Admission to intensive care: A qualitative study of triage and its determinants.

OBJECTIVE: To examine physicians' decision making and its determinants about admission to intensive care. DATA SOURCES/STUDY SETTING: ICU physicians (n = 12) and internists (n = 12) working in a Swiss tertiary care hospital. STUDY DESIGN: We conducted in-depth interviews. DATA COLLECTION/EXTRACTION METHODS: Interviews were analyzed using an inductive thematic approach. PRINCIPAL FINDINGS: Admission decisions regarding seriously ill or elderly patients with comorbidities are complex. Nonmedical factors such as ICU beds availability, health care resources on the ward, information about patient preferences, and family behavior determine the decision. Code status and the quality of interaction between physicians are key determinants. The absence of code status or poor documentation of code status discussions makes decisions more difficult and laden emotionally, as physicians feel they are making a life-death decision. Mutual respect and collaborative decision making facilitate the decision. Tensions arise due to ICU physicians' postponing the decision because of lack of beds, ICU physicians' dismissive attitudes, perceived shortcomings in the other physician's completion of expected tasks, and preconceptions about the other physician. CONCLUSIONS: Systematic documentation of code status, and fostering collaboration between ICU physicians and internists would facilitate ICU admission decisions in complex clinical situations.

[Clinical pharmacology of medical cannabinoids in chronic pain]. / Cannabinoïdes médicaux dans les douleurs chroniques: aspects pharmacologiques.

In Switzerland, medical cannabinoids can be prescribed under compassionate use after special authorization in justified indications such as refractory pain. Evidence of efficacy in pain is limited and the clinical benefit seems to be modest. Their drug-drug interactions (DDI) profile is poorly documented. Cytochromes P450 (CYP) 2C9 and 3A4 are involved in the metabolism of tetrahydrocannabinol and cannabidiol, which implies possible DDI with CYP450 inhibitor and inducer, such as anticonvulsivants and HIV protease inhibitors, which may be prescribed in patients with neuropathic pain.

Prioritization methodology for the monitoring of active pharmaceutical ingredients in hospital effluents.

The important number of active pharmaceutical ingredients (API) available on the market along with their potential adverse effects in the aquatic ecosystems, lead to the development of prioritization methods, which allow choosing priority molecules to monitor based on a set of selected criteria. Due to the large volumes of API used in hospitals, an increasing attention has been recently paid to their effluents as a source of environmental pollution. Based on the consumption data of a Swiss university hospital, about hundred of API has been prioritized following an OPBT approach (Occurrence, Persistence, Bioaccumulation and Toxicity). In addition, an Environmental Risk Assessment (ERA) allowed prioritizing API based on predicted concentrations and environmental toxicity data found in the literature for 71 compounds. Both prioritization approaches were compared. OPBT prioritization results highlight the high concern of some non steroidal anti-inflammatory drugs and antiviral drugs, whereas antibiotics are revealed by ERA as potentially problematic to the aquatic ecosystems. Nevertheless, according to the predicted risk quotient, only the hospital fraction of ciprofloxacin represents a risk to the aquatic organisms. Some compounds were highlighted as high-priority with both methods: ibuprofen, trimethoprim, sulfamethoxazole, ritonavir, gabapentin, amoxicillin, ciprofloxacin, raltegravir, propofol, etc. Analyzing consumption data and building prioritization lists helped choosing about 15 API to be monitored in hospital wastewaters. The API ranking approach adopted in this study can be easily transposed to any other hospitals, which have the will to look at the contamination of their effluents.

Providing Quality Therapeutics in Switzerland: Role of the Stakeholders and Recent Incentives for Further Improvements.

Quality therapeutics play an important role in Switzerland's health care and economy. Switzerland holds a key position in the world of research and development, as well as in drug production. Recently, new emphasis has been placed on promoting clinical research and maintaining Switzerland's position as a center of excellence in the field. Recent revisions to the law regarding medical trials in human research allow for better allocation of regulatory resources and simplified procedures for drugs already authorized in Switzerland. The country has its own regulatory agency, the Swiss Agency for Therapeutic Products (Swissmedic), which is a public institution of the Swiss government. Swissmedic is responsible for ensuring safety in medicines, particularly regarding authorizations and market surveillance in the sector of medicinal products and medical devices. Although the centralized authorization procedure of the European Union for medicines does not apply to Switzerland, there are mutual recognition mechanisms between the Swiss medicine regulatory authority and the European Medicines Agency. Swissmedic is also in charge of postmarketing safety and oversees the national pharmacovigilance center, which collaborates closely with the World Health Organization center in Uppsala. In addition, university hospital-based clinical pharmacologists, who are involved in basic science and clinical research, regulatory affairs, ethics committees, and pharmacovigilance, promote quality therapeutics. This article discusses the role of the various stakeholders and the recent efforts made to provide a better allocation of resources aimed at further improving quality therapeutics in Switzerland.

