Rapid Push vs Pump-Infused Subcutaneous Immunoglobulin Treatment: a Randomized Crossover Study of Quality of Life in Primary Immunodeficiency Patients.

PURPOSE: Subcutaneous immunoglobulin replacement therapy (IgRT) may be administered once a week with a pump or every other day with a syringe (rapid push). The objective of the study was to compare the impact of pump and rapid push infusions on patient's life quality index (LQI). METHODS: This study was a randomized, crossover, multicenter, non-inferiority trial conducted in adults with primary immunodeficiency (PID) accustomed to weekly infusions at home by pump. Patients used pump or rapid push for 3 months each according to the randomized sequence. Main criterion was PID-LQI factor I (treatment interference). Non-inferiority ratio was set at 90%. RESULTS: Thirty patients entered the study; 28 completed the two periods. IgRT exposure was similar during each period. At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and rapid push, respectively. There was a slightly larger effect of rapid push on treatment interference than with pump so that the primary endpoint could not be met. No difference was found on other LQI components, satisfaction (TSQM), or quality of life (SF36v2). Eight patients declared to prefer rapid push while 19 others preferred pump. Of rapid push infusions, 67.2% led to local reactions vs 71.8% of pump infusions (p = 0.11) illustrating its good tolerance. Rapid push and pump infusions achieved similar trough IgG levels with similar incidence of infections. Rapid push saved 70% of administration cost when compared to pump. CONCLUSIONS: Since IgRT is a lifelong treatment in PID patients, individualization of treatment is of paramount importance. Rapid push is a new administration method in the physician's armamentarium which is preferred by some patients and is cost-effective. CLINICALTRIALS. GOV IDENTIFIER: NCT02180763 CLINICAL IMPLICATIONS: Self-administration of small volumes of immunoglobulins at home, every other day, using a syringe (rapid push) is a cost-effective alternative to administration of larger volumes by pump once a week. This study compared subcutaneous infusions of immunoglobulins either weekly via a pump or every other day via a syringe (rapid push). Rapid push is preferred by some patients and is cost-effective, therefore completing a physician's armamentarium.

Translocator protein (18 kDa) mapping with [125I]-CLINDE in the quinolinic acid rat model of excitotoxicity: a longitudinal comparison with microglial activation, astrogliosis, and neuronal death.

Excitotoxicity leads to an inflammatory reaction involving an overexpression of: translocator protein 18 kDa (TSPO) in cerebral microglia and astrocytes. Therefore, we performed ex vivo explorations with [125]-CLINDE, a TSPO-specific radioligand, to follow the time course of TSPO expression, in parallel with lesion progression, over 90 days after induction of cerebral excitotoxicity in rats intrastriatally injected with quinolinic acid. Biodistribution data showed a significant increase in CLINDE uptake on the injured side from 1 days postlesion (dpl); the maximal striatal binding values evidenced a plateau between 7 and 30 dpl. [125I]-CLINDE binding was displaced from the lesion by PK11195, suggesting TSPO specificity. These results were confirmed by ex vivo autoradiography. Combined immunohistochemical studies showed a marked increase in microglial expression in the lesion, peaking at 14 dpl, and astrocytic reactivity enhanced at 7 and 14 dpl, whereas a prominent neuronal cell loss was observed. At 90 dpl, CLINDE binding and immunoreactivity targeting activated microglia, astrogliosis, and neuronal cell density returned to a basal level. These results show that both neuroinflammation and neuronal loss profiles occurred concomitantly and appeared to be transitory processes. These findings provide the possibility of a therapeutic temporal window to compare the differential effects of antiinflammatory treatments in slowing down neurodegeneration in this rodent model, with potential applications to humans.

Why is there no biosimilar of Erbitux®?

Monoclonal antibody (mAb)-based therapies have been a major advance in oncology patient care, even though they represent a significant healthcare cost. Biosimilars, launched in Europe in 2004 are an economically attractive alternative to expensive originator biological drugs. They also increase the competitiveness of pharmaceutical development. This article focuses on the case of Erbitux® (cetuximab). This anti-EGFR (Epidermal Growth Factor Receptor) monoclonal antibody is indicated for metastatic colorectal cancer (2004) and squamous cell carcinoma of the head and neck (2006). However, despite the expiration of the patent in Europe in 2014 and estimated annual sales of 1.681 million US dollars in 2022, Erbitux® has not yet faced any approved biosimilar challenges in the United States or in Europe. Here, we outline the unique structural complexity of this antibody highlighted by advanced orthogonal analytical characterization strategies resulting in risks to demonstrate biosimilarity, which may explain the lack of Erbitux® biosimilars in the European and US markets to date. The development of Erbitux® biobetters are also discussed as alternative strategies to biosimilars. These biologics offer expected additional safety and potency benefits over the reference product but require a full pharmaceutical and clinical development as for New Molecular Entities.

