The safety profile of probiotic VSL#3®. A meta-analysis of safety data from double-blind, randomized, placebo-controlled clinical trials.

The article "The safety profile of probiotic VSL#3®. A meta-analysis of safety data from double-blind, randomized, placebo-controlled clinical trials", by V. Panetta, A. Bacchieri, S. Papetti, E. De Stefani, P. Navarra, published in Eur Rev Med Pharmacol Sci 2020; 24 (2): 963-973-DOI: 10.26355/eurrev_202001_20082-PMID: 32017005, has been retracted based on commentary received from a new set of reviewers.  The authors will be able to resubmit a new article addressing the reviewers' comments for the Journal's consideration. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/20082.

Compassionate drug uses and saving for the national health system: the case study of Fondazione Policlinico Gemelli.

OBJECTIVE: Compassionate Drug Use (CDU) allows patients with a specific disease and no further treatment option to access unauthorized treatments. In this study, we analyzed the requests of CDU approved by the Ethics Committee of Fondazione Policlinico Gemelli in the period January 1, 2018-June 30, 2021. We also estimated the economic impact of CUs. MATERIALS AND METHODS: CDU requests were analyzed by year, by frequency and by regulatory status of the medicines requested. If an ex-factory price was available at the cutoff date of June 30, 2021, we estimated what would have been the costs for the National Health System (NHS) if the price was already negotiated at the time of CDU request. RESULTS: In the study period, 463 CDU requests were processed by the Ethics Committee. The number of requests increase linearly from 45 in 2018 to an estimated number of 260 in 2021. The requests included 68 medicines or combinations of medicines; 16 products out of 68 accounted for 75% of all requests. For 7 of these 16 highly requested treatments, accounting for 110 requests out of 463, it was possible to estimate the costs of therapies according to their ex-factory prices. If these products were to be purchased by the NHS, the estimated cost was € 5.472.225. CONCLUSIONS: The access to unauthorized drugs through CDUs is undergoing a huge increase in the last few years. Such increase meets the ethical need to provide patients with the most recent, often innovative, therapeutic options.

Effects of remifentanil on human C20 microglial pro-inflammatory activation.

OBJECTIVE: Remifentanil (RF) is a potent short-acting µ-opioid receptor agonist. Although preferred for its unique pharmacokinetics, the clinical use may be limited by hyperalgesia. Preclinical studies have shown a potential role of microglia on the development of hyperalgesia, with limited and conflicting evidence on RF. Considering the role of microglia in the initiation and maintenance of brain inflammation and their different responses among species, we aimed at characterizing RF effects on human adult microglia in vitro. MATERIALS AND METHODS: RF was tested at clinically relevant concentrations on the human microglial C20 cell line. Expression and release of interleukin-6 (IL-6) and brain derived neurotrophic factor (BDNF) were assessed under basal and inflammatory conditions. RESULTS: The expression and secretion of IL-6 significantly increased in C20 cells in response to pro-inflammatory cytokines. RF did not modify this response neither under basal nor under inflammatory conditions. No toxicity due to RF was detected. The drug displayed a modest stimulatory effect on the production of BDNF. CONCLUSIONS: Although RF does not exert direct pro-inflammatory actions on human adult microglia, its effects on BDNF, a crucial mediator of pain transmission, suggest a possible role on neuroinflammation and pain perception.

Relationship between injection site reactions and different adalimumab formulations. Analysis of the adverse events reported in Italy in the period 2016-2019.