Drug-related problems identification in general internal medicine: The impact and role of the clinical pharmacist and pharmacologist.

BACKGROUND: Patients admitted to general internal medicine wards might receive a large number of drugs and be at risk for drug-related problems (DRPs) associated with increased morbidity and mortality. This study aimed to detect suboptimal drug use in internal medicine by a pharmacotherapy evaluation, to suggest treatment optimizations and to assess the acceptance and satisfaction of the prescribers. METHODS: This was a 6-month prospective study conducted in two internal medicine wards. Physician rounds were attended by a pharmacist and a pharmacologist. An assessment grid was used to detect the DRPs in electronic prescriptions 24h in advance. One of the following interventions was selected, depending on the relevance and complexity of the DRPs: no intervention, verbal advice of treatment optimization, or written consultation. The acceptance rate and satisfaction of prescribers were measured. RESULTS: In total, 145 patients were included, and 383 DRPs were identified (mean: 2.6 DRPs per patient). The most frequent DRPs were drug interactions (21%), untreated indications (18%), overdosages (16%) and drugs used without a valid indication (10%). The drugs or drug classes most frequently involved were tramadol, antidepressants, acenocoumarol, calcium-vitamin D, statins, aspirin, proton pump inhibitors and paracetamol. The following interventions were selected: no intervention (51%), verbal advice of treatment optimization (42%), and written consultation (7%). The acceptance rate of prescribers was 84% and their satisfaction was high. CONCLUSION: Pharmacotherapy expertise during medical rounds was useful and well accepted by prescribers. Because of the modest allocation of pharmacists and pharmacologists in Swiss hospitals, complementary strategies would be required.

P-glycoprotein: a clue to vitamin K antagonist stabilization.

BACKGROUND: Acenocoumarol is a vitamin K antagonist used in some European countries. As warfarin, this drug is characterized by a narrow therapeutic index and a large interindividual variability. AIM: The objective of this study was to assess the involvement of ABCB1 polymorphisms on acenocoumarol treatment. MATERIALS & METHODS: An observational cohort study was conducted to assess whether there is an association between the presence of the allelic variants of the ABCB1 gene coding for P-glycoprotein and acenocoumarol stabilization and daily doses during the first 35 days of treatment. RESULTS: One hundred and fifteen patients met the inclusion criteria. The results of the clinical study showed that carriers of ABCB1 c.3435TT were more rapidly stabilized than wild-type patients (HR: 2.97, 95% CI: 1.23-7.18; p = 0.02). The same tendency was observed for the ABCB1 c.2677GT and 2677TT genotypes compared with ABCB1 c.2677GG. The ABCB1 c.2677TT genotype was also associated with a significant increase in doses of acenocoumarol (p = 0.03), the same tendency was observed with the ABCB1 c.3435TT genotype compared with the wild-type patients. CONCLUSION: These data suggest that ABCB1 polymorphisms could be involved in the response to acenocoumarol treatment.

Volunteers trained in palliative care at the hospital: an original and dynamic resource.

OBJECTIVE: Volunteers trained in palliative care are increasingly present in acute care units in general hospitals. Nevertheless, there still are few available data on this topic, especially concerning the integration of volunteers outside the palliative structures. Our present study aimed to describe the experience of volunteers trained in palliative care in the context of a primary care hospital. In particular, the difficulties and the benefits of this specific position were evaluated according to volunteers' own perceptions and words. METHOD: We employed a qualitative method. Various aspects of the volunteer's role were explored by means of semistructured questions, addressing their activity, their motivations, and their feelings. Participants were volunteers (n = 19) trained in palliative care and working at a university hospital. After giving written consent, they completed the semistructured questionnaire at home. Content analysis was used to identify the main categories of answers and the principal themes reported by the volunteers. RESULTS: The main difficulties were related to uncertainty of the context. As every situation is different, volunteers could not define their role once and for all. However, they derived great satisfaction from their activity. A supporting frame and a good balance between constraints and autonomy were facilitating factors. Besides, the complexity related to the context contributed to make the position valuable and challenging. SIGNIFICANCE OF RESULTS: Integrating a voluntary service in a primary care hospital is partly based on active participation of the volunteers in developing their position in a more adequate way. In return, this relative autonomy implies a rigorous and supportive attitude from the institution.