The contributions of metabolomics in the discovery of new therapeutic targets in Alzheimer's disease.

Alzheimer's disease (AD) leads to the progressive loss of memory and other cognitive functions. It is the most common form of dementia in the elderly and has become a major public health problem due to the increase in life expectancy. Although the detection of AD is based on several neuropsychological tests, imaging, and biological analyses, none of these biomarkers allows a clear understanding of the pathophysiological mechanisms involved in the disease, and no efficient treatment is currently available. Metabolomics, which allows the study of biochemical alterations underlying pathological processes, could help to identify these mechanisms, to discover new therapeutic targets, and to monitor the therapeutic response and disease progression. In this review, we have summarized and analyzed the results from a number of studies on metabolomics analyses performed in biological samples originated from the central nervous system, in AD subjects, and in animal models of this disease. This synthesis revealed modified expression of specific metabolites in pathological conditions which allowed the identification of significantly impacted metabolic pathways both in animals and humans, such as the arginine biosynthesis and the alanine, aspartate, and glutamate metabolism. We discuss the potential biochemical mechanisms involved, the extent to which they could impact the specific hallmarks of AD, and the therapeutic approaches which could be proposed as a result.

Compared benefits of educational programs dedicated to diabetic patients with or without community pharmacist involvement.

BACKGROUND: International guidelines on diabetes control strongly encourage the setting-up of therapeutic educational programs (TEP). However, more than half of the patients fail to control their diabetes a few months post-TEP because of a lack of regular follow-up by medical professionals. The DIAB-CH is a TEP associated with the follow-up of diabetic patients by the community pharmacist. AIM: To compare the glycated hemoglobin (HbA1c) and body mass index (BMI) in diabetic patients of Control (neither TEP-H nor community pharmacist intervention), TEP-H (TEP in hospital only) and DIAB-CH (TEP-H plus community pharmacist follow-up) groups. METHODS: A comparative cohort study design was applied. Patients included in the TEP-H from July 2017 to December 2017 were enrolled in the DIAB-CH group. The TEP-H session was conducted by a multidisciplinary team composed of two diabetologists, two dieticians and seven nurses. The HbA1c level and the BMI (when over 30 kg/m2 at M0) of patients in Control (n = 20), TEP-H (n = 20) and DIAB-CH (n = 20) groups were collected at M0, M0 + 6 and M0 + 12 months. First, HbA1c and BMI were compared between M0, M6 and M12 in the three groups with the Friedman test, followed by the Benjamini-Hochberg post-test. Secondly, the HbA1c and BMI of the three groups were compared at M0, M6 and M12 using the Kruskal-Wallis test. FINDINGS: While no difference in HbA1c was measured between M0, M6 and M12 in the Control group, Hb1Ac was significantly reduced in both TEP-H and DIAB-CH groups between M0 and M6 (P = 0.0072 and P = 0.0034, respectively), and between M0 and M12 only in the DIAB-CH group (P = 0.0027). In addition, a significant decrease in the difference between the measured HbA1c and the target assigned by diabetologists was observed between M0 and M6 in both TEP-H and DIAB-CH groups (P = 0.0072 and P = 0.0044, respectively) but only for the patients of the DIAB-CH group between M0 and M12 (P = 0.0044). No significant difference (P > 0.05) in BMI between the groups was observed. CONCLUSION: The long-lasting benefit on glycemic control of multidisciplinary group sessions associated with community pharmacist-led educational interventions on self-care for diabetic patients was demonstrated in the present study. There is thus evidence pointing to the effectiveness of a community/hospital care collaboration of professionals on diabetes control in primary care.

Short- and long-term cardioprotective effect of darbepoetin-alpha: role of Bcl-2 family proteins.

The purpose of this study was to assess the short- and long-term cardioprotective effects of darbepoetin-alpha (DA) in a rat myocardial ischemia and reperfusion model and to investigate the signaling pathway through which DA limits cardiomyocytes apoptosis. Rats were subjected to 40 minutes of coronary artery ligation followed by 72 hours or 4 weeks reperfusion and received either DA (3 or 30 microg/kg, DA3 and D30 groups) or vehicle (control) prior to ischemia. In the DA groups reperfused for 72 hours, left ventricular shortening fraction and left ventricular ejection fraction were higher than that in the control rats (P < 0.05), in agreement with a smaller left ventricular (LV) infarct size. DA treatment activated the JAK2/Akt signaling pathway, lowered cleaved caspase-3, and increased both phosphorylated-Bad and phosphorylated-GSK-3beta proteins. This was consistent with the decrease of reactive oxygen species production and the lowered binding of Bad to Bcl-xL and Bcl-2 in a DA30 group of rats. Similarly, in the DA-4-week group, LV function was greater compared to the control. Histology alterations implicated lower LV cardiac fibrosis and greater capillary density; furthermore, both Bcl-xL and Bcl-2 were upregulated. In conclusion, DA afforded short- and long-term cardioprotective effects. Antiapoptotic effects, through the activation of Akt that regulates the Bcl-2 family proteins and activates GSK-3beta, are central in the DA cardioprotective mechanism.