OBJECTIVE: The adalimumab originator Humira® introduced a new citrate-free formulation in 2016, before the patent expiry that occurred in the European Union in October 2018. Some of the adalimumab biosimilars that were subsequently marketed are citrate-free, while others are not. Since citrate as an excipient is associated with pain at the injection site, recent anecdotical reporting in Italy raised the issue of possible prescription biases related to the differences in formulation existing among the various adalimumab products. In this study, we analyzed the data obtained from the 'Rete Nazionale di Farmacovigilanza' (Pharmacovigilance National Network) to investigate whether, and to what extent, the differences in the formulation of the various adalimumab versions had an impact on the rate of injection site reactions reported in Italy in the period 2016-2019. MATERIALS AND METHODS: A search was conducted based on 3 search criteria: (1) time frame; (2) suspected drugs, and (3) adverse reaction type. Reports classified in the System Organ Class "Administration site conditions" were analyzed by year, product, and type of adverse event (whether including or not 'pain'). Data were reported both as absolute numbers, as well as signaling rates, considering the consumption data expressed as defined daily doses (DDD). RESULTS: We found that: (1) The change in Humira® formulation introduced in august 2016 was followed by a decrease in the reports of injection site reactions (from 45 in 2016 to 12, 12 and 8 in 2017, 2018, and 2019, respectively); (2) after the introduction of biosimilars during 2018, in 2019 a marked shift in reporting toward biosimilars was observed (52 out of 60; 87%). CONCLUSIONS: While the decrease in Humira® reports is consistent with the improved tolerability of the new formulation, the huge increase in biosimilar reporting may be only in part explained by the differences in formulation and cannot be accounted for by a parallel increase in exposure, since 58.3% of total DDDs provided in 2019 were still attributed to Humira®.

The safety profile of probiotic VSL#3®. A meta-analysis of safety data from double-blind, randomized, placebo-controlled clinical trials.

OBJECTIVE: A high-concentration of a multi-strain probiotic mixture, VSL#3® is widely used 'whenever it is useful to promote the balance of intestinal flora'. As a food supplement, VSL#3® has been so far scarcely investigated on the aspect of safety. To fill this gap, in this paper, we analyzed the adverse events (AEs) recorded during the conduct of three (3) double-blind, randomized, placebo-controlled trials carried out to explore the efficacy of VSL#3® in various clinical settings. Data from a large open-label observational trial were also considered. MATERIALS AND METHODS: All trials included in the analysis were carried out according to good clinical practice (GCP) rules. AEs were classified by System Organ Class (SOC), Preferred Term (PT) and frequency. Differences vs. placebo control were considered as statistically significant if the p-value was < 0.05. RESULTS: A total of 120 patients were analyzed, 70 patients being included in the randomized controlled trials. In this population, 45 patients had at least one AE, 20 (64.5%) in the placebo group and 25 (64.1%) in the VSL#3® group. 29 patients had at least one related AE, 14 (45.2%) and 15 (38.5%) in the two treatment groups, respectively. Only one AE was assessed as serious, i.e., Foetal malformation, which occurred in the placebo group and was considered unrelated. No significant difference was found between VSL#3® and placebo for any of the SOC considered, with the exception of Injury, poisoning and procedural complications, which was in favor of VSL#3®. CONCLUSIONS: Based on GCP-quality data from clinical trials, we conclude that VSL#3® is a safe and well-tolerated agent.

Relationship between blood remifentanil concentration and stress hormone levels during pneumoperitoneum in patients undergoing laparoscopic cholecystectomy.

OBJECTIVE: The effect of remifentanil on stress response to surgery is unclear. However, there are not clinical studies investigating the relationship between blood remifentanil concentrations and stress hormones. Therefore, the aim of the present study was to assess the association between blood remifentanil concentrations measured after pneumoperitoneum and cortisol (CORT) or prolactin (PRL) ratio (intraoperative/preoperative value), in patients undergoing laparoscopic cholecystectomy. PATIENTS AND METHODS: Patients did not receive any pre-anesthetic medication. Anesthesia induction was standardized. Anesthesia maintenance was performed with inhaled sevoflurane at age-adjusted 1.0 minimum alveolar concentration and intravenous remifentanil at infusion rate ranging from 0.1 to 0.4 mcg/kg/min. Blood samples were withdrawn before anesthesia induction and 5 min after achieving a pneumoperitoneum pressure of 12 mmHg. Correlation analyses were performed to evaluate the relationship between measured blood remifentanil concentrations, CORT or PRL ratio (intraoperative/preoperative value) and remifentanil dose delivered by the pump. RESULTS: A significant inverse correlation was found between CORT ratio and measured blood remifentanil concentration (p=0.03) or planned remifentanil dose (p=0.04). No correlations were found between blood remifentanil concentration and PRL ratio (p=0.83). CONCLUSIONS: Our data suggest that the CORT response to surgical stress is more efficiently counteracted by increased blood remifentanil concentration.