Doctors' decisions when faced with contradictory patient advance directives and health care proxy opinion: a randomized vignette-based study.

CONTEXT: Sometimes a written advance directive contradicts the opinion of a health care proxy. How this affects doctors' decision making is unknown. OBJECTIVES: To quantify the influence of contradictory instructions on doctors' decisions. METHODS: All the generalists and internists in French-speaking Switzerland were mailed the questionnaire. Respondents (43.5%) evaluated three vignettes that described medical decisions for incapacitated patients. Each vignette was produced in four versions: one with an advance directive, one with a proxy opinion, one with both, and one with neither (control). In the first vignette, the directive and proxy agreed on the recommendation to forgo a medical intervention; in the second, the advance directive opposed, but the proxy favored the intervention; and in the third, the roles were reversed. Each doctor received one version of each vignette, attributed at random. The outcome variables were the doctor's decision to forgo the medical intervention and the rating of the decision as difficult. RESULTS: Written advance directives and proxy opinions significantly influenced doctors' decision making. When both were available and concordant, they reinforced each other (odds ratio [OR] of forgoing intervention 35.7, P < 0.001 compared with no instruction). When the directive and proxy disagreed, the resulting effect was to forgo the intervention (ORs 2.1 and 2.2 for the two discordant vignettes, both P < 0.001). Discordance between instructions was associated with increased odds of doctors rating the decision as difficult (both ORs 2.0, P ≤ 0.001). CONCLUSION: Contradictions between advance directives and proxy opinions result in a weak preference for abstention from treatment and increase the difficulty of the decision.

Impact of advance directives and a health care proxy on doctors' decisions: a randomized trial.

CONTEXT: Advance directives or proxy designations are widely recommended, but how they affect doctors' decision making is not well known. OBJECTIVES: The aim of this study was to quantify the influence of advance directives and proxy opinions on doctors' decisions. METHODS: We mailed to all the generalists and internists in French-speaking Switzerland (N = 1962) three vignettes describing difficult decisions involving incapacitated patients. In each case, the advance directive requested that further care be withheld. One vignette tested the impact of a written advance directive vs. a proxy. Another compared the impact of a handwritten directive vs. a formalized document. The third vignette compared the impact of a family member vs. a doctor as a proxy. Each vignette was prepared in three or four versions, including a control version in which no directive or proxy was present. Vignettes were randomly allocated to respondents. We used logistic regression to predict the decision to forgo a medical intervention. RESULTS: Compared with the control condition, the odds of forgoing a medical intervention were increased by the written advance directive (odds ratio [OR] 7.3; P < 0.001), the proxy (OR 7.9; P < 0.001), and the combination of the two (OR 35.7; P < 0.001). The handwritten directive had the same impact (OR 13.3) as the formalized directive (OR 13.8). The effect of proxy opinion was slightly stronger when provided by a doctor (OR 11.3) rather than by family (OR 7.8). CONCLUSION: Advance directives and proxy opinions are equally effective in influencing doctors' decisions, but having both has the strongest effect. The format of the advance directive and the identity of the proxy have little influence on decisions.

Central pain sensitization, COMT Val158Met polymorphism, and emotional factors in fibromyalgia.

