Effect of selected antioxidants in β-cyfluthrin-induced oxidative stress in human erythrocytes in vitro

β-Cyfluthrin is one of the most widely used type II pyrethroid in agriculture. The aim of this study was to examine (1) the possibility of β-cyfluthrin to induce oxidative stress in human erythrocytes in vitro and its effect on catalase (CAT) and superoxide dismutase (SOD) activities as well as (2) the role of melatonin (MEL; 2 mM), its precursor – N-acetylserotonin (NAS; 1 mM), quercetin (Q; 80 μM) and rutin (R; 80 μM) in alleviating the cytotoxic effects of β-cyfluthrin. Erythrocytes were divided into portions. The first portion was incubated for 4 h at 37 °C with different concentrations (0, 43, 215, 1075 ppm) of β-cyfluthrin. The other portions were preincubated with selected antioxidant, respectively for 30 min and followed by β-cyfluthrin incubation for 4 h. Malondialdehyde (MDA) concentrations, CAT and SOD activities, as well as haemolysis percentage (H) were measured in all treatment portions of erythrocytes.It could be concluded that the in vitro toxicity of β-cyfluthrin may be associated with oxidative stress. Significant reduction in the activities of CAT was observed at all β-cyfluthrin concentrations, while SOD activities were significantly decreased only in erythrocytes incubated with the highest β-cyfluthrin concentration. SOD activity of the non-pretreated erythrocytes exposed to the lowest dose of β-cyfluthrin was significantly greater when compared to comparably β-cyfluthrin-exposed antioxidant pretreated cells. The highest concentration of β-cyfluthrin has caused over 35% haemolysis, and the lowest concentration about 15%. MEL pretreatment had no effect on H and MDA induction by β-cyfluthrin. NAS, Q and R reduced H and MDA level, but could not prevent induction of these parameters.Compared to other antioxidants NAS appeared to maintain better the CAT activity at control levels for all doses of β-cyfluthrin. Pretreatment with Q was found to protect against the decrease in SOD activity induced by β-cyfluthrin.     

Erlotinib in glioblastoma: lost in translation?

Glioblastoma represents the most common primary brain tumor in adults. Despite improvements of multimodal therapy, the prognosis of this disease remains unfavorable. Thus, great efforts have been made to identify therapeutic agents directed against those specific molecular targets whose presence was shown to be associated with worse clinical outcomes. The epidermal growth factor receptor (HER1/EGFR) has been identified as one such target, and different compounds were developed to inhibit HER1/EGFR and/ or its mutant form, EGFRvIII. However, clinical trials did not confirm the initial enthusiasm conveyed by promising results from experimental studies. Therefore, a therapeutic approach directed at inhibiting solely HER1/EGFR does not seem to translate into a clinical benefit. This review discusses the current therapeutic situation in the setting of glioblastoma while putting the spotlight on erlotinib, a HER1/EGFR-targeted small molecule tyrosine kinase inhibitor.     

Potential drug–drug interactions in internal medicine wards in hospital setting in Pakistan