Expression of iNOS, CD163 and ARG-1 taken as M1 and M2 markers of microglial polarization in human glioblastoma and the surrounding normal parenchyma.

Microglia and macrophages appear to be the most common cells in the GBM microenvironment. In the present study we investigated the status of macrophages/microglia activation in surgical specimens from 41 patients diagnosed with grade IV GBM. For each patient we analyzed both the center of tumor and the parenchyma surrounding the tumor. The specimens were stained for: i) IBA1, a 17-kDa EF hand protein specifically expressed in microglia/macrophages ii) CD163, a cell surface antigen associated with M2 phenotype; iii) iNOS, taken as a functional marker of M1 phenotype, and iv) ARG-I, taken as a functional marker of M2 phenotype. Staining was scored in a double-blinded score on a scale from 0 to 5. Our results suggest that CD163 expression is higher within the tumor than in surrounding periphery in both male and female patients; while iNOS is higher within the tumor in males, no significant difference was found for ARG-1. In addition, analyzing the data in TGCA database, we found that CD163 expression was significantly and inversely correlated with mean survival times, with average survival times ranging from 448days in patients having low expression, to 319 in mid, and 353 in patients with high CD163 expressing tumors. In contrast, no significant association was found between survival time and ARG-1 or iNOS expression.

Lacosamide inhibits calcitonin gene-related peptide production and release at trigeminal level in the rat.

BACKGROUND: Several classes of drugs are effective in prevention and treatment of migraine, although they may differ among each other in their mode of action and in indications. One such class is represented by antiepileptics. Lacosamide is an approved antiepileptic drug that also shows antinociceptive activity in animal models, including analgesic efficacy in central and trigeminal pain. Calcitonin gene-related peptide (CGRP) is considered the main neuro-mediator of trigeminal signalling, playing an essential role in headache, migraine in particular. Here, we investigated the effects of lacosamide on CGRP signalling in both in vitro and ex vivo/vitro models in the rat. METHODS: We assessed: (1) CGRP released from brainstem explants at baseline or after pharmacological challenges; and (2) CGRP levels in brain areas after in vivo treatments with test drugs. RESULTS: We found that: (1) lacosamide inhibits CGRP release from brainstem explants under basal conditions as well as after stimulation by 56 mM KCl, 10 µM veratridine or 1 µM capsaicin; and (2) the i.p. administration of nitroglycerine produces an increase in CGRP levels in the brainstem and trigeminal ganglia, which is inhibited by a pre-treatment with lacosamide. CONCLUSIONS: These findings provide preliminary evidence suggesting that lacosamide is able to control pain transmission under conditions affecting the trigeminal system, such as migraine.

Effects of the administration of epidermal growth factor receptor specific inhibitor cetuximab, alone and in combination with cisplatin, on proliferation and apoptosis of Hep-2 laryngeal cancer cells.

BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression and prognostic value in head and neck squamous cell cancer is the basis for targeting by anti-EGFR antibodies, which increase the efficacy of radiotherapy. In order to evaluate the best therapeutic schedule, the effects of cetuximab (C225) on Hep-2 cell proliferation, alone and in combination with cisplatin, were studied. METHODS: Hep-2 cells were treated with cetuximab alone or in combination with cisplatin. After determining cell viability with trypan blue, morphological features of apoptotic degeneration were analysed by fluorescence microscopy with Hoechst 33258 stain. RESULTS: Cetuximab alone mildly inhibited Hep-2 proliferation and showed no pro-apoptotic effects. When administered concomitantly with cisplatin, cetuximab synergistically increased inhibition of proliferation and apoptosis. CONCLUSION: The antiproliferative activity of cetuximab is consistent with its hypothesised role in inhibiting repopulation. However, the increase in the effects of pro-apoptotic agents induced by cetuximab may be even more relevant to its clinical effectiveness than the inhibition of repopulation.

Pharmacokinetics of etravirine in HIV-infected patients concomitantly treated with rifampin for tuberculosis.

Etravirine is metabolized by three cytochrome P450 enzymes that are in turn induced by rifampin. Consequently, co-administration of etravirine and rifampin is not recommended. To date, however, no clinical studies exploring the drug-drug interaction of this combination have been conducted. Here we report two cases of off-label etravirine use concurrently with antitubercular treatment, dictated by the unavailability of other treatments. Plasma drug concentrations were monitored by regular measurements. Our results appear to confirm the increased metabolism of etravirine through the induction of cytochrome P450 enzymes, but the adequacy of drug levels in all of the measurements and subsequent virological suppression suggest that this drug interaction may not be clinically relevant.

Stress-related biomarkers of dream recall and implicit memory under anaesthesia.

The aim of this study was to investigate whether auditory presentation of a story during general anaesthesia might influence stress hormone changes and thus affecting dream recall and/or implicit memory. One hundred and ten patients were randomly assigned either to hear a recording of a story through headphones or to have routine care with no auditory recording while undergoing laparoscopic cholecystectomy. Anaesthesia was standardised. Blood samples for cortisol and prolactin assays were collected 20 min before anaesthesia and 5 min after pneumoperitoneum. Dream recall and explicit/implicit memory were investigated upon awakening from anaesthesia and approximately 24 h after the end of the operation. Auditory presentation was associated with lower intra-operative serum prolactin concentration compared with control (p = 0.0006). Twenty-seven patients with recall of dreaming showed higher intra-operative prolactin (p = 0.004) and lower cortisol (p = 0.03) concentrations compared with those without dream recall. The knowledge of this interaction might be useful in the quest to ensure postoperative amnesia.

Molecular and pharmacological evidence for a facilitatory functional role of pre-synaptic GLUK2/3 kainate receptors on GABA release in rat trigeminal caudal nucleus.

BACKGROUND: Gamma-aminobutyric acid (GABA) and glutamate (GLU) are involved in nociceptive signals processing in the trigeminal system. In this study, we investigated the influence of excitatory transmission on GABA release in nerve terminals isolated from the rat trigeminal caudal nucleus (TCN). METHODS: We utilize biochemical (superfused synaptosomes loaded with [(3) H]GABA) and morphological (immunofluorescence experiments with specific antibody) techniques. RESULTS: Our results show that GLU potentiates the release of [(3) H]GABA evoked by 9, 15 and 30 mM [K(+)](e); 15 mM [K(+)](e)-evoked [(3) H]GABA release was also reinforced by domoate and kainate (KA), two naturally occurring GLU-receptor agonists. The enhancement of 15 mM [K(+)](e)-evoked [(3) H]GABA release produced by 100 µM KA was abolished by NBQX, a mixed AMPA/KA receptor antagonist, but was not affected by GYKI52466, a selective AMPA receptor antagonist. ATPA, a selective agonist for KA receptors containing the GLUK1 subunit, had no effect on depolarization-induced [(3) H]GABA release, and UBP310, which selectively antagonizes these same receptors, failed to reverse the KA-induced potentiation of 15 mM [K(+)](e)-evoked [(3) H]GABA release. The KA-induced potentiation was also unaffected by concanavalin A (10 µM), a positive allosteric modulator of GLUK1- and GLUK2-containing KA receptors. Immunofluorescence experiments revealed that GABAergic nerve terminals in the TCN differentially expressed GLUK subunits, with GLUK2/3-positive terminals being twice more abundant than GLUK1-containing synaptosomes. CONCLUSIONS: These findings indicate that pre-synaptic KA receptors facilitating GABA release from TCN nerve terminals mainly express GLUK2/GLUK3 subunits, supporting the notion that different types of KA receptors are involved in the various stages of pain transmission.