UNLABELLED: Neurobiological evidence points to altered central nervous system processing of nociceptive stimuli in fibromyalgia. Enzymes like catechol-O-methyl-transferase (COMT) are involved in the elimination of catecholamines playing a possible role in central sensitization and pain. We used quantitative sensory testing to evidence central sensitization in fibromyalgia patients and test whether COMTVal158Met polymorphism, associated with a reduction in enzyme activity, plays a role in sensitized patients. Pain evaluation and quantitative sensory testing were performed including the spinal nociceptive flexion reflex, a physiologic correlate for the evaluation of central nociceptive pathways. Quality of life and distress questionnaires were used. A total of 137 fibromyalgia patients were assessed and compared to 99 matched controls. Central sensitization (nociceptive flexion reflex <27 mA) was present in 95/134 (71%) patients. Among them, COMT p.Val158Met polymorphism displayed a significant linear "genotype effect" (P = .033), with the Met/Met (mean = 17.8 ± 4.8 mA) and Val/Val (mean = 21.4 ± 4.6 mA) subgroups at the opposite ends of the nociceptive flexion reflex threshold (Met/Met vs Val/Val P = .015) and the Val/Met subgroup (mean = 19 ± 4.9 mA) in between (Val/Met vs Val/Val P = .041). Spontaneous moderate to severe pain was more likely to be associated with COMT Met/Met genotype. Patients showed important emotional distress compared to controls. In sensitized patients, the COMT Met/Met subgroup showed systematically-though not significantly-worse scores for all psychological variables. PERSPECTIVE: The association between COMT p.Val158Met polymorphism and central sensitization in fibromyalgia is essential as it refers to the severity of central sensitization and may be a risk factor for treatment outcome.

Monitoring white blood cell count in adult patients with schizophrenia who are taking clozapine: a cost-effectiveness analysis.

BACKGROUND: Long-term monitoring of white blood cell count is compulsory in patients taking clozapine, although the incidence of drug-induced agranulocytosis is lower than previously expected. The cost-effectiveness of this monitoring is unknown. We aimed to assess the cost-effectiveness of various strategies to monitor white blood cell count in adult patients with schizophrenia taking clozapine. METHODS: We assessed the cost-effectiveness of four strategies for monitoring white blood cell count (national strategies used in the UK, USA, and European countries, and a hypothetical 8-week strategy) compared with that of no monitoring. We used a semi-Markov model to do the cost-utility analysis from a health-care perspective with a 3-year time horizon, assuming a probability of 0·7% that a patient would develop agranulocytosis. Clinical and resource parameters were based on data from national registries of patients treated with clozapine, study cohorts, and a pharmacovigilance database; we derived estimates of health-related quality of life and mortality from the scientific literature. We assessed model uncertainty, including time horizon, with one-way and probabilistic sensitivity analyses. FINDINGS: Compared with no monitoring, all four monitoring strategies increased quality-adjusted survival by less than 1 day per patient; more than 5000 patients would need to be monitored to avoid one death. The incremental cost-effectiveness ratios (ICERs) were at least US$970 000 per quality-adjusted life-year gained for all four strategies compared with no monitoring. The ICERs were highest in the strategies with highest frequencies and longest durations of monitoring. The results remained robust in the one-way and probabilistic sensitivity analyses, suggesting that no monitoring had the highest probability of being cost effective. INTERPRETATION: Existing strategies for monitoring white blood cell count in patients taking clozapine, based on divergent national requirements, do not seem to be cost effective. This finding should be taken into account by public health authorities and policy makers in the revision of guidance for clozapine prescription. FUNDING: University Hospitals of Geneva.

Drug-induced long QT in adult psychiatric inpatients: the 5-year cross-sectional ECG Screening Outcome in Psychiatry study.

OBJECTIVE: The authors aimed to determine the prevalence of drug-induced long QT at admission to a public psychiatric hospital and to document the associated factors using a cross-sectional approach. METHOD: All ECG recordings over a 5-year period were reviewed for drug-induced long QT (heart-rate corrected QT ≥500 ms and certain or probable drug imputability) and associated conditions. Patients with drug-induced long QT (N=62) were compared with a sample of patients with normal ECG (N=143). RESULTS: Among 6,790 inpatients, 27.3% had abnormal ECG, 1.6% had long QT, and 0.9% qualified as drug-induced long QT case subjects. Sudden cardiac death was recorded in five patients, and torsade de pointes was recorded in seven other patients. Relative to comparison subjects, patients with drug-induced long QT had significantly higher frequencies of hypokalemia, hepatitis C virus (HCV) infection, HIV infection, and abnormal T wave morphology. Haloperidol, sertindole, clotiapine, phenothiazines, fluoxetine, citalopram (including escitalopram), and methadone were significantly more frequent in patients with drug-induced long QT. After adjustment for hypokalemia, HCV infection, HIV infection, and abnormal T wave morphology, the effects of haloperidol, clotiapine, phenothiazines, and citalopram (including escitalopram) remained statistically significant. Receiver operating characteristic curve analysis based on the number of endorsed factors per patient indicated that 85.5% of drug-induced long QT patients had two or more factors, whereas 81.1% of patients with normal ECG had fewer than two factors. CONCLUSIONS: Drug-induced long QT and arrhythmia propensity substantially increase when specific psychotropic drugs are administered to patients with hypokalemia, abnormal T wave morphology, HCV infection, and HIV infection.

