Search

Aims: By meta-analysing pooled studies and available individual participant data, we aim to provide new insight on olanzapine therapeutic drug monitoring in schizophrenia. Method: We conducted a computerized search of bibliographic databases (Pubmed, Cochrane library, Web of Science and PsycINFO) to identify studies that assessed the relationship between olanzapine plasma concentration and the change in patients’ clinical scores. We investigated this relationship with olanzapine plasma level 12h00 post-intake using a random-effects model. Results: 7 studies were included in the pooled data analysis (781 patients). We found no difference in oral dose between responders and non-responders but a significantly higher concentration of 4.50 µg/L in responders (p

Ethambutol is considered to be safest first-line antitubercular drug, and patient acceptability is rather good in both intensive and continuation phase of the tuberculosis treatment with daily regimen. The important adverse effect associated with ethambutol is optic neuritis, resulting in loss of visual acuity, color vision, and field defects. The incidence of optic neuritis is generally directly proportional to the dose and duration of ethambutol therapy and rarely reported in a low standard dose. Here, we report a case of a 40-year-old female patient with complaints of progressive diminished vision (especially during day time) with a low daily dose (15 mg/kg/day) of ethambutol. She got diagnosed with cervical tuberculous lymphadenitis and was receiving isoniazid, rifampicin, ethambutol, and levofloxacin. In rare instances, ethambutol ocular toxicity may present with cecocentral scotoma. In rare instances, plasma levels are performed. An estimated plasma level of ethambutol was found to be in higher end (5.6 μg/ml) of the reported therapeutic range (2–6 μg/ml). Bilateral retrobulbar neuritis with cecocentral scotoma adverse effect due to ethambutol can be seen in plasma therapeutic range.

The cytoskeletal protein tau is implicated in the pathogenesis of Alzheimer's disease which is characterized by intra-neuronal neurofibrillary tangles containing abnormally phosphorylated insoluble tau. Levels of soluble tau are elevated in the brain, the CSF, and the plasma of patients with Alzheimer's disease. To better understand the causes of these elevated levels of tau, we propose a three-compartment kinetic model (brain, CSF, and plasma). The model assumes that the synthesis of tau follows zero-order kinetics (uncorrelated with compartmental tau levels) and that the release, absorption, and clearance of tau is governed by first-order kinetics (linearly related to compartmental tau levels). Tau that is synthesized in the brain compartment can be released into the interstitial fluid, catabolized, or retained in neurofibrillary tangles. Tau released into the interstitial fluid can mix with the CSF and eventually drain to the plasma compartment. However, losses of tau in the drainage pathways may be significant. The kinetic model estimates half-life of tau in each compartment (552 h in the brain, 9.9 h in the CSF, and 10 h in the plasma). The kinetic model predicts that an increase in the neuronal tau synthesis rate or a decrease in tau catabolism rate best accounts for observed increases in tau levels in the brain, CSF, and plasma found in Alzheimer's disease. Furthermore, the model predicts that increases in brain half-life of tau in Alzheimer's disease should be attributed to decreased tau catabolism and not to increased tau synthesis. Most clearance of tau in the neuron occurs through catabolism rather than release to the CSF compartment. Additional experimental data would make ascertainment of the model parameters more precise.

