 0.033+/-0.009 microg h mL(-1) (P < 0.01), respectively, versus 0.012+/-0.004 microg h mL(-1) for the control). IFN-alpha also delayed DTX absorption from 60 min in controls to about 95 min and 80 min in non-pegylated and pegylated treated animals, respectively. However, IFN-alpha did not affect intravenous DTX pharmacokinetics and it had a limited effect on tissue distribution at 240 min. [(14)C]DTX was decreased in intestine and enhanced in brain in both pre-treated groups. rhIFN-alpha modified the P-gp-dependent pharmacokinetics of DTX, limited its intestinal efflux and markedly enhanced its oral bioavailability.

Prognostic value of serum interleukin-6 (IL-6) levels in long term care.

The aim of this prospective study was to examine the relationship between IL-6 levels and survival in an elderly population in a long term hospital care ward. All of the 184 women and 65 men hospitalized in the geriatric unit regardless of their health status were included. The plasma levels of interleukin-6 were measured at baseline and deaths were assessed over a 2-year period. IL-6 levels of at least 3pg/ml in men and 5.6pg/ml in women were respectively associated with a relative risk of death of 2.28 (CI(95): 1.04-4.95) and 1.52 (CI(95): 1.06-2.18). After adjustment for age class, the reduced survival observed with these thresholds only remained unchanged in men, the difference in survival in women was not significant. Our conclusion is that even in an elderly hospitalized population, high IL-6 levels were associated with poor survival. The lower survival rate after adjustment for class of age found in men but not in women suggests a gender-related specificity.

Correlation between clinical response to sorafenib in hepatocellular carcinoma treatment and polymorphisms of P-glycoprotein (ABCB1) and of breast cancer resistance protein (ABCG2): monocentric study.

OBJECTIVES: We studied the relation between the polymorphism of P-glycoprotein (P-gp) and of breast cancer resistance protein (BCRP), encoded by ABCB1 and ABCG2 genes, respectively, and the pharmacokinetic variability and clinical response during the treatment with sorafenib of hepatocellular carcinoma. METHODS: At the Paul Brousse Hospital in Villejuif, France, 47 consecutive patients with advanced HCC treated with a single agent sorafenib, were enrolled. Sorafenib exposure was measured by its plasma concentration 3 h after oral administration of 400 mg (bid) by liquid chromatography. All enrolled patients were genotyped for ABCB1 (rs2032582; rs1045642) and ABCG2 (rs2231137; rs2231142; rs2622604) by blood genomic DNA extraction and Mass ARRAY genotyping. The clinical response was evaluated after 3months of treatment according to the RECIST criteria. KEY FINDINGS: Significant associations between sorafenib exposure and the studied polymorphisms were observed for ABCB1 3435C>T, ABCG2 34G>A, ABCG2 1143C>T and ABCG2 421C>A, but not for ABCB1 2677G>TA SNP. In heterozygous patients for ABCB1 3435 C>T, ABCG2 34 G>A and ABCG2 1143 C>T polymorphisms were significantly associated with the lowest sorafenib plasma levels. Those patients presented a tendency to have the best clinical evolution. CONCLUSION: Heterozygous forms of the studied polymorphisms could be associated with a better therapeutic response.

Development and validation of a method for the quantitation of Delta9 tetrahydrocannabinol in human plasma by high performance liquid chromatography after solid-phase extraction.

A high performance liquid chromatography (HPLC) procedure for the determination of Delta9 tetrahydrocannabinol (THC) in human plasma is described. A two-step solid-phase extraction on CN cartridges was coupled with a reversed phase HPLC system. THC was eluted using a mobile phase composed of methanol, acetonitrile and tetrabutylammonium perchlorate solution (0.005 M, pH 3.2), through a C18 Nucleosil column and detected at a wavelength of 215 nm. Calibration curve was linear over the range 5-100 ng/ml with a lower limit of quantification validated at 5 ng/ml. Extraction recovery using the developed extraction procedure was higher than 85%. This method is presently used for the quantification of THC in plasma samples from regular cannabis smokers.

Pharmacokinetics and neutrophil toxicity of paclitaxel orally administered in mice with recombinant interleukin-2.

