Pharmacokinetic interactions between clozapine and sertraline in smokers and non‐smokers

Clozapine is an effective antipsychotic drug for treatment‐resistant schizophrenia. Sertraline is a widely prescribed antidepressant and often concomitantly applied to address negative symptoms or depression. However, data on interactions between clozapine and sertraline are inconsistent. The aim of our study was to evaluate pharmacokinetic interactions between clozapine and sertraline analysing a therapeutic drug monitoring database of 1644 clozapine‐medicated patients. We compared four groups: non‐smokers (n = 250) and smokers (n = 326) with co‐medication without known effects on cytochrome P450 and without sertraline, and non‐smokers (n = 18) and smokers (n = 17) with sertraline co‐medication. Measured and dose‐corrected concentrations (C/D) of clozapine were compared between the groups using non‐parametrical tests with a significance level of 0.05. Post hoc analyses included pairwise comparisons to account for smoking status. Although we detected significant differences for clozapine levels and C/D values between study groups (P < .001 for Kruskal‐Wallis test in both cases), post hoc analyses revealed no differences for concentrations and C/D values of clozapine (P > .05 for Mann‐Whitney U test in both cases). A negative correlation between the sertraline dose and the clozapine concentration was found in non‐smokers (Spearman's rank correlation, rs = ?0.535, P = .048). A potential pharmacokinetic interaction between clozapine and a standard therapeutic sertraline dose seems to be of minor clinical importance.     

Interaction alerts: A comparison of classifications and recommendations for clinical management between Janusmed and three other knowledge resources

Classifications of drug interaction alerts differ between knowledge resources, but agreement regarding recommendations for clinical management is less explored. Starting from the medication lists of 274 older patients with ≥2 drugs, all unique drug pairs that triggered a clinically significant interaction alert in Janusmed were included: 100 Category C (manageable by, e.g. dose adjustment) and nine Category D interactions (should be avoided). Out of 109 C/D alerts in Janusmed, 89 (82%), 75 (69%) and 45 (41%) drug pairs triggered an alert of similar clinical significance in Lexicomp, Micromedex® and Stockley's Drug Interactions/Checker (Stockley), respectively. Eight (7%), 20 (18%) and 10 (9%) drug pairs did not trigger any alert in these resources. For 81 (74%), 81 (74%) and 94 (86%) drug pairs, Lexicomp, Micromedex and Stockley provided at least one recommendation for clinical management similar to those provided by Janusmed. For 16 (15%), 9 (8%) and 21 (19%) drug pairs, these resources provided recommendation(s) entirely in agreement with Janusmed. Although many drug pairs elicit alerts of similar significance, and partly concordant recommendations, a non-negligible proportion do not. The findings encourage medical/pharmaceutical reflection by prescribing clinicians and dispensing pharmacists; recommendations provided by knowledge resources vary considerably and cannot be considered definite.     

Genotype‐sensitive reversible and time‐dependent CYP2D6 inhibition in human liver microsomes

Cytochrome P450 (CYP) 2D6 metabolizes a wide range of xenobiotics and is characterized by a huge interindividual variability. A recent clinical study highlighted differential magnitude of CYP inhibition as a function of CYP2D6 genotype. The aim of this study was to investigate the effect of CYP2D6 genotype on the inhibition of dextromethorphan O‐demethylation by duloxetine and paroxetine in human liver microsomes (HLMs). The study focused on genotypes defined by the combination of two fully functional alleles (activity score 2, AS 2, n = 6), of one fully functional and one reduced allele (activity score 1.5, AS 1.5, n = 4) and of one fully functional and one non‐functional allele (activity score 1, AS 1, n = 6), which all predict extensive metabolizer phenotype. Kinetic experiments showed that maximal reaction velocity was affected by CYP2D6 genotype, with a decrease in 33% of V_max in AS 1 HLMs compared to AS 2 (P = 0.06). No difference in inhibition parameters K_i, K_I and k_inact was observed neither with the competitive inhibitor duloxetine nor with the time‐dependent inhibitor paroxetine. Among the genotypes tested, we found no difference in absolute CYP2D6 microsomal levels with ELISA immunoquantification. Therefore, our results suggest that genotype‐sensitive magnitude of drug‐drug interactions recently observed in vivo is likely to be due to differential amounts of functional enzymes at the microsomal level rather than to a difference in inhibition potencies across genotypes, which motivates for further quantitative proteomic investigations of functional and variant CYP2D6 alleles.     