BackgroundCalcitonin gene related peptide (CGRP) plays a key role in the pathophysiology of migraine and is therefore considered a potential biomarker for primary headache disorders. The challenge remaining is establishing standardized protocols for its assessment in various extracellular compartments and identifying pathological situations associated with an increase in CGRP.MethodsWe performed longitudinal measurements of CGRP plasma levels in 30 volunteers with the diagnosis of episodic migraine with and without aura under controlled circumstances during an induced migraine attack under a hypoxic challenge. Blood samples were collected from a cubital vein and CGRP plasma levels measured using ELISA.ResultsCGRP levels varied significantly between the subjects at baseline (15.48–1,889.31 pg/ml) but were neither associated with socio-demographic data nor with headache/migraine frequency or intensity collected before hypoxic exposure. CGRP levels during hypoxia fluctuated around baseline and increased with prolonged hypoxia but did not differ significantly in subjects with migraine or headache compared to those without. However, subjects experiencing migraine without aura showed significantly higher levels than those with aura. Ictal CGRP levels were increased in females, in subjects with a negative family history regarding headaches, in those older than 30 years of age or with a recent headache attack before the experiment (p < 0.05).ConclusionCGRP plasma levels seem to be highly variable even at baseline in migraine patients and increased during hypoxic challenge and migraine attacks. This is the first in human longitudinal measurement of peripheral CGRP levels during induced migraine attacks using a highly standardized protocol.

Abstract Introduction Apixaban, a direct factor Xa inhibitor, has been shown to be at least as safe and probably more effective than dalteparin for the treatment of cancer‐associated thrombosis (CAT) as reported in the ADAM‐VTE and Caravaggio studies, which included a low percentage of underweight patients. Lower‐weight–based dosing is supported by cancer‐specific studies such as half‐dose edoxaban in the Hokusai‐VTE cancer trial in individuals weighing 60 kg treated with apixaban 5 mg twice daily, patients weighing ≤60 kg also receiving apixaban 5 mg twice daily, and patients weighing ≤60 kg given half‐dose apixaban (2.5 mg twice daily). Apixaban plasma steady‐state trough levels were determined on a single occasion. Results Mean apixaban plasma trough levels were similar for patients weighing >60 kg on full‐dose apixaban to those weighing ≤60 kg taking 2.5 mg twice daily (mean, 109 ng/dL; 95% confidence interval [CI], 74‐145; standard deviation [SD]: 77.6; and mean,101 ng/dL, 95% CI, 67‐135; SD: 80, respectively). Mean values for low‐weight patients (≤60 kg) on the full 5 mg twice‐daily dosing tended to be higher (mean, 136 ng/dL; 95%CI, 70‐201; SD:114), without statistical significance (P = .22). Conclusions This study supports the rationale for studying weight‐based adjustments in apixaban dosing in prospective studies evaluating safety and efficacy of dose reduction in low‐weight patients with cancer.

Vincenzo Russo,1 Andrea Paccone,2 Anna Rago,1 Valeria Maddaloni,3 Dario Iafusco,4 Riccardo Proietti,5 Umberto Atripaldi,3 Antonio D’Onofrio,1 Paolo Golino,1 Gerardo Nigro1 1Chair of Cardiology, University of Campania “Luigi Vanvitelli”- Monaldi Hospital, Naples, Italy; 2Chair of Cardiology, University of Bari “Aldo Moro”, Bari, Italy; 3Chemical Biochemistry Unit, Monaldi Hospital, Naples, Italy; 4Department of Pediatrics, University of Campania “Luigi Vanvitelli”, Naples, Italy; 5Chair of Cardiology, University of Padua, Padua, ItalyCorrespondence: Vincenzo RussoChair of Cardiology, University of Campania “Luigi Vanvitelli”-Monaldi Hospital, Via Leonardo Bianchi, Naples 80126, ItalyTel +39 0817062355Email v.p.russo@libero.itAbstract: We present the case of a 45-year-old man with atrial fibrillation and morbid obesity (weight 128 kg, height 168 cm, BMI 45.4) who was switched from Warfarin 5 mg once daily to Apixaban 5 mg twice daily because he did not achieve at least 60% of the time in therapeutic range. We performed serial determinations of apixaban plasma concentration (at 2, 6, 12, 24 hrs after intake) showing drug levels within reference range, even when the patient lose weight.Keywords: atrial fibrillation, obesity, non-vitamin k oral anticoagulant, plasma levels, apixaban, weight loss

