Intrauterine exposure to antidepressants may lead to neonatal symptoms from the central nervous system, respiratory system and gastrointestinal system. Finnegan score (Neonatal Abstinence Score, NAS) ...has routinely been used to assess infants exposed to antidepressants in utero.
The purpose was to study neonatal maladaptation syndrome in infants exposed to selective serotonin reuptake inhibitors (SSRI) or serotonin-norepinephrine reuptake inhibitors (SNRI) in utero.
Retrospective cohort study of women using antidepressants during pregnancy and their infants. Patients were identified from the electronic health record system at Karolinska University Hospital Huddinge containing pre-, peri- and postnatal information. Information was collected on maternal and infant health, social factors and pregnancy. NAS sheets were scrutinized.
220 women with reported 3rd trimester exposure to SSRIs or SNRIs and who gave birth between January 2007 and June 2009 were included. Seventy seven women (35%) used citalopram, 76 used (35%) sertraline, 34 (15%) fluoxetine and 33 (15%) other SSRI/SNRI. Twenty-nine infants (13%) were admitted to the neonatal ward, 19 were born prematurely. NAS was analyzed in 205 patients. Severe abstinence was defined as eight points or higher on at least two occasions (on a scale with maximum 40 points), mild abstinence as 4 points or higher on at least two occasions. Seven infants expressed signs of severe abstinence and 46 (22%) had mild abstinence symptoms. Hypoglycemia (plasma glucose <2.6 mmol/L) was found in 42 infants (19%).
Severe abstinence in infants prenatally exposed to antidepressants was found to be rare (3%) in this study population, a slightly lower prevalence than reported in previous studies. Neonatal hypoglycemia in infants prenatally exposed to antidepressant may however be more common than previously described.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Global Health is a young discipline with equity of health and services as its core value. The discipline has a tradition of close links between practice and research in line with the 'Health for All' ...declaration launched by the World Health Organization (WHO) in 1978. The multitude of existential health crises facing mankind require a research agenda in line with Global Health Research core values and methods, such as transdisciplinary collaboration, long time series of population-based observations and multifaceted interventions. Knowledge gaps cover climate effects on health and mechanisms for global spread and control of antibiotic resistance across species. Such health threats are preferably studied at Health and Demographic Surveillance Sites, a scientific infrastructure for Global Health Research in Africa and Asia, that gains to expand and monitor climate parameters and include sites in the northern hemisphere. Global Health Scientists together with science societies can ensure long-term funding of a global network of population-based health-climate sites. Global Health Scientists and scientific journals should jointly provide data and evidence on global health to governance bodies on regional, national and global levels, in particular to WHO and United Nations in charge of the programme with Sustainable Development Goals.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
During exploratory space flights astronauts risk exposure to toxic planetary dust. Exhaled nitric oxide partial pressure (PENO) is a simple method to monitor lung health by detecting airway ...inflammation after dust inhalation. The turnover of NO in the lungs is dependent on several factors which will be altered during planetary exploration such as gravity (G) and gas density. To investigate the impacts of these factors on normal PENO, we took measurements before and during a stay at the International Space Station, at both normal and reduced atmospheric pressures. We expected stable PENO levels during the preflight and inflight periods, with lower values inflight. With reduced pressure we expected no net changes of PENO.
Ten astronauts were studied during the pre-flight (1 G) and inflight (µG) periods at normal pressure 1.0 ata (atmospheres absolute), with six of them also monitored at reduced (0.7 ata) pressure and gas density. The average observation period was from 191 days before launch until 105 days after launch. PENO was measured together with estimates of alveolar NO and the airway contribution to the exhaled NO flux.
The levels of PENO at 50 mL/s (PENO50) were not stable during the preflight and inflight periods respectively but decreased with time (
= 0.0284) at a rate of 0.55 (0.24) mean (SD) mPa per 180 days throughout the observation period, so that there was a significant difference (
< 0.01, N = 10) between gravity conditions. Thus, PENO50 averaged 2.28 (0.70) mPa at 1 G and 1.65 (0.51) mPa during µG (-27%). Reduced atmospheric pressure had no net impact on PENO50 but increased the airway contribution to exhaled NO.
The time courses of PENO50 suggest an initial airway inflammation, which gradually subsided. Our previous hypothesis of an increased uptake of NO to the blood by means of an expanded gas-blood interface in µG leading to decreased PENO50 is neither supported nor contradicted by the present findings. Baseline PENO50 values for lung health monitoring in astronauts should be obtained not only on ground but also during the relevant gravity conditions and before the possibility of inhaling toxic planetary dust.
Pharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess ...the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans.
In total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg.
EFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients.
Results of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There has been an increase in 'risk sharing' schemes for pharmaceuticals between healthcare institutions and pharmaceutical companies in Europe in recent years as an additional approach to provide ...continued comprehensive and equitable healthcare. There is though confusion surrounding the terminology as well as concerns with existing schemes.
A literature review was undertaken to identify existing schemes supplemented with additional internal documents or web-based references known to the authors. This was combined with the extensive knowledge of health authority personnel from 14 different countries and locations involved with these schemes.
A large number of 'risk sharing' schemes with pharmaceuticals are in existence incorporating both financial-based models and performance-based/outcomes-based models. In view of this, a new logical definition is proposed. This is "risk sharing' schemes should be considered as agreements concluded by payers and pharmaceutical companies to diminish the impact on payers' budgets for new and existing schemes brought about by uncertainty and/or the need to work within finite budgets". There are a number of concerns with existing schemes. These include potentially high administration costs, lack of transparency, conflicts of interest, and whether health authorities will end up funding an appreciable proportion of a new drug's development costs. In addition, there is a paucity of published evaluations of existing schemes with pharmaceuticals.
We believe there are only a limited number of situations where 'risk sharing' schemes should be considered as well as factors that should be considered by payers in advance of implementation. This includes their objective, appropriateness, the availability of competent staff to fully evaluate proposed schemes as well as access to IT support. This also includes whether systematic evaluations have been built into proposed schemes.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Approximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agents for HIV treatment in children and adults. There are concerns about ...the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults.
To investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight.
EFV plasma concentrations measured for clinical purposes from all children less than 18 years old at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on country of origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected from their medical records.
Thirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements from children of African, Asian and Latin American origin were included. EFV plasma concentration varied 21-fold between measurements (n = 182) (0.85-19.3 mg/L) and 9-fold measured as mean EFV plasma concentration across the subjects (1.55-13.4 mg/L). A multivariate mixed-effects restricted maximum likelihood regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to loge concentration/(dose/weight). The contribution of the model to the intra- and interindividual variation were 6 and 75%, respectively (Bryk/Raudenbush R-squared level).
Genetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzyme genes could improve clinical safety and genotype directed dosing could achieve more predictable EFV plasma concentrations in HIV-infected children.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Early diagnosis and prompt, effective treatment of uncomplicated malaria is critical to prevent severe disease, death and malaria transmission. We assessed the impact of rapid malaria diagnostic ...tests (RDTs) by community health workers (CHWs) on provision of artemisinin-based combination therapy (ACT) and health outcome in fever patients.
Twenty-two CHWs from five villages in Kibaha District, a high-malaria transmission area in Coast Region, Tanzania, were trained to manage uncomplicated malaria using RDT aided diagnosis or clinical diagnosis (CD) only. Each CHW was randomly assigned to use either RDT or CD the first week and thereafter alternating weekly. Primary outcome was provision of ACT and main secondary outcomes were referral rates and health status by days 3 and 7. The CHWs enrolled 2930 fever patients during five months of whom 1988 (67.8%) presented within 24 hours of fever onset. ACT was provided to 775 of 1457 (53.2%) patients during RDT weeks and to 1422 of 1473 (96.5%) patients during CD weeks (Odds Ratio (OR) 0.039, 95% CI 0.029-0.053). The CHWs adhered to the RDT results in 1411 of 1457 (96.8%, 95% CI 95.8-97.6) patients. More patients were referred on inclusion day during RDT weeks (10.0%) compared to CD weeks (1.6%). Referral during days 1-7 and perceived non-recovery on days 3 and 7 were also more common after RDT aided diagnosis. However, no fatal or severe malaria occurred among 682 patients in the RDT group who were not treated with ACT, supporting the safety of withholding ACT to RDT negative patients.
RDTs in the hands of CHWs may safely improve early and well-targeted ACT treatment in malaria patients at community level in Africa.
ClinicalTrials.gov NCT00301015.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•An LC–MS/MS dried blood spot method for common antiepileptic drugs was validated.•96-well format, automatic punching and barcode reading for improved workflow.•The method is accurate in a hematocrit ...range of 0.35–0.50L/L.•Unknown blood volumes between 15 and 50μL can be measured with bias within ±10%.•Stability tests showed that DBS shipping and storage for these drugs were robust.