Background Multiple drugs therapies may be the potential source of drug–drug interactions that can result in alteration of therapeutic response and/or increase untoward effects of many drugs. Objective To identify the frequency and levels of potential drug–drug interactions (pDDIs) in internal medicine wards and their association with patients’ age, gender, length of hospital stay and number of prescribed medications; and to describe management of frequently identified major or moderate pDDIs. Setting Internal medicine wards of two major tertiary care hospitals of Khyber Pakhtunkhwa, Pakistan. Method Micromedex Drug-Reax system was used to screen patient’s profiles for pDDIs. Logistic regression was applied to determine the odds ratio for specific risk factors of pDDIs i.e., age, gender, hospital-stay and number of medications. Main outcome measure Overall prevalence and prevalence of contraindicated, major, moderate and minor pDDIs; levels of pDDIs; frequently identified major or moderate interactions; and odds ratios for risk factors. Results Total, 188 interacting drug-combinations were identified that contributed to 675 pDDIs. Of 400 patients, 52.8 % patients were presented with at least one pDDI (overall prevalence), 21.3 % with at least one major-pDDI, and 44.3 % with at least one moderate-pDDI. Of 675 pDDIs, most were of moderate (63.6 %) or major severity (23 %); good (61.2 %) or fair (25.5 %) type of scientific evidence; and delayed onset (50.2 %). Most frequently identified major or moderate interactions resulted in 45.3 % of all pDDIs. Their potential adverse outcomes included hepatotoxicity, bleeding, ototoxicity, nephrotoxicity, hypoglycemia, hyperglycemia, risk of thrombosis, hypotension, cardiac arrhythmias and reduction in therapeutic-effectiveness. There was significant association of the occurrence of pDDIs with patients’ age of 60 years or more (OR = 2.1; 95 % CI = 1.3–3.3; p = 0.003), hospital stay of 6 days or longer (OR = 2.6; 95 % CI = 1.5–4.5; p = 0.001), and seven or more number of prescribed medications (OR = 5.9; 95 % CI = 3.6–9.6; p < 0.001). Conclusion The present study has recorded a high prevalence of pDDIs in internal medicine wards. Patients with old age, longer hospital stay and increased number of prescribed medications were at higher risk.     

Drug release in vitro--an aid in clinical trials?

The topic of this article is biopharmacy. Using delayed release tablets with the active ingredient theophylline as a practical example, it was demonstrated that prior to clinical trials, galenical preparations can be characterized according to drug release in vitro and, that profiles of in vitro drug release can be compared with each other (LEVY-plot). Drug release from the retard tablets was examined following the Cube Root Law which describes the dependency of release rate on surface and agitation. Comparing profiles of in vitro release to a hypothetical or even known profile of in vivo release, produce results that are open to interpretation (LEVY-plot). A postulated correlation between the nonanalogous parameters, relative bioavailability and the mean in vitro dissolution time was confirmed. Due to established in vitro/in vivo correlations, we can in our case, predict the hypothetical in vivo release profiles for tablets showing more or less retarded release profiles in vitro and the relative bioavailability can be estimated. In addition, prediction of blood level is possible. In vitro/in vivo correlations can also provide information about residence times of the delayed release tablets in components of the gastrointestinal tract (stomach, small bowel and large bowel). Thus, using these methods, delayed release tablets (with the active ingredient theophylline) can be optimized for their use in clinical trials.     

Biomarkers in Amyloid-β Immunotherapy Trials in Alzheimer's Disease

Drug candidates directed against amyloid-β (Aβ) are mainstream in Alzheimer''s disease (AD) drug development. Active and passive Aβ immunotherapy is the principle that has come furthest, both in number and in stage of clinical trials. However, an increasing number of reports on major difficulties in identifying any clinical benefit in phase II–III clinical trials on this type of anti-Aβ drug candidates have caused concern among researchers, pharmaceutical companies, and other stakeholders. This has provided critics of the amyloid cascade hypothesis with fire for their arguments that Aβ deposition may merely be a bystander, and not the cause, of the disease or that the amyloid hypothesis may only be valid for the familial form of AD. On the other hand, most researchers argue that it is the trial design that will need refinement to allow for identifying a positive clinical effect of anti-Aβ drugs. A consensus in the field is that future trials need to be performed in an earlier stage of the disease and that biomarkers are essential to guide and facilitate drug development. In this context, it is reassuring that, in contrast to most brain disorders, research advances in the AD field have led to both imaging (magnetic resonance imaging (MRI) and PET) and cerebrospinal fluid (CSF) biomarkers for the central pathogenic processes of the disease. AD biomarkers will have a central role in future clinical trials to enable early diagnosis, and Aβ biomarkers (CSF Aβ42 and amyloid PET) may be essential to allow for testing a drug on patients with evidence of brain Aβ pathology. Pharmacodynamic Aβ and amyloid precursor protein biomarkers will be of use to verify target engagement of a drug candidate in humans, thereby bridging the gap between mechanistic data from transgenic AD models (that may not be relevant to the neuropathology of human AD) and large and expensive phase III trials. Last, downstream biomarker evidence (CSF tau proteins and MRI volumetry) that the drug ameliorates neurodegeneration will, together with beneficial clinical effects on cognition and functioning, be essential for labeling an anti-Aβ drug as disease modifying.     