Rapamycin reduces clinical signs and neuropathic pain in a chronic model of experimental autoimmune encephalomyelitis.

Current treatments used in Multiple Sclerosis (MS) are partly effective in the early stages of the disease but display very limited benefits in patients affected by progressive MS. One possible explanation is that these therapies are unable to target the inflammatory component most active during the progressive phase of the disease, and compartmentalized behind the blood-brain barrier. Our findings show that Rapamycin ameliorates clinical and histological signs of chronic EAE when administered during ongoing disease. Moreover, Rapamycin significantly reduced the hyperalgesia observed before clinical development of EAE which, in turn, is completely abolished by the administration of the drug.

Relationship between antiretroviral plasma concentration and emergence of HIV-1 resistance mutations at treatment failure.

PURPOSE: The relationship between antiretroviral pharmacokinetic exposure and acquisition of human immunodeficency virus-1 (HIV-1) drug resistance mutations (DRM) is not fully understood. The aim of this study was to investigate whether antiretroviral plasma concentration could predict the emergence of DRM at treatment failure. METHODS: The study cohort comprised retrospectively selected patients with failing antiretroviral regimens for whom a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) trough concentration measurement (TDM) had been obtained before failure, a genotypic resistance test (GRT1) had been performed before the TDM, and a genotypic resistance test (GRT2) had been performed at therapeutic failure. Drug levels were classified as undetectable/detectable or subtherapeutic/therapeutic according to limits of quantification of a high-performance liquid chromatography-ultraviolet assay or pre-defined efficacy thresholds, respectively. The number of DRM acquired at treatment failure was evaluated by comparing the results of the GRT2 and GRT1. RESULTS: A total of ten and 57 failure episodes occurred among our patients on NNRTI-based and PI-based regimens, respectively, and included in the evaluation. PI concentration was subtherapeutic in 28.1% of patients, among which the levels were undetectable in 21.1%. Twenty-five (43.9%) patients acquired at least one new PI-DRM according to the GRT2. Patients with undetectable PI levels showed a lower emergence of PI-DRM (minor + major) than those with detectable levels (8.3 vs. 53.3%, p = 0.007). Multivariate analysis confirmed that undetectable PI levels were independent negative predictors of DRM selection. NNRTI measurements were subtherapeutic in 2/10 (20%) patients. NNRTI-DRM were acquired by all patients regardless of NNRTI levels. CONCLUSIONS: A PI measurement showing undetectable drug levels prior to treatment failure predicted the lack of emergence of PI-DRM at failure. These results suggest that PI levels can help clinicians interpret the reasons for treatment failure and guide the type of interventions needed.

AMPA- and P2X7-receptor-mediated facilitation of [3H]D-aspartate release from nerve terminals isolated from the rat caudal brainstem.