Background: Human Keratinocyte Growth Factor (KGF) is an FGF family protein produced by mesenchymal cells. KGF promotes epithelial cell proliferation, plays a role in wound healing and may also support tumor growth. It is expressed by some colorectal cancers (CRC). Surgery's impact on KGF levels is unknown. This study's purpose was to assess plasma KGF levels before and after minimally invasive colorectal resection (MICR) for CRC.Aim: To determine plasma KGF levels before and after minimally invasive colorectal resection surgery for cancer pathology.Method: CRC MICR patients (pts) in an IRB approved data/plasma bank were studied. Pre-operative (pre-op) and post-operative (post-op) plasma samples were taken/stored. Late samples were bundled into 7 day blocks and considered as single time points. KGF levels (pg/ml) were measured via ELISA (mean ± SD). The Wilcoxon paired t-test was used for statistical analysis.Results: Eighty MICR CRC patients (colon 61%; rectal 39%; mean age 65.8 ± 13.3) were studied. The mean incision length was 8.37 ± 3.9 and mean LOS 6.5 ± 2.6 days. The cancer stage breakdown was; I (23), II (26), III (27), and IV (4). The median pre-op KGF level was 17.1 (95 %CI: 14.6–19.4; n = 80); significantly elevated (p < 0.05) median levels (pg/ml) were noted on post-op day (POD) 1 (23.4 pg/ml; 95% CI: 21.4–25.9; n = 80), POD 3 (22.5 pg/ml; 95% CI: 20.7–25.9; n = 76), POD 7–13 (21.8 pg/ml; 95% CI: 17.7–25.4; n = 50), POD 14–20 (20.1 pg/ml; 95% CI: 17.1–23.9; n = 33), POD 21–27 (19.6 pg/ml; 95% CI: 15.2–24.9; n = 15) and on POD 28–34 (16.7 pg/ml; 95% CI: 14.0–25.8; n = 12).Conclusion: Plasma KGF levels were significantly elevated for 5 weeks after MICR for CRC. The etiology of these changes is unclear, surgical trauma related acute inflammatory response and wound healing process may play a role. These changes, may stimulate angiogenesis in residual tumor deposits after surgery.

Antipsychotic plasma levels have been extensively used in the assessment of poor treatment response, lack of adherence and adverse events in delusional disorder. It has not been used as an indicator of metabolizer status, to determine whether a delusional disorder patient is a poor, intermediate, or ultra-rapid metabolizer of antipsychotics. Pharmacogenetic probes are, of course, the right method for the latter task, but they are not readily available for clinical use. We report the case of a 46-year-old woman with delusional disorder who developed unexpected adverse effects to treatment with relatively low dose risperidone and poor symptomatic response. Blood level monitoring indicated high levels of risperidone and a high concentration-to-dose ratio, which suggested accumulation of unmetabolized risperidone. Paradoxically, extrapyramidal side effects increased when, after reducing the risperidone dose, 5 mg/day of aripiprazole was added. Consequently, the patient was switched to olanzapine 5 mg/day. Sertraline 150 mg/day was later added for comorbid depression. A complete symptomatic response was achieved. Although other factors may well have been at play, this sequence of events suggests that the patient was a slow metabolizer of CYP2D6, which metabolizes both risperidone and aripiprazole. With pharmacogenetic assessment not available, therapeutic drug monitoring helped clinicians decide on appropriate management.