Monitoring of antiepileptic drugs in children with epilepsy require multiple visits at a clinic for blood collection. Dried blood spot sampling is an alternative way of collection, performed at home by self-collection and can save time and costs for patients and family members. The aim was to develop and validate an LC–MS/MS dried blood spot method for carbamazepine, lamotrigine, levetiracetam and valproic acid with the requirements of using standard equipment and material in a routine laboratory setting.
Whatman-903 filter paper was utilized, and discs were punched into a 96 well plate with an automated puncher and barcode reading. Extraction with methanol/water solution including internal standards on an orbital shaker was followed by a vacuum centrifuge step and reconstitution in mobile phase. Bioanalytical validation was performed according to guidelines from European Medicines Agency and additional dried blood spot specific validation.
Calibration curves of the four included drugs had R2 values ≥0.994. Therapeutic relevant concentrations were well within measuring ranges. Within and −between run precision had %CV:s of 2.9–10.5%. Accuracy (%bias) was between −16.5% (lower limit of quantification) to +7.4%. Blood spots in a volume range of 15–50μL with hematocrit in expected ranges for this patient group were within precision and accuracy limits. To test the method, concentrations from dried blood spot venous and capillary patient samples (n=50) were compared with plasma concentrations. Good correlations for all four drugs with R2 of >0.92 was shown.
In summary, a fast method for dried blood spots based on a 96 well format was developed for four commonly prescribed antiepileptic drugs. This validated method with traceability in sample preparation by bar code reading makes it suitable for the clinical laboratory.
Older individuals with functional decline and homecare are frequent visitors to emergency departments (ED). Homecare workers (HCWs) interact regularly with their clients and may play a crucial role ...in their well-being. Therefore, this study explores if and how HCWs perceive they may contribute to the prevention of ED visits among their clients.
In this qualitative study, 12 semi-structured interviews were conducted with HCWs from Sweden between July and November 2022. Inductive thematic analysis was used to identify barriers and facilitators to prevent ED visits in older home-dwelling individuals.
HCWs want to actively contribute to the prevention of ED visits among clients but observe many barriers that hinder them from doing so. Barriers refer to care organisation such as availability to primary care staff and information transfer; perceived attitudes towards HCWs as co-workers; and client-related factors. Participants suggest that improved communication and collaboration with primary care and discharge information from the ED to homecare services could overcome barriers. Furthermore, they ask for support and geriatric education from primary care nurses which may result in increased respect towards them as competent staff members.
HCWs feel that they have an important role in the health management of older individuals living at home. Still, they feel as an untapped resource in the prevention of ED visits. They deem that improved coordination and communication between primary care, ED, and homecare organisations as well as proactive care would enable them to add significantly to the prevention of ED visits.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Efavirenz is metabolized by highly polymorphic enzymes, CYP2B6 and CYP3A. The effect of the different variant alleles on efavirenz population ...pharmacokinetics has not yet been fully explored.
• CYP2B6*6 influences efavirenz steady‐state pharmacokinetics. Together with sex it explains 11% of the between‐subject variability in apparent oral clearance, but predictions could potentially be improved if additional alleles causing reduced drug metabolism were identified.
• ABCB1 (3435C→T) may have effect on efavirenz single‐dose and steady‐state pharmacokinetics.
WHAT THIS STUDY ADDS
• A new polymorphism in ABCB1 gene (rs3842) and CYP2B6*11 in addition to sex and CYP2B6*6 genotype predict efavirenz single‐dose pharmacokinetics.
• A combined population pharmacogenetic/pharmacokinetic modelling approach allows determination and simulation of determinant factors for efavirenz single‐dose pharmacokinetics based on data on gender, biochemical variables and genetic factors in relevant genes (a total of 30 SNPs in CYP2B6, ABCB1 and CYP3A4 genes) in Ugandan population.
AIMS
Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single‐dose efavirenz pharmacokinetics among Ugandan subjects, using nonmem.
METHODS
Efavirenz plasma concentrations (n= 402) from 121 healthy subjects were quantified by high‐performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two‐compartment model with zero‐ followed by first‐order absorption.
RESULTS
Apparent oral clearance (95% confidence interval) was 4 l h l−1 (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men.
CONCLUSIONS
The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single‐dose administration. Use of mixed‐effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
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