Dual reuptake inhibitor milnacipran and spinal pain pathways in fibromyalgia patients: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Investigations based on quantitative sensory testing have consistently shown evidence of allodynia in fibromyalgia syndrome (FMS) patients involving both the spinal and supraspinal pain regulatory systems. Functional imaging studies have demonstrated enhanced neural activities in pain-related brain areas as well as impairment of pain inhibition in the descending nociceptive regulatory system. A higher state of excitability of spinal nociceptive neurons as evidenced by lowered nociceptive flexion reflex R-III (NFR) threshold was reported for FMS patients. The NFR procedure has been shown to be a valuable tool to evaluate pharmacologically active therapeutic agents at the spinal level. OBJECTIVE: Serotonin-noradrenaline reuptake inhibitors have been shown to reduce pain in FMS patients possibly through descending monoaminergic pain pathways modulation. This randomized double-blind placebo-controlled trial assessed the pharmacodynamic activity of the dual-reuptake inhibitor milnacipran (MLN) at the spinal level by means of the objective spinal NFR. STUDY DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: A single academic medical center, outpatient setting. METHODS: Seven-week exposure (100, 150, 200mg/day) in women fibromyalgia patients. Evaluation consisted of extensive quantitative sensory testing including determination of the NFR threshold, self-reported standard questionnaires investigating pain, visual analog scales, fibromyalgia impact, health-related quality of life, depression and anxiety questionnaires, as well as the Patient's Global Impression of Change (PGIC). Analysis of covariance adjusted for baseline value was used for all endpoints. RESULTS: Seventy-seven (39 placebo, 38 milnacipran all doses) out of 80 randomized patients were available for analysis. The absence of influence of MLN (any dose) on the NFR surprisingly contrasted with the dose-dependent analgesic effect observed in MLN-treated patients with an adjusted change difference of -18.4mm (-30.9; -5.8) in pain reduction between placebo and the maximum dosage (200 mg) MLN groups (P = 0.02). Unchanged depression and anxiety scores confirmed the predominant selectivity of the analgesic effect of MLN on nociceptive pain pathway. Self-reported questionnaires consistently reflected the positive effects of MLN on quality of life and psychological well-being. Odds ratio 5.1 for PGIC responders (i.e. much/very much improved) was significantly in favor of MLN (P = 0.04). CONCLUSION: Milnacipran has a predominantly supraspinal analgesic effect as evidenced by the significant clinical benefits and the absence of changes in the nociceptive spinal reflex threshold. Higher dose was associated with higher pain reduction. Reported analgesia was independent of patients' emotional status.

Patented drug extension strategies on healthcare spending: a cost-evaluation analysis.