Abstract Background Oxytocin is a key hormone in childbirth, and synthetic oxytocin is widely administered to induce or speed labour. Due to lack of synthetized knowledge, we conducted a systematic review of maternal plasma levels of oxytocin during physiological childbirth, and in response to infusions of synthetic oxytocin, if reported in the included studies. Methods An a priori protocol was designed and a systematic search was conducted in PubMed, CINAHL, and PsycINFO in October 2015. Search hits were screened on title and abstract after duplicates were removed (n = 4039), 69 articles were examined in full-text and 20 papers met inclusion criteria. As the articles differed in design and methodology used for analysis of oxytocin levels, a narrative synthesis was created and the material was categorised according to effects. Results Basal levels of oxytocin increased 3–4-fold during pregnancy. Pulses of oxytocin occurred with increasing frequency, duration, and amplitude, from late pregnancy through labour, reaching a maximum of 3 pulses/10 min towards the end of labour. There was a maximal 3- to 4-fold rise in oxytocin at birth. Oxytocin pulses also occurred in the third stage of labour associated with placental expulsion. Oxytocin peaks during labour did not correlate in time with individual uterine contractions, suggesting additional mechanisms in the control of contractions. Oxytocin levels were also raised in the cerebrospinal fluid during labour, indicating that oxytocin is released into the brain, as well as into the circulation. Oxytocin released into the brain induces beneficial adaptive effects during birth and postpartum. Oxytocin levels following infusion of synthetic oxytocin up to 10 mU/min were similar to oxytocin levels in physiological labour. Oxytocin levels doubled in response to doubling of the rate of infusion of synthetic oxytocin. Conclusions Plasma oxytocin levels increase gradually during pregnancy, and during the first and second stages of labour, with increasing size and frequency of pulses of oxytocin. A large pulse of oxytocin occurs with birth. Oxytocin in the circulation stimulates uterine contractions and oxytocin released within the brain influences maternal physiology and behaviour during birth. Oxytocin given as an infusion does not cross into the mother’s brain because of the blood brain barrier and does not influence brain function in the same way as oxytocin during normal labour does.

Clozapine is the gold standard for treatment-resistant schizophrenia. Serious and even life-threatening adverse effects, mostly granulocytopenia, myocarditis, and constipation, are of great clinical concern and constitute a barrier to prescribing clozapine, thus depriving many eligible patients of a lifesaving treatment option. Interestingly, clozapine presents variable pharmacokinetics affected by numerous parameters, leading to significant inter- and intra-individual variation. Therefore, therapeutic drug monitoring of plasma clozapine levels confers a significant benefit in everyday clinical practice by increasing the confidence of the prescribing doctor to the drug and the adherence of the patient to the treatment, mainly by ensuring effective treatment and limited dose-related side effects. In the present systematic review, we aimed at identifying how a full range of adverse effects relates to plasma clozapine levels, using the Jadad grading system for assessing the quality of the available clinical evidence. Our findings indicate that EEG slowing, obsessive-compulsive symptoms, heart rate variability, hyperinsulinemia, metabolic syndrome, and constipation correlate to plasma clozapine levels, whereas QTc, myocarditis, sudden death, leucopenia, neutropenia, sialorrhea, are rather unrelated. Rapid dose escalation at the initiation of treatment might contribute to the emergence of myocarditis, or leucopenia. Strategies for managing adverse effects are different in these conditions and are discussed accordingly.

High-dose methotrexate is a cornerstone agent in the chemotherapeutic treatment of patients with osteosarcoma. However, patients often develop methotrexate-induced toxicities. We aim to identify determinants of methotrexate-induced toxicities in osteosarcoma patients by investigating the relation between drug plasma levels, methotrexate-induced toxicities, and germline variants in genes related to drug absorption, distribution, metabolism, and elimination. A cohort of 114 osteosarcoma patients was genotyped for 1,931 variants in 231 genes using the Drug Metabolism Enzymes and Transporters Plus array. Methotrexate plasma levels and laboratory measurements during and after high-dose methotrexate treatment concerning renal function, liver damage, and myelopoiesis to reflect toxicity outcomes were obtained. One hundred and thirteen patients and a subset of 545 variants in 176 genes passed quality control checks. Methotrexate plasma levels showed associations with creatinine, alanine aminotransferase, and hemoglobin. Genetic variant rs3736599 in the 5’-untranslated region of SULT1E1 was associated with lower 48 hour methotrexate plasma levels [coef -0.313 (95% CI -0.459 – -0.167); p = 2.60 × 10-5]. Association with methotrexate-induced decreased thrombocyte counts was found for two intronic variants in CYP2B6 {rs4803418 [coef -0.187 (95% CI -0.275 – -0.099); p = 3.04 × 10-5] and rs4803419 [coef -0.186 (95% CI -0.278 – -0.093); p = 8.80 × 10-5]}. An association with increased thrombocyte counts was identified for the intronic variant rs4808326 in CYP4F8 [coef 0.193 (95% CI 0.099 – 0.287); p = 6.02 × 10-5]. Moreover, a secondary analysis with a binary approach using CTCAE toxicity criteria resulted in a nominal significant associations (p < 0.05) for two out of three variants (rs4803418 and rs4808326). This is the first study to identify genetic variants in SULT1E1, CYP2B6, and CYP4F8 to be associated with methotrexate pharmacokinetics and toxicities. Validation of these variants in an independent cohort and further functional investigation of variants in the identified genes is needed to determine if and how they affect methotrexate plasma levels and the development of methotrexate-induced toxicities.