Heme oxygenase-1 inducer hemin attenuates the progression of remnant kidney model.

BACKGROUNDS/AIMS: Heme oxygenase-1 (HO-1) has been shown to protect against fibrotic proliferation and apoptosis in several models of renal damage. The purpose of this study was to evaluate the impact of a treatment with the HO-1 inducer hemin on the progression of chronic kidney disease in nephrectomized rats versus the AT1 receptor antagonist losartan. METHODS: The rats underwent 5/6 renal ablation and after the procedure received either losartan (20 mg/kg/day; n = 9), hemin (50 mg/kg/twice a week; n = 8) or vehicle (n = 8) over a 12-week period. At week 12, blood pressure was measured, urine, blood and remnant kidney were collected for biochemical (proteinuria, urea, creatinine) and histopathological (degrees of glomerulosclerosis and tubular atrophy) analysis. The expressions of HO-1, bone morphogenic protein 7 (BMP-7) and TGF-beta were assessed by immunochemistry, and the level of the apoptosis marker protein caspase-3 by Western blot, on the remnant kidney. RESULTS: Hemin significantly reduced blood pressure, proteinuria, inhibited the expression of TGF-beta and caspase-3 protein and increased BMP-7 expression protein. Hemin-treated rats had lower glomerulosclerosis and tubular atrophy indexes than controls. CONCLUSION: Hemin treatment attenuates the progression of chronic kidney disease and appears more efficient than losartan in our rat model hypothetically because of the impact of hemin on the renal expression of BMP-7.

[Names and indications of antibodies facing regulations and pharmaceutical company practices]. / Dénominations et indications des anticorps face à la réglementation et aux pratiques des laboratoires pharmaceutiques.

The names and therapeutic indications of monoclonal antibodies must comply with current regulations, which does not prevent the development of commercial strategies around trade names. Some of these practices are based on territorial or legal considerations while others are motivated by real medical concerns. Finally, some of these have a significant financial impact on the community.

TITLE: Dénominations et indications des anticorps face à la réglementation et aux pratiques des laboratoires pharmaceutiques. ABSTRACT: Les dénominations et les indications des anticorps monoclonaux thérapeutiques doivent répondre aux réglementations en vigueur, mais s'accompagnent du développement de stratégies commerciales autour des noms commerciaux. Certaines de ces pratiques obéissent à des considérations territoriales ou juridiques, tandis que d'autres sont motivées par de réelles préoccupations médicales. Enfin, certaines ont un impact financier non négligeable pour la collectivité.

Alpha-7 nicotinic acetylcholine receptor agonist treatment in a rat model of Huntington's disease and involvement of heme oxygenase-1.

Neuroinflammation is a common element involved in the pathophysiology of neurodegenerative diseases. We recently reported that repeated alpha-7 nicotinic acetylcholine receptor (α7nAChR) activations by a potent agonist such as PHA 543613 in quinolinic acid-injured rats exhibited protective effects on neurons. To further investigate the underlying mechanism, we established rat models of early-stage Huntington's disease by injection of quinolinic acid into the right striatum and then intraperitoneally injected 12 mg/kg PHA 543613 or sterile water, twice a day during 4 days. Western blot assay results showed that the expression of heme oxygenase-1 (HO-1), the key component of the cholinergic anti-inflammatory pathway, in the right striatum of rat models of Huntington's disease subjected to intraperitoneal injection of PHA 543613 for 4 days was significantly increased compared to the control rats receiving intraperitoneal injection of sterile water, and that the increase in HO-1 expression was independent of change in α7nAChR expression. These findings suggest that HO-1 expression is unrelated to α7nAChR density and the increase in HO-1 expression likely contributes to α7nAChR activation-related neuroprotective effect in early-stage Huntington's disease.

Heme oxygenase-1 inducer hemin prevents vascular thrombosis.