High willingness to use drug consumption rooms among people who inject drugs in Scotland: findings from a national bio-behavioural survey among people who inject drugs

BackgroundTo address rising drug-related harms (including significant transmission of HIV) among people who inject drugs (PWID) in Glasgow, officials have proposed the introduction of the UK's first drug consumption room (DCR) in Glasgow city centre. Using a nationally representative sample, this study aimed to determine willingness to use a DCR among PWID nationally, in Glasgow city centre (the proposed DCR location), other Scottish city centres (excluding Glasgow) and the rest of Scotland (excluding city centres).MethodsBio-behavioural survey, of 1469 current PWID (injected in last 6 months) across Scotland during 2017-18. Willingness to use DCRs was examined by drug-related risk behaviours and harms overall in Scotland, and then stratified by Glasgow city centre (n = 219), other Scottish city centres (n = 226) and the rest of Scotland (n = 1024).ResultsThe majority of PWID overall in Scotland (75%) were willing to use a DCR; willingness was higher among those recruited in Glasgow city centre (83%) and other Scottish city centres (83%), compared to the rest of Scotland (72%) (p < 0.001). Willingness was greater among PWID who reported (compared to those who did not report) injecting heroin (76%, p = 0.002), cocaine injecting (79%, p = 0.014), homelessness (86%, p < 0.001), public injecting (87%, p < 0.001) and an overdose (80%, p = 0.026). Willingness was found to be associated with a cumulative multiple risk variable: increased from 66% among those with a score of zero to 85% with a score of at least three (p < 0.001).ConclusionsThe vast majority of PWID at greatest risk of drug-related harm in Glasgow and elsewhere in Scotland would be willing to use a DCR, supporting proposals for the introduction of DCRs nationally.     

The provision of care provided by the pharmacy workforce in relation to complementary medicines in Australia

BackgroundThe use of complementary medicines (CMs) is prevalent across the world. Some CMs, such as St John's Wort, when taken with specific pharmaceutical medicines, may cause drug-herb interactions. In this context, pharmacists have the opportunity to play an important role in preventing harm to patients.ObjectiveThe aim of this study was to explore real-life pharmacy practice in relation to CMs in New South Wales, Australia.MethodsThe study design involved ‘pseudo-patient’ pharmacy visits while posing as a patient's relative requesting St John's Wort and using a standardized set of questions to document details of the interaction with a range of pharmacy staff.ResultsOf the 110 metropolitan pharmacy visits made, the pharmacy workforce who were involved in assisting the pseudo-patient's request included 51 pharmacists (46.4%), 57 pharmacy assistants (51.8%) and 1 naturopath (0.9%). Advice that may have resulted in harm to the patient, was offered by pharmacists in 11.8% (n = 13) of the encounters, and 20.9% (n = 23) by pharmacy assistants. Conversely, advice that prevented harm was provided by only 17.3% (n = 19) pharmacists and 10.9% (n = 12) pharmacy assistants. History-taking was not attempted by 84 pharmacy staff.ConclusionThe majority of pharmacy staff involved in this study did not manage a request for a CM with known drug-herb interactions in a way that would prevent harm. These findings highlight the need for the pharmacy workforce to engage in education and training in CMs, with a focus on how to consult evidence-based resources regarding interactions in the interest of patient safety.     

The role of the pharmacist in mental health: An investigation of the impact of pharmacist-led interventions on psychotropic medication adherence in patients with diabetes