We present the case of a 80-year-old man with atrial fibrillation, morbid obesity (weight 123 kg, height 167 cm, BMI 44.1), high clearance of creatinine and pharmacological polytherapy, in which the serial determinations of edoxaban plasma levels help us to choose the appropriate dose.

Abstract Background Ethnicity variation is one of the main factors that may affect drug response in clinical practice. As MTHFR gene affects different transcriptome and proteome which affect the clinical response of drugs. Purpose of the current study was to observe possible variations in plasma levels of carbamazepine monotherapy and seizures’ control in Pakhtun population of Khyber Pakhtunkhwa (KP) in the context of MTHFR (C677T and A1298C) gene polymorphisms. Methods Blood was collected from the epileptic patients treated with carbamazepine monotherapy for the first time following respective oral doses on its steady state concentration after 3 h of morning dose at 3rd and 6th month of the therapy. Plasma carbamazepine levels were determined using reverse phase high performance liquid chromatography after method validation. MTHFR (C677T, AA298C) gene was genotyped. Patients were followed on 3rd and 6th month of the therapy for monitoring of response to carbamazepine therapy. Results Following for 3rd and 6th month of duration of carbamazepine therapy, poor seizure controlled patients were more likely noticed in heterozygous variants (677CT and 1298 AC) of MTHFR gene (P 0.05) difference in the dose and plasma level of carbamazepine among different genotypes of MTHFR (C677T and A1298C) gene. Similarly, the difference in dose and plasma level of carbamazepine was not significant (P > 0.05) in the responder and non-responder people with epilepsy. Conclusion Our study suggests that heterozygous variants of MTHFR (C677T and A1298C) gene are associated with poor seizure control in Pakhtun population of KP despite the fact that plasma level of carbamazepine were found within the therapeutic range.

An increasing amount of data suggests a role of the eye vascular system and oxidative stress in glaucoma pathogenesis. Reports have suggested endothelin-1 (ET-1) and its receptor (ETR-A) as possible glaucoma biomarkers. This study explored the diagnostic and prognostic abilities of ET-1 and ETR-A plasma concentrations in primary open angle glaucoma (POAG). Seventy-five participants were divided into three groups: controls, early and advanced POAG stage, graded by a perimetric visual field test. All of them underwent a standard ophthalmological examination including optical coherence tomography. The statistical analysis showed a significant difference between the ET-1 values in the controls (4.88 ± 1.75 pg/mL) and the glaucoma patients, but lack of statistical significance in the glaucoma severity (early POAG: 6.33 ± 2.38 pg/mL and advanced POAG: 6.34 ± 1.56 pg/mL). The mean ETR-A values were significantly different between the three groups (controls 1209.28 ± 314.48 pg/mL, early POAG: 673.44 ± 283.02 pg/mL and advanced POAG: 992.28 ± 264.22 pg/mL). Two mathematical models were developed concerning the two perimetric indices (MD/PSD) and ETR-A in the early glaucoma group. ETR-A showed a very high diagnostic accuracy. Only ETR-A had significant diagnostic ability for advanced glaucoma after the comparison between the two glaucoma groups. Every 1 pg/mL increase in the ET-1 plasma concentration increased the possibility for early glaucoma changes by 2.124 times, whereas every 1 pg/mL increase in the ETR-A level decreased this possibility by 1%. Our results indicate that ET-1 and ETR-A could be two very good diagnostic parameters for early POAG changes.