BACKGROUND: Drug manufacturers have developed "evergreening" strategies to compete with generic medication after patent termination. These include marketing of slightly modified follow-on drugs. We aimed to estimate the financial impact of these drugs on overall healthcare costs and also to examine the impact of listing these drugs in hospital restrictive drug formularies (RDFs) on the healthcare system as a whole ("spillover effect"). METHODS AND FINDINGS: We used hospital and community pharmacy invoice office data in the Swiss canton of Geneva to calculate utilisation of eight follow-on drugs in defined daily doses between 2000 and 2008. "Extra costs" were calculated for three different scenarios assuming replacement with the corresponding generic equivalent for prescriptions of (1) all brand (i.e., initially patented) drugs, (2) all follow-on drugs, or (3) brand and follow-on drugs. To examine the financial spillover effect we calculated a monthly follow-on drug market share in defined daily doses for medications prescribed by hospital physicians but dispensed in community pharmacies, in comparison to drugs prescribed by non-hospital physicians in the community. Estimated "extra costs" over the study period were €15.9 (95% CI 15.5; 16.2) million for scenario 1, €14.4 (95% CI 14.1; 14.7) million for scenario 2, and €30.3 (95% CI 29.8; 30.8) million for scenario 3. The impact of strictly switching all patients using proton-pump inhibitors to esomeprazole at admission resulted in a spillover "extra cost" of €330,300 (95% CI 276,100; 383,800), whereas strictly switching to generic cetirizine resulted in savings of €7,700 (95% CI 4,100; 11,100). Overall we estimated that the RDF resulted in "extra costs" of €503,600 (95% CI 444,500; 563,100). CONCLUSIONS: Evergreening strategies have been successful in maintaining market share in Geneva, offsetting competition by generics and cost containment policies. Hospitals may be contributing to increased overall healthcare costs by listing follow-on drugs in their RDF. Therefore, healthcare providers and policy makers should be aware of the impact of evergreening strategies.

Impact of CYP2C9 polymorphisms on the vulnerability to pharmacokinetic drug-drug interactions during acenocoumarol treatment.

AIM: The objective of this study was to investigate the impact of CYP2C9 polymorphisms and drug-drug interactions on the risk of overanticoagulation in patients treated with acenocoumarol, a vitamin K antagonist. MATERIALS & METHODS: A prospective observational study was performed on patients starting acenocoumarol (n = 115). CYP2C9 genotypes were assessed. Data on International Normalized Ratio, comedications and doses of acenocoumarol were collected during the first 35 days of therapy. Overanticoagulation was defined as the occurrence of at least one International Normalized Ratio ≥4. RESULTS: The presence of a CYP2C9 inhibitor or a CYP2C9 polymorphisms statistically increased the risk of overanticoagulation (hazard ratio [HR]: 2.8, p < 0.001 and HR: 1.7, p = 0.04, respectively). The presence of CYP2C9 polymorphisms almost tripled the risk of overanticoagulation (HR: 2.91, p = 0.01) in the presence of a clinically significant drug-drug interaction. CONCLUSION: These findings support the fact that CYP2C9 genotyping could be useful to identify patients requiring closer monitoring, especially when a drug-drug interaction is expected.

Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model.

Vitamin K antagonists (VKAs) are prescribed worldwide and remain the oral anticoagulant of choice. These drugs are characterized by a narrow therapeutic index and a large inter- and intra-individual variability. P-glycoprotein could contribute to this variability. The aim of this study was to investigate the involvement of P-gp in the transport of acenocoumarol, phenprocoumon and warfarin using an in vitro Caco-2 cell monolayer model. These results were compared with those obtained with rivaroxaban, a new oral anticoagulant known to be a P-gp substrate. The transport of these four drugs was assessed at pH conditions 6.8/7.4 in the presence or absence of the P-gp inhibitor cyclosporine A (10 µM) and the more potent and specific P-gp inhibitor valspodar (5 µM). Analytical quantification was performed by LC/MS. With an efflux ratio of 1.7 and a significant decrease in the efflux (Papp B-A), in the presence of P-gp inhibitors at a concentration of 50 µM, acenocoumarol can be considered as a weak P-gp substrate. Concerning phenprocoumon, the results suggest that this molecule is a poor P-gp substrate. The P-gp inhibitors did not affect significantly the transport of warfarin. The efflux of rivaroxaban was strongly inhibited by the two P-gp inhibitors. In conclusion, none of the three VKAs tested are strong P-gp substrates. However, acenocoumarol can be considered as a weak P-gp substrate and phenprocoumon as a poor P-gp substrate.

Evidence of drug-drug interactions through uptake and efflux transport systems in rat hepatocytes: implications for cellular concentrations of competing drugs.