Mutagenicity tests on epristeride in vitro and in vivo

目的：评价治疗良性前列腺肥大的新药依立雄胺（Ｅｐｒ）的遗传影响．方法：１）鼠沙门氏菌体外回复突变试验测试能否诱发基因突变；２）ＣＨＬ细胞染色体的损伤和畸变实验；３）ＩＣＲ小鼠一次ｉｇＥｐｒ后测试是否导致骨髓嗜多染红细胞染色体的损伤；４）昆明种小鼠连续ｉｇＥｐｒ５ｄ，３０ｄ后统计精子头部异常情况．结果：１）Ｅｐｒ不诱导细菌回复突变．２）ＣＨＬ细胞染色体畸变低于３％不造成细胞染色体损伤．３）Ｅｐｒ不诱导小鼠嗜多染红细胞微核的形成．４）Ｅｐｒ高、中、低剂量组引起的头部畸形率分别为５．３％±２．７％，５．３％±１．９％，５．２％±１．２％，与对照组相比不引起显著的精子头部异常．结论：Ｅｐｒ在体内外实验中没有表现出遗传毒性．     

Trends in women’s authorship in pharmacy literature

ObjectivesThe purpose of this evaluation was to determine whether the percentage of women as first authors in pharmacy journals has continued to increase over the past decade.MethodsKey pharmacy practice journals were identified from the American Association of Colleges of Pharmacy Core List of Journals for Pharmacy Education. Articles were analyzed from January 2007 through December 2017. The outcome of interest was the proportion of articles having feminine names as the first author. Femininity was determined for first authors by matching the first name to data from the U.S. Social Security Administration or genderize.io. The Cochran–Armitage trend test was used to determine differences in proportion of women as first authors over time.ResultsThe listed first authors over the past decade were 52.7% female for all studied journals from 2007 through 2017. All but 1 journal demonstrated a significant increase in the proportion of female first authors over the time period studied. Subanalyses of journals (1) containing more than 90% gender-identifiable articles, (2) focused predominantly on contemporary drug therapy or pharmacy practice and not typically including pharmaceutical- or pharmacokinetics-related topics, and (3) that did not focus predominantly on contemporary therapy or practice and included pharmaceutical- or pharmacokinetics-related topics were each significant.ConclusionFemale first authorship in pharmacy practice journals appears to have increased in the past decade but may potentially be reaching a plateau. The proportion of female first authorship is close to reaching that of women in the U.S. pharmacy workforce when compared over the same time period.     

Evaluation of vancomycin use in a large university‐affiliated hospital in eastern France in 1999

Objective: In 1999, we conducted a retrospective drug utilization review to determine the volume and pattern of vancomycin use in a universityaffiliated hospital in eastern France. Methods: Total vancomycin use was determined and expressed as vancomycin courses per 100 admitted patients and defined daily doses (DDD) of vancomycin per 100 patientdays. The indication for vancomycin use was classified as appropriate or inappropriate according to the guidelines issues by the HICPAC. Results: A total of 311 vancomycin courses were given, as 2098 DDD, giving crude incidences of 1.17 courses per 100 admitted patients and of 1.19 defined daily doses per 100 patientdays. The frequency of appropriate courses was 66.7%. Of the 63 inappropriate courses of vancomycin, 39.7% and 28.6% were empiric therapy for nosocomial and communityacquired infections, respectively, 20.6% and 6.3% were specific therapy for nosocomial and communityacquired infections, respectively, and 4.7% were prophylactic. Conclusions: This study shows that vancomycin use in our hospital resulted in a lower selection pressure than has been reported for US universityaffiliated hospitals and that comprehensive programs to improve use of vancomycin are needed in our institution.     