The present study evaluated the IL8-251 A/T polymorphism in samples from 74 patients with chronic hepatitis B (HBV), 100 patients with chronic hepatitis C (HCV), and 300 healthy donors (CG). The correlations of this polymorphism with plasma IL-8 and disease stage were calculated. Polymorphisms were identified by real-time PCR. IL-8 was measured by enzyme-linked immunosorbent assay. The IL8-251 A/T genotype was not associated with susceptibility to infection by HBV or HCV. The wild-type allele (A) was associated with higher levels of inflammation (p = 0.0464) and fibrosis scores (p = 0.0016) in the HBV group, representing an increased risk for increased inflammatory activity (OR = 1.84; p = 0.0464) and for high fibrosis scores (OR = 2.63; p = 0.0016). Viral load was higher in HBV patients with polymorphic genotypes (TA and TT) at the IL8-251 A/T polymorphism than in those with the wild-type genotype (p = 0.0272 and p = 0.0464, respectively). Plasma IL-8 was higher among patients infected with HBV or HCV than in the control group (p = 0.0445 and p = 0.0001, respectively). The polymorphic genotype was associated with lower IL-8 than the wild-type genotype in the HBV group (p = 0.0239) and the HCV group (p = 0.0372). The wild-type genotype for IL8-251 A/T and high IL-8 were associated with a worse prognosis for infections; therefore, they may contribute to viral persistence and the development of more severe forms of chronic viral liver diseases.

Background and Purpose Standard operating procedures (SOP) incorporating plasma levels of rivaroxaban might be helpful in selecting patients with acute ischemic stroke taking rivaroxaban suitable for IVthrombolysis (IVT) or endovascular treatment (EVT). Methods This was a single-center explorative analysis using data from the Novel-Oral-Anticoagulants-in-Stroke-Patients-registry (clinicaltrials.gov:NCT02353585) including acute stroke patients taking rivaroxaban (September 2012 to November 2016). The SOP included recommendation, consideration, and avoidance of IVT if rivaroxaban plasma levels were 100 ng/mL, respectively, measured with a calibrated anti-factor Xa assay. Patients with intracranial artery occlusion were recommended IVT+EVT or EVT alone if plasma levels were ≤100 ng/mL or >100 ng/mL, respectively. We evaluated the frequency of IVT/EVT, door-to-needle-time (DNT), and symptomatic intracranial or major extracranial hemorrhage. Results Among 114 acute stroke patients taking rivaroxaban, 68 were otherwise eligible for IVT/EVT of whom 63 had plasma levels measured (median age 81 years, median baseline National Institutes of Health Stroke Scale 6). Median rivaroxaban plasma level was 96 ng/mL (inter quartile range [IQR] 18‒259 ng/mL) and time since last intake 11 hours (IQR 4.5‒18.5 hours). Twenty-two patients (35%) received IVT/EVT (IVT n=15, IVT+EVT n=3, EVT n=4) based on SOP. Median DNT was 37 (IQR 30‒60) minutes. None of the 31 patients with plasma levels >100 ng/mL received IVT. Among 14 patients with plasma levels ≤100 ng/mL, the main reason to withhold IVT was minor stroke (n=10). No symptomatic intracranial or major extracranial bleeding occurred after treatment. Conclusions Determination of rivaroxaban plasma levels enabled IVT or EVT in one-third of patients taking rivaroxaban who would otherwise be ineligible for acute treatment. The absence of major bleeding in our pilot series justifies future studies of this approach.