ObjectiveTo evaluate the impact of targeted telepharmacist mental health adherence interventions for patients with type 2 diabetes.MethodsThis retrospective review involved the analysis of a telepharmacist-led mental health intervention. The subjects included: patients aged 18 years or more with type 2 diabetes, enrolled in an adherence service and who had been prescribed psychotropics. Psychotropic medication adherence was measured using the proportion of days covered (PDC) 6 months before and after the telepharmacist-led medication intervention.ResultsA total of 8167 patients (67% women), with a mean age of 63 ± 11 years, were included in the study. Most alerts for psychotropics were for selective serotonin reuptake inhibitors (SSRIs) (53%, n = 4334), selective norepinephrine reuptake inhibitors (SNRIs) (22%, n = 1775), second-generation antipsychotics (11%, n = 909), and bupropion (10%, n = 782). Alerts with the greatest volume of PDCs (above 85%) at postintervention follow up included SSRIs (51%, n = 2228), SNRIs (50%, n = 884), and second-generation antipsychotics (47%, n = 424). Before the alert, the mean PDC was 66% ± 12% across all medications studied. Post intervention, the mean PDC rose to 79% ± 19. A paired t-test revealed statistically significant improvement in adherence overall, with the greatest change observed in these alert groups: SSRIs (P < 0.001), alpha-2 antagonist (P < 0.001), SNRIs (P < 0.001), and bupropion (P < 0.001).ConclusionThis retrospective review showed that pharmacist-led targeted, adherence interventions greatly improved psychotropic medication adherence in adult patients with type 2 diabetes. Future work is warranted to investigate the impact on type 2 diabetes medication adherence and health markers (e.g., HbA1c values) in larger and more diverse populations of patients with comorbid type 2 diabetes and a mental health condition.     

Which factors predict the time spent answering queries to a drug information centre?

Objective To develop a model based upon factors able to predict the time spent answering drug-related queries to Norwegian drug information centres (DICs). Setting and method Drug-related queries received at 5 DICs in Norway from March to May 2007 were randomly assigned to 20 employees until each of them had answered a minimum of five queries. The employees reported the number of drugs involved, the type of literature search performed, and whether the queries were considered judgmental or not, using a specifically developed scoring system. Main outcome measures The scores of these three factors were added together to define a workload score for each query. Workload and its individual factors were subsequently related to the measured time spent answering the queries by simple or multiple linear regression analyses. Results Ninety-six query/answer pairs were analyzed. Workload significantly predicted the time spent answering the queries (adjusted R ² = 0.22, P < 0.001). Literature search was the individual factor best predicting the time spent answering the queries (adjusted R ² = 0.17, P < 0.001), and this variable also contributed the most in the multiple regression analyses. Conclusion The most important workload factor predicting the time spent handling the queries in this study was the type of literature search that had to be performed. The categorisation of queries as judgmental or not, also affected the time spent answering the queries. The number of drugs involved did not significantly influence the time spent answering drug information queries.     

Case‐control pharmacogenetic study of HCN1/HCN2 variants and genetic generalized epilepsies

Epilepsy is a common complex neurological disorder, and some forms are resistant to drug treatment. The HCN1/HCN2 genes encode hyperpolarization‐activated cyclic nucleotide‐gated channels, which play important roles in the electrophysiology of neurons. We investigated the association between HCN1/HCN2 variants and drug resistance or the risk of genetic generalized epilepsies (GGEs). We used matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry to assess nine variants of HCN1/HCN2 in 284 healthy participants and 483 GGEs (279 drug‐responsive, 204 drug‐resistant). Frequencies of HCN2 rs7255568 and rs3752158 G alleles differed in GGEs and in controls (P = .039, P = .027, respectively). The frequency of HCN2 haplotype (CAC) was higher in patients than controls (P = .046). The frequency of the HCN1 rs10462087 CC+CT genotype was lower in patients with childhood absence epilepsy (CAE) than controls (P = .047). Rs7255568 was associated with the risk of CAE (P = .028) and juvenile myoclonic epilepsy (JME) (P = .02). Rs3752158 was associated with the risk of generalized tonic‐clonic seizures, JME, and febrile seizures (all P < .05). The frequency of the HCN2 haplotype (CAC) was higher in patients with JME (P = .015) and in those with febrile seizures (P = .024) than in controls. No significant association was found between HCN1/HCN2 alleles, genotypes or haplotypes, and drug resistance in patients. After Bonferroni's multiple comparisons correction, only the HCN2 rs3752158 C allele and GC+CC genotype frequencies in patients with JME were higher than those in controls (19.2% vs 11.6%, odds ratio (OR) = 1.71, 95% CI = 1.18‐2.32), P = .004 < 0.05/9; 36% vs 22.2%, OR = 1.62(1.18‐2.23), P = .003 < 0.05/9). Our study suggests that HCN2 rs3752158 is involved in the susceptibility to JME.     

Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole‐induced liver injury

Methimazole (MMI) has been used in the therapy of Grave's disease (GD) since 1954, and drug‐induced liver injury (DILI) is one of the most deleterious side effects. Genetic polymorphisms of drug‐metabolizing enzymes and drug transporters have been associated with drug‐induced hepatotoxicity in many cases. The aim of this study was to investigate genetic susceptibility of the drug‐metabolizing enzymes and drug transporters to the MMI‐DILI. A total of 44 GD patients with MMI‐DILI and 118 GD patients without MMI‐DILI development were included in the study. Thirty‐three single nucleotide polymorphisms (SNPs) in twenty candidate genes were genotyped. We found that rs12422149 of SLCO2B1, rs2032582_AT of ABCB1, rs2306283 of SLCO1B1 and rs4148323 of UGT1A1 exhibited a significant association with MMI‐DILI; however, no significant difference existed after Bonferroni correction. Haplotype analysis showed that the frequency of SLCO1B1*1a (388A521T) was significantly higher in MMI‐DILI cases than that in the control group (OR = 2.21, 95% CI = 1.11‐4.39, P = 0.023), while the frequency of SLCO1B1*1b (388G521T) was significantly higher in the control group (OR = 0.52, 95% CI = 0.29‐0.93, P = 0.028). These results suggested that genetic polymorphisms of SLCO1B1 were associated with susceptibility to MMI‐DILI. The genetic polymorphism of SLCO1B1 may be important predisposing factors for MMI‐induced hepatotoxicity.     

Management of pharmacotherapy‐related problems in acute coronary syndrome: Role of clinical pharmacist in cardiac rehabilitation unit

Acute coronary syndrome (ACS) is one of the leading causes of mortality worldwide and negatively impacts healthcare costs, productivity and quality of life. Polymorbidity and polypharmacy predispose ACS patients to medication discrepancies between cardiologist‐prescribed medication and drug use by the patient, drug‐related problems (DRPs) and inadequate drug adherence. This study aimed to evaluate the impact of clinical pharmacist–provided services on the outcome of ACS patients. This was a prospective, randomized, controlled study on ACS patients participating in a cardiac rehabilitation programme. Forty ACS patients were randomly assigned to either control group, who received standard medical care, or intervention group, who received standard medical care plus clinical pharmacist–provided services. Services included DRP management, clinical assessment and enforcing the patient education and adherence. For both groups, the following were assessed at baseline and after 3 months: DRPs, adherence (assessed by 8‐item Morisky Adherence Questionnaire), patient's knowledge (assessed by Coronary Artery Disease Questionnaire), 36‐Short Form Health Survey (SF‐36), heart rate, systolic and diastolic blood pressure, low‐density lipoprotein (LDL), total cholesterol (TC) and fasting blood glucose (FBG). After 3 months, there was a significant difference between the intervention and control groups in the per cent change of DRPs (median: ?100 vs 5.882, P = 0.0001), patient's adherence score (median: 39.13 vs ?14.58, P = 0.0001), knowledge score (median: 30.28 vs ?5.196, P = 0.0001), SF‐36 scores, heart rate (mean: ?10.04 vs 6.791, P = 0.0001), diastolic blood pressure (mean: ?17.87 vs 10.45, P = 0.0001), systolic blood pressure (mean: ?16.22 vs 4.751, P = 0.0001), LDL (median: ?25.73 vs ?0.2538, P = 0.0071), TC (median: ?14.62 vs 4.123, P = 0.0005) and FBG (median: ?11.42 vs 5.422, P = 0.0098). Clinical pharmacists can play an important role as part of a cardiac rehabilitation team through patient education and interventions to minimize DRPs.     

The Effects of Lidocaine Used in Sciatic Nerve on the Pharmacodynamics and Pharmacokinetics of Ropivacaine in Sciatic Nerve Combined with Lumbar Plexus Blockade: A Double‐Blind,Randomized Study