Possible involvement of β₁ receptors in various emetogen-induced increases in salivary amylase activity in rats

We investigated the inhibitory effects of β₁- or β₂-adrenoceptor (AR) antagonists on salivary amylase secretion produced by various emetic agents, such as cisplatin, apomorphine, and lithium chloride (LiCl), or the non-emetic agent β_1/2-AR agonist isoprenaline in rats. We also determined the inhibitory effect of metoclopramide, a dopamine D₂–receptor antagonist, on increases in the salivary amylase activity induced by apomorphine or granisetron, a 5-HT₃–receptor antagonist, on LiCl-induced increased salivary amylase activity. Isoprenaline (0.01 mg/kg, s.c.) produced an increase in salivary amylase and the increase was inhibited by the β_1/2-AR antagonist propranolol (5 mg/kg, s.c.) and β₁-AR antagonist atenolol (2 mg/kg, s.c.) but not by the β₂-AR antagonist butoxamine (8 mg/kg, s.c.). The increased amylase activity induced by cisplatin (15 mg/kg, i.v.), apomorphine (3 mg/kg, s.c.), or LiCl (120 mg/kg, i.p.) was inhibited significantly by atenolol (2 mg/kg, s.c.) but not by butoxamine (8 mg/kg, s.c.). In addition, increases in amylase activities induced by apomorphine and LiCl were inhibited significantly by metoclopramide (10 mg/kg, i.v.) and granisetron (3 mg/kg, i.v.), respectively. These results suggest that salivary amylase secretion induced by various emetogens is involved in β₁-adrenoceptor activity and that salivary amylase activity is useful to detect emetogens with no direct β₁-AR activation in rats, a species that does not exhibit vomiting.     

Role of δ-opioid receptor subtypes in anxiety-related behaviors in the elevated plus-maze in rats

Rationale Recent studies have shown that endogenous opioid systems are associated with the regulation of emotional responses. In particular, it has been reported that δ-opioid receptors act naturally to inhibit stress and anxiety. Objective The present study was designed to examine the possible involvement of opioid δ-receptor subtypes in the anxiety-related behavior in the elevated-plus-maze test. Methods Six-week-old male Lewis rats were used. The total numbers of visits to the closed and open arms and the cumulative time spent and visits in the open arms were determined. Plasma corticosterone levels were measured by enzyme immunoassay. Results Naltrindole (NTI), a δ-opioid receptor antagonist (3 mg/kg s.c.), induced a significant decrease in the percentages of time spent and visits in the open arms. Naltriben (NTB), a δ₂-opioid receptor antagonist (3 mg/kg s.c.), but not 7-benzylidenenaltrexone, a δ₁-opioid receptor antagonist, produced similar anxiety-related behaviors in the elevated plus-maze. These effects of NTI and NTB were antagonized by pretreatment with (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), a δ-opioid receptor agonist. Furthermore, after exposure to the elevated plus-maze, the maximal increase in the plasma corticosterone level in NTI-treated rats was clearly higher than that in vehicle-treated rats. However, when NTI and SNC80 were coadministered, higher levels of plasma corticosterone were not seen after exposure to the elevated plus-maze. Conclusion These results suggest that endogenous δ₂-opioid-receptor-mediated systems are involved in the regulation of anxiety-related behaviors and might play a physiologically important role in the regulation of adrenocortical activity.     

Leishmania antibodies in children’s serum samples in correlation with the disease in dogs

Sera of 489 children from Northern Greece aged between 6 months and 15 years of age and aflicted with different clinical entities, were tested for anti ? Leishmania infantum specific IgG and IgM antibodies, using an ELISA (enzyme linked immunosorbent assay) technique. In this survey, a remarkably high percentage (8.5%) of hospitalized children reacted positively to this method. Twenty three out of 489 children (4.7%) had IgG antibodies, seventeen (3.5%) IgM, while two (0.4%) had both IgG and IgM antibodies against soluble antigen of L. infantum promastigotes. Females had a higher seropositivity than males. The highest prevalence was observed in males aged between 6 months and 5 years old (10 out of 19), while the lowest was observed also in males aged between 11 and 15 years old (5 out of 11). Seropositivity rate was higher in children below 5 years of age. Some epidemiologic, as well as clinical data of canine Leishmaniosis from Northern Greece are discussed.     