PURPOSE: Intrinsic P-glycoprotein (P-gp) expression in the gut limits paclitaxel uptake and, thus, its bioavailability when administered orally. Interleukin-2 has been reported to be a P-gp modulator in vitro and in vivo in mice. In the work described here, the effects of interleukin-2 pretreatment on pharmacokinetics and toxicity of paclitaxel orally administered were investigated. METHODS: For the pharmacokinetic study, 96 mice were allocated to two groups receiving either 10 mg/kg of paclitaxel by the oral route alone or 16.5 microg of human recombinant interleukin-2 (rIL2) by the intraperitoneal route twice daily for 3 days and then paclitaxel. Pharmacokinetic profiles were analysed first by the Bailer method, and then using a compartmental approach. For the toxicity study, 90 Swiss mice were allocated to three groups receiving paclitaxel (10 mg/kg orally), rIL2 alone (16.5 microg i.p. twice daily for 3 days, control group), or both treatments. Haematological parameters were measured and the three groups were compared using the Bailer method. A Bonferroni correction was applied to the test. RESULTS: A complex absorption of paclitaxel was revealed. The Bailer method showed that the mean area under the curve (AUC) values over 0-24 h were not significantly different in the two groups, despite a trend to reduced AUC in the pretreated group. The AUC over 0-0.5 h was significantly higher in the group pretreated with rIL2, but represented only a fraction of total exposure. These results were confirmed by the compartmental analysis. The elimination rate constant remained the same across both groups. rIL2 thus increased paclitaxel absorption for the 15 min following oral intake of the drug but did not enhance the overall exposure. CONCLUSION: We found that a 3-day pretreatment with rIL2 had some in vivo inhibitory effects on P-gp activity for a short period after oral dosing of paclitaxel. Those results encourage further investigation of the effect of rIL2 on the overall exposure of paclitaxel. On the other hand, it seems that the joint administration of the two drugs did not increase the risk of myelosuppression, which might be worth knowing to treat advanced cancers.

Therapy with boceprevir or telaprevir in HIV/hepatitis C virus co-infected patients to treat recurrence of hepatitis C virus infection after liver transplantation.

OBJECTIVE: Severe hepatitis C virus (HCV) recurrence affects post-transplant survival in HIV/HCV co-infected patients. This article describes the results of triple anti-HCV therapy with boceprevir or telaprevir in seven HIV/HCV co-infected patients following liver transplantation. METHODS: All patients had severe HCV recurrence [fibrosis stage ≥F2 or acute hepatitis ≥A2 (n = 5) or fibrosing cholestatic hepatitis (n = 2)] associated with genotype 1a (n = 4) or 1b (n = 3). Patients were treated with Peg-interferon/ribavirin and boceprevir (n = 2) or telaprevir (n = 5) immediately (n = 3) or after a 4-week lead-in phase (n = 4). Immunosuppression included either cyclosporine (n = 5) or tacrolimus (n = 2). Prior to introducing telaprevir, combined antiretroviral therapy was switched in one patient to prevent drug-drug interactions. RESULTS: At 24 weeks after the end of treatment, sustained virological response was observed in 60% (3/5) of the patients treated with telaprevir; no responders were observed in the boceprevir group. Triple anti-HCV therapy was prematurely discontinued in six patients [treatment failure (n = 2), infection (n = 2), acute rejection (n = 1) and myocardial infarction (n = 1)]. Anaemia occurred in all patients, requiring erythropoietin, ribavirin dose reduction and red blood cell transfusions in five patients.Average cyclosporine doses were reduced by 50-84% after telaprevir initiation and by 33% after boceprevir initiation. Tacrolimus doses were reduced by 95% with telaprevir. CONCLUSION: Our data suggest that in HIV/HCV co-infected patients, triple anti-HCV therapy with telaprevir greatly improved efficacy despite poor tolerability. Significant decreases in cyclosporine or tacrolimus doses are necessary prior to introduction of boceprevir or telaprevir. Close monitoring is essential to prevent drug-drug interactions among antiretroviral therapy, immunosuppressive agents and anti-HCV therapy.

MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients.