In this controlled, randomized, double‐blind study, we compared the pharmacodynamics and pharmacokinetics of ropivacaine and staged injection of lidocaine and ropivacaine in a combined lumbar plexus–sciatic nerve block. The experiment was performed in two parts: pharmacodynamics study (Group r, n = 20; Group lr, n = 20) and pharmacokinetics study (Group R, n = 10; Group LR, n = 10). The sciatic nerve blockade was performed using either (1) 10 mL of 2% lidocaine and then 10 mL of 0.75% ropivacaine (Group lr and Group LR) or (2) 10 mL of normal saline (N.S.) and then 10 mL of 0.75% ropivacaine (Group r and Group R). Two kinds of solutions were ‘staged’ injection. The sensory onset time and sensory recovery time were assessed in the pharmacodynamics study. Arterial blood samples were collected for the pharmacokinetics study. Sciatic sensory block onset times were reduced, and the sensory recovery times were decreased in Group lr. C_max of ropivacaine in Group LR was significantly higher than that in Group R. A significant increase in AUC_(0–t) and AUC_(0–∞) was observed in Group LR compared with Group R. When 2% lidocaine and 0.75% ropivacaine are used for a combined sciatic nerve–lumbar plexus block by ‘staged’ injection, lidocaine induced faster onset times, decreased the block duration and increased the AUC and C_max of ropivacaine.     

Renal pharmacists’ perceptions and current practices of assessing medication adherence in dialysis patients

Background Medication nonadherence is a major problem in chronic kidney failure patients undergoing dialysis. Pharmacists play a vital role in improving medication-related patient outcomes, reducing drug-related problems, and improving medication adherence. However, little is known about how pharmacists assess medication adherence in dialysis patients. Objective To measure pharmacists’ perceptions, current practices, and barriers to assessing adherence in dialysis patients. Setting Australian renal-specialised pharmacists. Method An online survey was conducted between March and May 2016. Survey included five psychometric scales measuring perceived prevalence, contributors, effective methods, barriers, and confidence to assess adherence on a 10-point Likert scale (1 = strongly disagree; 10 = strongly agree). Current practices were identified using a 4-point graded response (1 = do not practice; 4 = practice for all). Main outcome measure: Perception scores, scale reliability, and responses to current practices questionnaire. Results 41 pharmacists completed the survey (response rate, 91.1%). The majority (91.9%, n = 34; median = 8.0) agreed patients were nonadherent to medication. Time constraints (43.8%, n = 14) and hospital support (31.3%, n = 10) were perceived as barriers to assessment. Objective blood monitoring was frequently used to determine nonadherence (57.1%, n = 16), whereas subjective interviews were rarely conducted (27.6%, n = 8). Though all pharmacists support the presence of dedicated pharmacist for assessing adherence (100.0%, n = 33), only 24.2% were actually performing this function. Conclusion Pharmacists were rarely assigned for adherence assessment in dialysis settings. Established self-report methods were under-utilised compared to objective methods. Future research should investigate the effectiveness of pharmacists’ involvement in facilitating adherence promotion and early identification of medication-related issues in dialysis patients.

     

Diabetes care in Qatar: a survey of pharmacists’ activities,attitudes and knowledge

Background Diabetes mellitus is recognized as a major public health issue and is one of the top ten causes of death in Qatar. Objective To describe the activities, and attitudes of Qatar pharmacists toward diabetes, to measure their diabetes knowledge and to assess their perceived barriers for diabetes care. Setting Community and ambulatory pharmacies in Qatar. Method Study objectives were addressed in a cross sectional survey of community and ambulatory pharmacists in Qatar. A phone call explaining the study was made to all community and ambulatory pharmacists in Qatar. Consenting pharmacists anonymously completed the survey either online or as paper. Main outcome measure Diabetes related activities, knowledge, attitudes and perceived barriers. Results Over 7 months, 126 surveys were collected (28% response rate). The majority of pharmacists always or often counselled patients on the appropriate time to take each medication and on medication side effects (90%, n = 100/111 and 73%, n = 81/111 respectively). Yet around 50% always or often provided education on the importance of screening for nephropathy (n = 59/112) and retinopathy (n = 58/109). In addition, 41% always or often provided education about the importance of immunization (n = 45/111) and 45% always or often provided therapy recommendations to physicians (n = 49/111). Using Diabetes Attitude Scale-3, most respondents had positive attitudes toward the need for special training, psychosocial impact of diabetes, and patient autonomy. Around 25% (n = 32/126) scored less than 6 out of 10 on the diabetes related knowledge test. The top three barriers for providing diabetes services were lack of time (53%, n = 67/126) shortage of personnel (42%, n = 53/126) and lack of private counseling area (42%, n = 53/126). Conclusion Qatar pharmacists mainly provide basic services for diabetic patients. They have an average diabetes related knowledge. Yet overall, they have positive attitudes toward diabetes, which is a vital component of any successful diabetes care service.