Methanol-Vergiftungen in Hamburg in den Jahren 1945–1950

Ohne Zusammenfassung     

Is nitrotyrosine generated in human erythrocytes in circulation?

Nitrotyrosine is considered a stable biomarker of reactive nitrogen species, including nitrogen dioxide (NO2) and peroxynitrous acid (ONOOH) in biomaterials. There are inconsistent observations on the detection of free and protein-associated nitrotyrosine in normal human plasma. Human erythrocytes, differentiated from erythrocyte precursor cells in the bone marrow, circulating in the body for an average of 120 d, and finally removed by spleen macrophages, may be exposed to reactive nitrogen species. In the present study, membrane proteins and hemoglobin from the senescent erythrocyte population were compared with those from young erythrocytes separated from the same individuals in their nitrotyrosine presence using newly prepared rabbit polyclonal anti-nitrotyrosine-ribonuclease A and anti-nitro(N-butoxycarbonyl)tyrosine-bovine serum albumin antibodies. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the membranes and hemoglobin, and subsequent Western blot analysis, showed that these antibodies only slightly bind to the bands of the proteins from both young and senescent erythrocytes, whereas these antibodies definitely bind to the protein bands of membranes and hemoglobin nitrated by NO2 or ONOOH in vitro. This result indicates that nitrotyrosine is not detected in the membrane proteins and hemoglobin in human normal erythrocytes in circulation. However, this does not conclude that erythrocytes are not exposed to reactive nitrogen species in the circulation.     

A role for PPARα in the medial prefrontal cortex in formalin-evoked nociceptive responding in rats

Background and PurposeThe nuclear hormone receptor, PPARα, and its endogenous ligands, are involved in pain modulation. PPARα is expressed in the medial prefrontal cortex (mPFC), a key brain region involved in both the cognitive-affective component of pain and in descending modulation of pain. However, the role of PPARα in the mPFC in pain responding has not been investigated. Here, we investigated the effects of pharmacological modulation of PPARα in the rat mPFC on formalin-evoked nociceptive behaviour and the impact of formalin-induced nociception on components of PPARα signalling in the mPFC.Experimental ApproachThe effects of intra-mPFC microinjection of a PPARα agonist (GW7647) or a PPARα antagonist (GW6471) on formalin-evoked nociceptive behaviour in rats were studied. Quantitative real-time PCR and LC-MS/MS were used to study the effects of intraplantar injection of formalin on PPARα mRNA expression and levels of endogenous ligands, respectively, in the mPFC.Key ResultsIntra-mPFC administration of GW6471, but not GW7647, resulted in delayed onset of the early second phase of formalin-evoked nociceptive behaviour. Furthermore, formalin-evoked nociceptive behaviour was associated with significant reductions in mPFC levels of endogenous PPARα ligands (N-palmitoylethanolamide and N-oleoylethanolamide) and a 70% reduction in PPARα mRNA but not protein expression.Conclusions and ImplicationsThese data suggest that endogenous ligands may act at PPARα in the mPFC to play a facilitatory/permissive role in second phase formalin-evoked nociceptive behaviour in rats.Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6     

Interferon-γ in Starch Microparticles: Nitric Oxide-Generating Activity in Vitro and Antileishmanial Effect in Mice

Recombinant mouse interferon- (mu IFN-) was covalently coupled to polyacryl starch microparticles, a lysosomotropic drug carrier. The microparticle-bound mu IFN- was found to activate cultured macrophages for nitrite production and had an anti-leishmanial effect in mice. Low doses of mu IFN-, which had no effect in the free form, when bound to microparticles significantly reduced the load of Leishmania donovani in infected mice. Further, inducement of nitrite production in cultured macrophages by microparticle-bound mu IFN- required intact cell membrane receptors.     