Hemin is a heme oxygenase-1 (HO-1) inducer which provides endogenous carbon monoxide known for playing roles in cell proliferation, inflammation or aggregation process. The objective of the current study was to examine the effect of prophylactic treatment with hemin in a thrombosis vascular model. Three groups of Wistar rats, control (n = 6), hemin (n = 6) and hemin + HO-1 inhibitor (n = 6), were used for this study. Hemin-treated animals received hemin (50 mg/kg/d; I.P.) for seven days and HO-1 inhibitor group received hemin at the same dose and SnPP IX (60 mg/kg/d; I.P.). All animals were exposed to electric stimulation of the left carotid according to Kawasaki's procedure to induce reproducible thrombus formation. The hemin treatment did not induce blood pressure disturbance. Effects of hemin on vascular thrombosis were quantified by histopathology and its influence on haemostasis was assessed by measuring prothrombin time (PT), activated partial thromboplastin time (APTT) and blood parameters at the end of treatment. The HO-1 mRNA and protein level variation were also checked out. Results showed that chronic treatment with hemin significantly (p < 0.01) reduced the vascular occlusion degree when compared to control and hemin SnPP groups with 7.2 +/- 4.6 vs. 71.1 +/- 14.7 and 74.0 +/- 8.8%, respectively. Moreover, we observed significant (p < 0.05) perturbations of blood parameters in hemin-treated and hemin-SnPP treated rats. Interestingly, hemin treatment did not significantly increase both PT and APTT. Finally, the HO-1 mRNA and protein levels were increased in hemin-treated carotid artery. In conclusion, hemin by inducing HO-1 expression may be a preventive agent against clinical disorders associated to an increased risk of thrombosis events and may limit haemorrhagic risks.

Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases.

Neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's diseases, are all characterized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. Several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluated in vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist.

Neuroprotective effect of the alpha 7 nicotinic receptor agonist PHA 543613 in an in vivo excitotoxic adult rat model.

Neuroinflammation is a key component of the pathophysiology of neurodegenerative diseases. The link between nicotine intake and positive outcome has been established, suggesting a role played by nicotinic receptors (nAChRs), especially α7nAChRs. The objective of this study was to evaluate the potential dose effects of PHA 543613 on neuron survival and striatal microglial activation in a rat model of brain excitotoxicity. A preliminary study was performed in vitro to confirm PHA 543613 agonist properties on α7nAChRs. Rats were lesioned in the right striatum with quinolinic acid (QA) and received either vehicle or PHA 543613 at 6 or 12mg/kg twice a day until sacrifice at Day 4 post-lesion. We first compared the translocator protein quantitative autoradiography in QA-lesioned brains with [3H]DPA-714 and [3H]PK-11195. The effects of PHA 543613 on microglial activation and neuronal survival were then evaluated through [3H]DPA-714 binding and immunofluorescence staining (Ox-42, NeuN) on adjacent brain sections. We demonstrated that [3H]DPA-714 provides a better signal-to-noise ratio than [3H]PK-11195. Furthermore, we showed that repeated PHA 543613 administration at a dose of 12mg/kg to QA-lesioned rats significantly protected neurons and reduced the intensity of microglial activation. This study reinforces the hypothesis that α7nAChR agonists can provide beneficial effects in the treatment of neurodegenerative diseases through potential modulation of microglial activation.

Dexfenfluramine does not worsen but moderates progression of chronic hypoxia-induced pulmonary hypertension.

This study shows for the first time, that dexfenfluramine, a 5-HT(2) receptor agonist, attenuates the development of chronic hypoxia-induced pulmonary hypertension. Chronic exposure to hypoxia, 4 weeks, induced hypoxic pulmonary hypertension in adult rat as haemodynamic and cardiac measurements showed significant modifications in right ventricle parameters (free wall right ventricle thickness; pulmonary acceleration time and velocity time integral) in chronic hypoxic control when compared to normoxic control animals. We observed that free wall right ventricle thickness and pulmonary velocity time integral were significantly less in chronic hypoxic rats treated with dexfenfluramine when compared to chronic hypoxic control rats. Similarly, rats exposed to chronic hypoxia exhibited an increase in both right ventricle pressure and weight by comparison to normoxic control animals but those variations were significantly diminished in dexfenfluramine-treated rats, indicating the moderating influence exerted by dexfenfluramine on chronic hypoxia-induced pulmonary hypertension and cardiac alterations. Thus, we report here the ability of dexfenfluramine to limit chronic hypoxia-induced pulmonary hypertension, emphasizing the importance of the time after the dexfenfluramine treatment discontinuation to assess the influence of this 5-HT receptor agonist on the development of chronic hypoxia-induced pulmonary hypertension.

Exercise and vasorelaxing effects of CO-releasing molecules in hypertensive rats.