For drugs with hepatobiliary transport across hepatocytes, the interplay between uptake and efflux transporters determines hepatic concentrations of drugs, but the evolution over time of these concentrations is difficult to measure in humans other than with magnetic resonance imaging contrast agents in the liver. Gadobenate dimeglumine (BOPTA) is a contrast agent used in liver magnetic resonance imaging that enters into human hepatocytes through organic anion transporting polypeptides (OATP) and exits unchanged into bile through the multiple resistance-associated protein 2 (MRP2). Rifampicin (RIF) is transported by the same membrane proteins and may compete with BOPTA for hepatic uptake. Simultaneous drug-drug interactions through uptake and efflux transport systems in hepatocytes according to the cellular concentrations of competing drugs were never investigated. In perfused rat liver preparations, we demonstrate how the drug-drug interactions through transporters determine cellular concentrations of the competing drugs BOPTA and RIF, and we show that the cellular concentrations by modulating transport through membranes regulate the rat Oatp-Mrp2 interplay. Moreover, drug interactions through transporters change greatly over time.

Intraocular penetration of penciclovir after oral administration of famciclovir: a population pharmacokinetic model.

OBJECTIVES: We developed a population model that describes the ocular penetration and pharmacokinetics of penciclovir in human aqueous humour and plasma after oral administration of famciclovir. METHODS: Fifty-three patients undergoing cataract surgery received a single oral dose of 500 mg of famciclovir prior to surgery. Concentrations of penciclovir in both plasma and aqueous humour were measured by HPLC with fluorescence detection. Concentrations in plasma and aqueous humour were fitted using a two-compartment model (NONMEM software). Inter-individual and intra-individual variabilities were quantified and the influence of demographics and physiopathological and environmental variables on penciclovir pharmacokinetics was explored. RESULTS: Drug concentrations were fitted using a two-compartment, open model with first-order transfer rates between plasma and aqueous humour compartments. Among tested covariates, creatinine clearance, co-intake of angiotensin-converting enzyme inhibitors and body weight significantly influenced penciclovir pharmacokinetics. Plasma clearance was 22.8±9.1 L/h and clearance from the aqueous humour was 8.2×10(-5) L/h. AUCs were 25.4±10.2 and 6.6±1.8 µg·h/mL in plasma and aqueous humour, respectively, yielding a penetration ratio of 0.28±0.06. Simulated concentrations in the aqueous humour after administration of 500 mg of famciclovir three times daily were in the range of values required for 50% growth inhibition of non-resistant strains of the herpes zoster virus family. CONCLUSIONS: Plasma and aqueous penciclovir concentrations showed significant variability that could only be partially explained by renal function, body weight and comedication. Concentrations in the aqueous humour were much lower than in plasma, suggesting that factors in the blood-aqueous humour barrier might prevent its ocular penetration or that redistribution occurs in other ocular compartments.

Influence of CYP2D6 activity on pre-emptive analgesia by the N-methyl-D-aspartate antagonist dextromethorphan in a randomized controlled trial of acute pain.

BACKGROUND: There is some evidence that dextromethorphan (DM) is effective as a pre-emptive analgesic agent.  DM is mainly metabolized to dextrorphan (DOR) by CYP2D6 whose activity can be inhibited by pharmacologic intervention. OBJECTIVES: To investigate the efficacy of DM as a pre-emptive analgesic agent and describe the population pharmacokinetics in the presence of normal and poor CYP2D6 metabolism in acute post-operative pain. STUDY DESIGN: Double blind, randomized, placebo-controlled trial SETTING: Post-surgical analgesic consumption after knee ligament surgery, a setting of acute pain. METHODS: Forty patients were randomized to a single oral dose of 50 mg quinidine or placebo, administered 12 hours before 50 mg DM. Patients were genotyped for the major CYP2D6 and ABCB1 variants and phenotyped for CYP2D6 using urine DM/DOR metabolic ratios and blood samples for population pharmacokinetic modeling. RESULTS: Quinidine was effective in inhibiting CYP2D6 activity, with 2-fold reduction of DM to DOR biotransformation clearance, prolonged DM half-life, and increased DM systemic availability. Patients in the quinidine group required significantly less often NSAIDs than patients in the placebo group (35.3% vs. 75.0%, P = 0.022). The odds ratio for NSAID consumption in the placebo vs. quinidine group was 5.5 (95% confidence interval (CI) 1.3 - 22.7) at 48 hours after surgery. LIMITATIONS: While this study shows an impact of DM on pre-emptive analgesia and is mechanistically interesting, the findings need to be confirmed in larger trials. CONCLUSION: CYP2D6 inhibition by quinidine influenced the pre-emptive analgesic effectiveness of DM confirming that CYP2D6 phenotypic switch increases the neuromodulatory effect of oral dextromethorphan.