Challenges in providing services in methadone maintenance therapy clinics in China: Service providers’ perceptions

BackgroundThe Methadone Maintenance Therapy (MMT) program has been initiated in China since 2004. As of the end of November, 2008, 558 MMT clinics had been established countrywide. The objective of this study was to elucidate the difficulties and challenges as perceived by service providers working in MMT clinics.MethodsOne service provider from each of the 28 MMT study clinics in Zhejiang and Jiangxi Provinces of China participated in a face-to-face in-depth interview for about 1–2 h to describe their perceptions of working in MMT clinics. Qualitative data were analysed using ATLAS.ti. The grounded theory was used to guide the data analysis.ResultsParticipants identified major problems in providing services in MMT clinics including lack of resources, professional training, and institutional support. Difficulties in pursuit of career, concern for personal safety, low income, heavy working load, and poor opinion of MMT by Chinese society often contributed to greater stress and burnout among the service providers.ConclusionThe MMT programs in China desperately need additional resource allocation and institutional support for the current and perhaps future expansion of the programs. The service providers are in urgent need of professional training to improve the quality of care they can offer MMT clients.     

Relapses in bipolar patients: changes in social rhythm?

The Ramadan month represents a valuable opportunity to test the hypothesis that the course of the illness of bipolar patients can be disrupted by the change in social rhythm which usually occurs during this month. The objectives of this study were to follow up the mood state and blood lithium level of fasting Muslim bipolar patients who had been on lithium therapy for at least 3 months, and were clinically stable before being included in the study. Twenty bipolar patients were enrolled during the month of Ramadan in 1997. Diagnosis of bipolar disorder was according to ICD-10 criteria. Patients were assessed during the week before Ramadan, the second and the fourth weeks of the fasting month and the first week after its end, with the Hamilton Depression and Bech-Rafaelsen scales. The plasma concentration of lithium was also assessed. The main finding of the study was that 45% of the patients relapsed, 70% during the second week and the remaining patients at the end of Ramadan. These relapses were not related to plasma concentration of lithium. Most of the relapses were manic (71.4 %). Patients who did not relapse had insomnia and anxiety during the second and third weeks of the study. Side-effects of lithium increased and were observed in 48% of the sample, mostly dryness of the mouth with thirst and tremor. The result of this pilot study indicates that the Ramadan month may disrupt the mood state of bipolar patients. More studies are needed to confirm this observation and to evaluate the validity of the Ramadan model to study the impact of social rhythms on bipolar patients.     

Effect of lactoferrin- and transferrin-conjugated polymersomes in brain targeting： in vitro and in vivo evaluations

Aim:

To evaluate the effect of lactoferrin (Lf) and transferrin (Tf) in brain targeting.

Methods:

Polymersomes (PSs), employed as vectors, were conjugated with Lf or Tf and were characterized by morphology, particle size, zeta potential, and surface densities of the Lf or Tf molecules. In vitro uptake of Lf-PS and Tf-PS by bEnd.3 cells was investigated using coumarin-6 as a fluorescent probe. In vivo tissue distribution and pharmacokinetics of ¹²⁵I-Lf-PS and ¹²⁵I-Tf-PS were also examined.

Results:

The mean particle size of PS, Lf-PS, and Tf-PS was around 150 nm and the zeta potential of the PSs was about -20 mV. Less than 0.12% of the coumarin was released from coumarin-6-loaded PS in 84 h indicating that coumarin-6 was an accurate probe for the PSs'' behavior in vitro. It was shown that the uptake of Lf-PS and Tf-PS by bEnd.3 cells was time-, temperature-, and concentration-dependent. Both Lf and Tf could increase the cell uptake of PSs at 37°C, but the uptake of Tf-PS was significantly greater than that of Lf-PS. In vivo tissue distribution and pharmacokinetics in mice revealed higher brain uptake and distribution of Tf-PS than Lf-PS, which was in accordance with in vitro uptake results. The drug targeting index (DTI) of Tf-PS with regard to Lf-PS was 1.51.

Conclusion:

Using a PS as the delivery vector and bEnd.3 cells as the model of the blood-brain barrier (BBB), Tf was more effective than Lf in brain targeting.