Glutamate (GLU) plays a key role in the transmission and modulation of sensory input to the trigeminal caudal nuclei (TCN). In the present study, we investigated the regulation of previously taken-up [3H]D-aspartate ([3H]D-ASP) release from nerve terminals isolated from rat caudal brainstem, in particular from the zone containing the TCN. TCN neurons can be considered integrative relay neurons linking peripheral and central pain mechanisms. Understanding the mechanisms that control the release of GLU in this area could lead to more effective treatment of migraines and other types of pain associated with the trigeminal nerve. In isolated rat caudal brainstem synaptosomes, exposure to AMPA dose-dependently potentiated [K+](e)-stimulated release of [3H]D-ASP (maximum increase: 218±13.08%; EC(50): 1.60±0.08 µM). This effect was inhibited by selective AMPA-receptor antagonists (competitive [NBQX] and non-competitive [GYKI52466]) but not by the kainate receptor subunit antagonists NS102 and ACET. AMPA-evoked responses were significantly enhanced by preventing AMPA receptor desensitization with cyclothiazide (10 µM). Basal release of [3H]D-ASP was stimulated by millimolar concentrations of ATP (maximum increase: 197.80±11.85%; EC(50): 545±3.15 µM) and by the selective P2X7-receptor agonist benzoylbenzoyl-ATP. ATP also potentiated the release of [3H]D-ASP induced by depolarization. Its effect on basal [3H]D-ASP release was inhibited by the selective P2X7-receptor antagonist A-438079 and by the non-selective antagonist PPADS, but it was only partially suppressed by the ionotropic purinergic receptor antagonist TNP-ATP. Our findings demonstrate that glutamatergic nerve terminals in rat caudal brainstem express AMPA receptors that can facilitate [3H]D-ASP during terminal depolarization and P2X7 receptors that can also enhance this release under basal conditions.

Mid-dosing interval concentration of atazanavir and virological outcome in patients treated for HIV-1 infection.

OBJECTIVES: We investigated the clinical significance of monitoring the mid-dosing interval atazanavir (ATV) concentration (measured 12 +/- 2 h after intake; C(12 h)) in patients taking this drug once daily in the evening. METHODS: We retrospectively selected HIV-infected patients harbouring ATV-susceptible virus who underwent therapeutic drug monitoring (TDM) of ATV C(12 h) during routine out-patient visits, and we correlated C(12 h) to the 24-week virological response and toxicity. RESULTS: A total of 115 plasma samples from 86 patients (76.7% with baseline HIV RNA<50 HIV-1 RNA copies/mL) were analysed. ATV plasma concentrations showed high inter-individual variability. ATV plasma levels were higher in samples obtained from patients taking boosted regimens (P<0.001) and not concomitantly receiving acid-reducing agents (P=0.007). In a multivariate model, ritonavir boosting, use of acid-reducing agents and liver cirrhosis showed an independent association with ATV level. Virological response at 24 weeks was observed for 94 of the 115 samples (81.7%). We identified a concentration cut-off of 0.23 mg/L which predicted virological response at 24 weeks: samples with a C(12 h)< or =0.23 mg/L showed virological failure in 41.2% of cases, whereas samples with a C(12 h)>0.23 mg/L showed virological failure in 14.3% of cases (P=0.021). In multivariate analysis, C(12 h)>0.23 mg/L was an independent predictor of virological response [odds ratio (OR) 4.23, P=0.031]. ATV levels correlated with concomitant unconjugated bilirubin levels (r=0.223, P=0.037), but a concentration cut-off predictive of moderate/severe hyperbilirubinaemia could not be identified. CONCLUSIONS: We identified a C(12 h) efficacy threshold that predicted virological response; this could be useful for morning TDM in selected subjects receiving ATV in the evening. Results must be interpreted with caution given the retrospective design of the study.

[Health and growth: a brief review of the literature]. / Salute e crescita economica: una breve rassegna della letteratura.

Improving health around the world is an important social objective, which provides direct payoffs in terms of longer and better lives. There is also a large consensus that improving health can have equally large indirect payoffs through accelerating economic development. The role that health conditions play in affecting growth is mainly analyzed via two channels: the direct labour productivity effect and the indirect incentive effect. The labour productivity hypothesis asserts that individuals who are healthier have higher returns to labour input. This is well tested in the empirical literature with mixed conclusions. The incentive effect is borne of the theoretical literature, and individuals who are healthier and have a greater life expectancy will have the incentive to invest in education as the time horizon over which returns can be earned is extended. Education is the driver of economic growth, and thus health plays an indirect role. Other minor channels have developed in the literature through which health affect economic development. However, although cross-country empirical works show a strong correlation between measures of health (for example, life expectancy) and economic growth, a causal effect of health and disease on economic development has not been established in the literature. A recent study challenges the view that different health conditions explain cross-country income differences. This study suggests that an improvement in mortality rate due to more effective public health measures and the introduction of new chemicals and drugs starting in the 1940s determines an increase in the population size which in turn reduces income per capita and economic growth.