Endothelin-1 (ET-1) is a potent vasoconstrictor and is considered to have a key role in the regulation of ocular perfusion and glaucoma pathogenesis. High ET-1 and ETA-receptor levels are reported in patients with primary open-angle glaucoma (POAG). We compared the mean plasma ET-1 and ETA-receptor concentration of controls and patients with early and advanced POAG stage, and assessed the correlation with the retinal nerve fibre layer (RNFL) thickness. The study included a total of 75 participants, aged 45–83 years: 25 (controls), 22 (early glaucoma) and 28 (advanced glaucoma). The plasma concentration of ET-1 and ETA-receptor was determined by enzyme-linked immunosorbent assay. The RNFL thickness was evaluated with spectral-domain optical coherence tomography. The mean ET-1 concentration was lower in the control group (4.88 ± 1.75 pg/mL) than in the early and advanced POAG group (6.33 ± 2.38 and 6.34 ± 1.56 pg/mL). Statistically significant difference was found between the mean ET-1 concentrations in controls and glaucoma patients (p = 0.029 – early glaucoma, p = 0.018 – advanced glaucoma), and no significant difference was observed between the two POAG groups (p = 0.998). The mean ETA-receptor concentration was highest in the control group (1209.28 ± 314.48 pg/mL) and the differences between the three groups were significant. Significant relationship was found only between ET-1 and RNFL. This study demonstrated the role of ET-1 in glaucoma pathogenesis based on the observed significant high ET-1 and ETA-receptor plasma levels in POAG patients. A new therapeutical approach needs to be considered in some patients.

Patients with AD often show altered levels of some immune molecules in their peripheral blood which correlate with cognitive impairment. Downs' syndrome (DS) subjects are at high risk of developing Alzheimer's disease (AD). Here we studied immune molecules, such as interleukin-6 (IL-6), C reactive protein (CRP) and neopterin, in the blood of non demented children with DS to investigate whether altered peripheral immune phenotype could be present in this subjects without dementia, many years before the presentation of clinical signs of cognitive deterioration. Plasma levels of neopterin and IL-6 were measured by commercially available ELISA kits, whereas plasma CRP concentration was evaluated by nephelometric immunoassay technique. We studied a group of 40 patients with DS, 20 healthy controls and 100 patients w ith AD. Plasma levels of IL-6 and CRP were significantly higher in DS than in control children. The increase of IL-6 and CRP from DS children was similar to that found in elderly patients with clinical AD. In the present research we have also studied blood levels of neopterin which were in the normal range either in DS or control. Increased or normal levels of this metabolite have been found in the blood of AD patients. However, increased blood neopterin was likely to be only elevated in patients with advanced clinical stage of AD. Peripheral altered immune phenotype in healthy young subjects with DS might be an early sign of CNS alterations leading many years later to cognitive deterioration and dementia.