     

Phase II trial of pyrazoloacridine (NSC#366140) in patients with metastatic breast cancer

Purpose: Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases 1 and 2. We conducted a phase II clinical study to determine the efficacy and toxicities of PZA in patients with metastatic breast cancer (MBC). Experimental Design: In this phase II multicenter study, patients who were treated with no more than one prior chemotherapy for MBC were treated with 750 mg/m2 of PZA given as a 3-hour intravenous infusion every 3 weeks. Treatment cycles were continued until disease progression or unacceptable toxicities. The study was designed to distinguish between a response rate of <15% vs >30% (alpha = 0.10, beta = 0.10) using Simons optimal 2-stage design. At least 2 responses were required in the first 12 patients in the 1st stage and 6 of 35 in the 2nd stage to recommend the agent for further study. Results: Two patients in the first stage had a response allowing accrual to second stage. A total of 15 patients (out of 35 planned) were treated on the study prior to premature closure. Three patients had a partial response (20%) lasting 4.5–6 months. Two patients had stable disease for 3 and 5 months. The dose limiting toxicity was granulocytopenia with ten patients requiring dose reduction or dose delay for grade 4 neutropenia. Other grade 3 and 4 toxicities include vomiting (n = 2), nausea (n = 2), neurotoxicity (n = 1), fatigue (n = 1), anemia (n = 1), dyspnea 9n = 1) and renal (n = 1). Conclusions: Pyrazoloacridine demonstrated modest activity in patients with metastatic breast cancer.     

Antiretroviral adherence program in HIV patients: a feasibility study in the Swiss HIV Cohort Study

Objective To evaluate the feasibility of a comprehensive, interdisciplinary adherence program aimed at HIV patients. Setting Two centers of the Swiss HIV Cohort Study: Lausanne and Basel. Method 6-month, pilot, quasi-experimental, 2-arm design (control and intervention). Patients starting a first or second combined antiretroviral therapy line were invited to participate in the study. Patients entering the intervention arm were proposed a multifactorial intervention along with an electronic drug monitor. It consisted of a maximum of six 30-min sessions with the interventionist coinciding with routine HIV check-up. The sessions relied on individualized semi-structured motivational interviews. Patients in the control arm used directly blinded EDM and did not participate in motivational interviews. Main outcome measures Rate of patients’ acceptance to take part in the HIV-adherence program and rate of patients’ retention in this program assessed in both intervention and control groups. Persistence, execution and adherence. Results The study was feasible in one center but not in the other one. Hence, the control group previously planned in Basel was recruited in Lausanne. Inclusion rate was 84% (n = 21) in the intervention versus 52% (n = 11) in the control group (P = 0.027). Retention rate was 91% in the intervention versus 82% in the control group (P = ns). Regarding adherence, execution was high in both groups (97 vs. 95%). Interestingly, the statistical model showed that adherence decreased more quickly in the control versus the intervention group (interaction group × time P < 0.0001). Conclusion The encountered difficulties rely on the implementation, i.e., on the program and the health care system levels rather than on the patient level. Implementation needs to be evaluated further; to be feasible a new adherence program needs to fit into the daily routine of the centre and has to be supported by all trained healthcare providers. However, this study shows that patients’ adherence behavior evolved differently in both groups; it decreased more quickly over time in the control than in the intervention group. RCTs are eventually needed to assess the clinical impact of such an adherence program and to verify whether skilled pharmacists can ensure continuity of care for HIV outpatients.     

Assessment of lead exposure in Spanish imperial eagle (<Emphasis Type="Italic">Aquila adalberti</Emphasis>) from spent ammunition in central Spain

The Spanish imperial eagle (Aquila adalberti) is found only in the Iberian Peninsula and is considered one of the most threatened birds of prey in Europe. Here we analyze lead concentrations in bones (n = 84), livers (n = 15), primary feathers (n = 69), secondary feathers (n = 71) and blood feathers (n = 14) of 85 individuals collected between 1997 and 2008 in central Spain. Three birds (3.6%) had bone lead concentration > 20 μg/g and all livers were within background lead concentration. Bone lead concentrations increased with the age of the birds and were correlated with lead concentration in rachis of secondary feathers. Spatial aggregation of elevated bone lead concentration was found in some areas of Montes de Toledo. Lead concentrations in feathers were positively associated with the density of large game animals in the area where birds were found dead or injured. Discontinuous lead exposure in eagles was evidenced by differences in lead concentration in longitudinal portions of the rachis of feathers.     