Atazanavir and lopinavir with ritonavir alone or in combination: analysis of pharmacokinetic interaction and predictors of drug exposure.

OBJECTIVES: Studies on the pharmacokinetic interaction between atazanavir and lopinavir with ritonavir (lopinavir/ritonavir) report contradictory results. We aimed to establish the in vivo interaction between these two protease inhibitors as well as the variables influencing drug exposure. METHODS: Pharmacokinetic parameters were investigated in HIV-infected patients treated with atazanavir 300 mg with ritonavir 100 mg q24h (group A) or lopinavir/ritonavir 400/100 mg q12h (group B) or atazanavir 300 mg q24h with lopinavir/ritonavir 400/100 mg q12h (group C). Patients receiving other concomitant protease inhibitors or non-nucleoside reverse transcriptase inhibitors were excluded. RESULTS: In group A (n=10), mean +/- standard deviation atazanavir C(min) was 390 +/- 460 ng/mL, C(max) 3051 +/- 1996 ng/mL and AUC(24) 29 913 +/- 17 686 ng/mL/h. In group B (n=9), lopinavir C(min) was 7562 +/- 4292 ng/mL, C(max) 12 944 +/- 4838 ng/mL and AUC(0-12) 122 313 +/- 38 225 ng/mL/h. In group C (n=7), atazanavir C(min) was 876 +/- 460 ng/mL (P=0.039 vs. group A), C(max) 3421 +/- 3399 ng/mL and AUC(0-24) 65 055 +/- 49 843 ng/mL/h (two-sided P>0.05 for each comparison with group A), lopinavir C(min) was 7471 +/- 3745 ng/mL, C(max) 10 143 +/- 5217 ng/mL and AUC(0-12) 104 501 +/- 43 565 ng/mL/h (P>0.05 for each comparison with group B). When analysing all the groups, including controls from routine clinical practice, higher body mass index was associated with lower atazanavir C(min) and with lower lopinavir C(max). Atazanavir C(min) showed a correlation with total bilirubin levels. CONCLUSIONS: Combination with lopinavir/ritonavir provides higher atazanavir C(min) than combination with ritonavir alone, possibly because of an effect of the additional ritonavir dose. Low BMI may be associated with higher drug exposure.

Dyslipidemia can reduce the immunosuppressive effects of cyclosporine.

AIMS: Dyslipidemia is a significant risk factor for the development of atherosclerotic disease and of chronic allograft rejection. Few data are available on the effects of dyslipidemia on the immunosuppressive action of immunosuppressive agents. We investigate the in vitro effects of lipids solution on the immunosuppressive action of cyclosporine (CsA). METHODS: Peripheral blood mononuclear cells (PBMC) were PHA or OKT3 activated in vitro with/without different concentrations of Intralipid solution (INT, range 0.5% to 15%). CsA inhibition of activation was measured after a 3 day incubation, by adding H3-thimidine. The intracellular concentration of CsA was measured by radioimmunoassay and related to the CsA inhibitory effects. RESULTS: Increasing INT concentration in the medium, CsA inhibition of PBMC activation by PHA or OKT3 was reduced from 72+/-13% to 8+/-2% and from 80+/-10% to 18+/-3%, respectively. A significant reduction of the intracellular CsA concentration was also evident with increasing INT concentrations and was related to the inhibitory activity of CsA. CONCLUSIONS: These results suggest that dyslipidemia may reduce the availability of intracellular CsA concentration to inhibit the immune activation process and may explain the relationship between dyslipidemia and chronic allograft loss.