BACKGROUND: Cyclosporine A (CsA) is characterized by high interindividual variations in oral bioavailability and a narrow therapeutic index. CsA is a substrate for P-glycoprotein, a member of the ABC transporter family encoded by the multiple drug-resistant gene MDR1. METHODS: Because MDR1 gene exon 26 C3435T polymorphism influences intestinal P-glycoprotein expression, we investigated whether this polymorphism was correlated with variation in CsA dose requirement and concentration/dose ratio in 44 liver-transplant recipients during 1 month after transplantation. CsA concentration was measured 2 hours after administration (C2), according to international recommendations. RESULTS: The MDR-1 wild-type genotype (3435CC) was observed in 15 patients (34%), whereas 21 (48%) patients were heterozygous (3435CT), and 8 (18%) patients were homozygous for the mutation (3435TT). There was no significant difference between the three groups regarding corticosteroids treatment or renal function during this period. One to 3 days after liver transplantation, when every patient received a similar CsA weight-adjusted dose, the concentration/dose ratio was correlated with exon 26 single nucleotide polymorphism and was significantly higher in subjects homozygous for the mutation (P=0.012). This was confirmed 1 month after transplantation (P=0.049), when the dose was adjusted to maintain the C2 target level of 1,000 microg/L and we observed that TT patients required approximately 50% lower weight-adjusted CsA dose than wild-type patients (P=0,033). CONCLUSIONS: These findings demonstrate that the MDR1 exon 26 C3435T polymorphism is a major determinant of CsA concentration/dose ratio in liver-transplant recipients and is predictive of the dose of CsA to be administered to achieve the target C(2) concentration.

Enhanced oral bioavailability of paclitaxel by recombinant interleukin-2 in mice with murine Lewis lung carcinoma.

The effect of recombinant interleukin-2 (rIL-2) pretreatment on the pharmacokinetics of paclitaxel was investigated in the murine Lewis lung carcinoma model in C57B1/6 mice. Paclitaxel 15 mg/kg was administrated orally to mice, either alone or after 3 days pretreatment with twice daily dose of 16.5 microg rIL-2. Plasma concentrations of paclitaxel were estimated by reversed phase HPLC. Pharmacokinetic parameters were determined using MicroPharm software. Using Bailer's method, a significant difference was observed in the AUCs of paclitaxel administrated alone and with rIL-2 pretreatment (928.2 +/- 136.8 vs 2549.6 +/- 131.3 ng.h.ml(-1), p <0.0001). Pretreatment with rIL-2 resulted in a 3-fold increase in the oral bioavailability of paclitaxel without altering its elimination half-life (0.798 vs 0.747 h). This could be due to the inhibition of P-glycoprotein (P-gp) mediated transport, thus enhancing paclitaxel intestinal absorption. The combination of these two drugs could be of interest in clinical practice due to their activity in pulmonary cancer.

Effects of electromagnetic fields on the immune systems of occupationally exposed humans and mice.

The authors examined immunological disorders in 6 individuals who had been exposed occupationally to environmental electromagnetic fields. Comparable effects on mice exposed in a similar environment were also investigated. The human subjects had worked 8 hr/day for 5 yr in a laboratory located above electrical transformers and high-tension cables, and in which there were low-frequency electromagnetic fields of 0.2-6.6 microtesla (microT). The 6 control subjects (matched for socioeconomic parameters, sex, and age) had worked away from the immediate vicinity of transformers and high-tension cables. The authors found statistically significantly lower total lymphocyte, CD4, and CD3 counts, and significantly increased natural killer (NK) cells, in exposed subjects vs. controls. Six months after exposure had ceased, total lymphocyte counts had increased, as had CD4, CD3, and CD19 counts (+13%, +28%, +22%, and +17%, respectively), and NK cell counts were decreased by 26% (not significant) in the same human subjects. In the second part of this study, 12 Swiss male mice housed in cages were exposed in the same room in which the human subjects had been exposed (i.e., 5-microT, 50-Hz magnetic field) for 109 days; 12 additional mice were used as unexposed controls. The total lymphocyte, leukocyte, polymorphonuclear neutrophil, CD4, and NK counts of the exposed mice at 109 days were significantly lower than those of controls. In addition, plasma glucose levels (at 30 days) and amylase activity (at 109 days) were significantly lower, whereas plasma sodium and chloride levels were significantly elevated at 109 days. Results from this study suggest that chronic exposure to a 0.2-6.6-microT magnetic field can lead to decreased immunological parameters (total lymphocytes and CD4 counts) in both humans and mice. The increase in some values once exposure was terminated suggests a causal relationship with exposure to electromagnetic fields, as do the changes in mice, particularly the changes in total lymphocyte and CD4 counts.