For the last 40 years, schizophrenia has been considered to be the result primarily of a dysfunction in brain dopaminergic pathways. In this review, it is described and discussed findings concerning nitric oxide-mediated neurotransmission in schizophrenia. Studies were searched in PubMed, SciELO, and LILACS using the terms schizophrenia and nitric oxide plasma levels or nitric oxide serum levels, with no time limit. The reference lists of selected articles were also hand-searched for additional articles. From 15 potential reports, 10 were eligible to be included in the review and meta-analysis. These studies included a total of 505 patients with schizophrenia and 339 healthy volunteers. No significant difference was found between patients and healthy controls regarding total nitrite plasma/serum levels (effect size g = 0.285, 95%CI = -0.205 to 0.774, p = 0.254). However, when studies with patients under antipsychotic treatment were examined separately, there was a significant difference between patients and healthy volunteers (effect size g = 0.663, 95%CI = 0.365 to 0.961, p < 0.001), showing that patients under treatment have higher levels of plasma/serum nitric oxide than controls. These results suggest that antipsychotics increase nitric oxide plasma/serum levels and that the nitrergic pathway would be a fertile target for the development of new treatments for patients with schizophrenia.Durante os últimos 40 anos, a esquizofrenia foi considerada, principalmente, como o resultado de disfunções dopaminérgicas no cérebro. Esta revisão descreve e discute algumas descobertas sobre a neurotransmissão mediada pelo óxido nítrico na esquizofrenia. A busca foi feita nas bases PubMed, SciELO e LILACS usando-se os termos schizophrenia e nitric oxide plasma levels ou nitric oxide serum levels, sem limites de tempo. As listas de referências dos artigos selecionados foram examinadas em busca de outras publicações pertinentes. Dentre 15 artigos passíveis de serem incluídos, 10 preenchiam os critérios estabelecidos para a revisão e metanálise. Esses estudos incluíram 505 pacientes com esquizofrenia e 339 voluntários saudáveis. Não foram encontradas diferenças significativas entre pacientes e voluntários saudáveis quanto aos níveis plasmáticos de nitrito total (effect size g = 0,285, IC 95% = -0,205 a 0,774, p = 0,254). No entanto, o exame separado dos estudos envolvendo pacientes em tratamento antipsicótico apresentou diferenças significativas entre pacientes e voluntários saudáveis (effect size g = 0,663, IC 95% = 0,365 to 0,961, p < 0,001), demonstrando que pacientes em tratamento possuem níveis plasmáticos mais altos de óxido nítrico. Esses resultados sugerem que os antipsicóticos podem aumentar os níveis plasmáticos de óxido nítrico e que a via nitrérgica (e sua estimulação) constituiria um alvo propício para o desenvolvimento de novos tratamentos para pacientes com esquizofrenia.

Due to the narrow therapeutic range of theophyline, plasma concentrations of this drug are monitored in patients undergoing chronic therapy. Slow-release preparations avoid the fluctuations in plasma levels and improve patient compliance. In this study, we have compared the pharmacokinetic profiles of a theophylline slow-release tablet and a syrup form, when administered in multiple doses to healthy adult volunteers. The classification based upon releasing patterns is confirmed.

Introduction of the ketogenic diet did not change the plasma levels of antiepileptic drugs in an open study of 51 children (mean age 6.6 years) with refractory epilepsy studied at Karolinska University Hospital, Stockholm, Sweden.

OBJECTIVE: To evaluate the factors associated with plasma concentrations of atazanavir (ATV) in a cohort of well-controlled HIV infected subjects (undetectable viremia). Design: Cross-sectional study where 69 subjects were consecutively enrolled between April and November, 2011. METHODS: Patients had to be on atazanavir for at least six months, undetectable viral load for a period equal to or longer than 12 months, T CD4+ lymphocyte count higher than 200 cells/mm³, and aged between 18 years and 70 years old. Exclusion criteria were pregnancy, any neurologic disease, active opportunistic disease, hepatitis or cancer. Atazanavir plasma levels were measured by ultra-performance liquid chromatography. RESULTS AND DISCUSSION: Overall, 54 patients (mean age of 47 years and 50% women) were included in the analysis. Those without ritonavir (unboosted atazanavir) had statistically lower plasma concentrations than those with ritonavir boosted atazanavir (p = 0.001) and total and indirect bilirubin were statistically associated with plasma concentration of atazanavir (r = 0.32 and r = 0.33 respectively; p < 0.05 in both cases). no statistical association was found among gender, ethnicity, age, weight, body mass index (BMI), lipid profile, and the plasma concentration of atazanavir. CONCLUSION: in summary, as expected, concomitant ritonavir use was the only factor associated with atazanavir plasma levels. prospective studies with a larger sample size might help to observe an association of atazanavir concentrations to other characteristics such as body weight, since the p-value showed to be close to significance (p = 0.068).