Improved Anti‐Emetic Efficacy of 5‐HT3 Receptor Antagonists in Cancer Patients with Genetic Polymorphisms of ABCB1 (MDR1) Drug Transporter

Chemotherapy‐induced nausea and vomiting (CINV) remains a major adverse effect decreasing quality of life in patients with cancer. Genetic variations among patients may be responsible for part of the lack of efficacy of anti‐emetic drugs. The aim of this study was to investigate how the genetic variants of the drug transporter ABCB1 (MDR1) gene affect anti‐emetic treatment with 5‐HT₃ receptor antagonists. Patients (n = 239) receiving moderately or highly emetogenic chemotherapy and ondansetron or granisetron were included in the study. Anti‐emetic responses were recorded daily. The primary end‐point of the assessment was the total control rates of CINV in the acute and delayed phases after chemotherapy. Genotyping was performed by PCR‐RFLP. In the acute phase, patients with ABCB13435TT, 1236TT or 2677TT genotypes had a higher control rate of CINV than other genotype groups: (64.7% in 3435TT versus 45.7% in 3435CC+CT, p = 0.016; 65.1% in 1236TT versus 46.4% in 1236CC+CT, p = 0.027; 66.7% in 2677TT versus 46.5% in other genotypes, p = 0.021). Subjects carrying homozygous variant alleles together (TT‐TT‐TT) showed a significantly higher protection from nausea and vomiting (67.7% in TT‐TT‐TT versus 47.1% in other genotypes, p = 0.032). After the logistic regression analysis with adjustment for other known covariates, the total control rate was significantly higher in the 3435TT genotype group during the acute phase (p = 0.021). No significant change was found between the total control rates among genotypes in the delayed phase. Each of three 3435TT, C1236TT, 2677TT genotypes of ABCB1 and their combination was associated with about 50% higher anti‐emetic response to 5‐HT₃ receptor antagonists in the acute phase of chemotherapy in patients with cancer receiving moderately or highly emetogenic chemotherapy. ABCB1 (MDR1) genotypes may contribute to predict the anti‐emetic efficacy of 5‐HT₃ antagonists.     

Safety of an injection with a mixture of extracts from Herba Artemisiae annuae, Fructus Gardeniae and Flos Lonicerae

Objective This study aimed to evaluate the safety for an injection with a mixture of extracts from Herba Artemisiae annuae, Fructus Gardeniae and Flos Lonicerae and to determine the risk factors that may affect its adverse drug reactions. Methods A drug-oriented prospective observational study was performed. Physicians filled in clinical observation forms with detailed information of the patients including general information, drug information, therapeutic effects and adverse drug events. The adverse drug reaction factors were analyzed by both mono-factor and multiple-factor logistic regression methods. Results From April to July 2007, we collected 12,427 observation forms from 46 hospitals in Jiangsu Province of China. Among the 11,707 observation forms we analyzed, 8,074 patients were children younger than 14 years old (69%). Among 51 reported adverse drug events, 45 cases were adverse drug reactions. The total adverse drug reaction incidence of the injection was 0.38%. While most adverse drug reactions were previously known (e.g., rash, pruritus, vomiting and diarrhea), we observed three new ADR symptoms: shiver, phlebitis and anhelation. All the adverse drug reactions were controlled very well through the follow-up therapy, and none of them was life threatening. The mono-factor analysis showed that adverse drug reactions of the injection were significantly correlated with total medication dose (P = 0.0049) and combination medication (P = 0.0143), especially with antimicrobial drugs (P = 0.0079) and macrolides (P = 0.0017). The multiple factor analysis confirmed these results: medication dosage and combination medication had a crucial impact on adverse drug reactions of the injection; the risk was increased by 24.8% (the estimated value of relative risk was 1.248, 95% confidence interval: 1.054–1.479) and 89% (1.890, 1.001–3.566), respectively. Conclusion The total adverse drug reaction incidence of the injection was 0.38% and lower than we expected. Moreover, we observed three new adverse drug reactions, none of which was severe.