PURPOSE: Because carbon monoxide (CO) has been reported able to induce relaxation, we aimed to investigate the effects of exercise training on the rat thoracic aorta responsiveness to a CO-releasing molecule (CORM), tricarbonyldichlororuthenium ([Ru(CO)3Cl2]2). METHODS: Male Wistar rats (N = 32) were divided in hypertensive and normotensive groups using the two-kidney, one-clip model of Goldblatt or SHAM surgery. Hypertensive and normotensive groups were assigned to an exercise training protocol on a level treadmill over a 10-wk period or were assigned to remain sedentary. After the exercise training protocol, blood pressure and cardiac tissue weight were assessed. The responsiveness of endothelium-denuded thoracic aortic rings to [Ru(CO)3Cl2]2 was evaluated by isometric contractions recordings. RESULTS: Systolic, diastolic, and mean blood pressures were significantly increased in hypertensive rats compared with control rats. Exercise training did not significantly alter blood pressure but decreased pulse pressure in hypertensive animals compared with sedentary hypertensive rats. In all groups, application of [Ru(CO)3Cl2]2 induced relaxation in precontracted aortic rings. Compared with normotensive rats, CO-induced relaxation was significantly decreased in hypertensive rats. Nevertheless, training exercise increased relaxation markedly in response to [Ru(CO)3Cl2]2 application in hypertensive rats, whereas it remained without effect in control rings. Pretreatment with TEA, a nonselective K+ channel inhibitor, decreased [Ru(CO)3Cl2]2-induced relaxation in all groups that became similar. In trained hypertensive rats, iberiotoxin had effects similar to those of TEA. CONCLUSIONS: This finding supports the concept that the CORM [Ru(CO)3Cl2]2 can induce relaxation in both normotensive and hypertensive rats with an impairment of the CO-induced relaxation during hypertension. However, exercise training improves the aorta's ability to relax in response to [Ru(CO)3Cl2]2 during hypertension, probably by increasing K+ channel activity.

[Not Available]. / Traitement des surinfections bronchiques: stabilité des antibiotiques dans les diffuseurs portatifs.

UNLABELLED: Treatment of Bronchial Superinfections: Data Related to Stability of Antibiotics in Portable Pumps. INTRODUCTION: Given many data about the stability of antibiotics in portable pump (elastomer) are lacking, this study was designed to make a point about available data and to evaluate the stability of antibiotics when exposed to temperature within 35°C (average temperature measured in real conditions of use). MATERIAL AND METHODS: First, to collect information about the stability of antibiotics in portable pump and to confront them with the local antibiotics protocols dedicated to the treatment of bronchial superinfection in patients with cystic fibrosis; second, to evaluate the stability of piperacillin associated with tazobactam at 35°C. RESULTS: While measured concentrations in tazobactam did not show significant variation during the study, piperacillin measurements showed a major reduction of concentration (up to 33%), both time and concentration related to. DISCUSSION: Such information must be pointed out to prescribers and patients to ensure a cold accumulator is placed in the pump can'ying-bag and to limit the duration of infusion to 24h with a single pump. CONCLUSION: This experimental program will keep on going with the stability study of both ticarcillin and cefsulodin in portable pump.

[Treatment of bronchial superinfections: data related to stability of antibiotics in portable pumps]. / Traitement des surinfections bronchiques: stabilité des antibiotiques dans les diffuseurs portatifs.

INTRODUCTION: Given many data about the stability of antibiotics in portable pump (elastomer) are lacking, this study was designed to make a point about available data and to evaluate the stability of antibiotics when exposed to temperature within 35 degrees C (average temperature measured in real conditions of use). MATERIAL AND METHODS: First, to collect information about the stability of antibiotics in portable pump and to confront them with the local antibiotics protocols dedicated to the treatment of bronchial superinfection in patients with cystic fibrosis; second, to evaluate the stability of piperacillin associated with tazobactam at 35 degrees C. RESULTS: While measured concentrations in tazobactam did not show significant variation during the study, piperacillin measurements showed a major reduction of concentration (up to 33%), both time and concentration related to. DISCUSSION: Such information must be pointed out to prescribers and patients to ensure a cold accumulator is placed in the pump carrying-bag and to limit the duration of infusion to 24 h with a single pump. CONCLUSION: This experimental program will keep on going with the stability study of both ticarcillin and cefsulodin in portable pump.

Direct implication of carbon monoxide in the development of heart failure in rats with cardiac hypertrophy subjected to air pollution.

Pollution is known to particularly affect patients with respiratory insufficiency and right ventricle abnormalities. We therefore hypothesized that carbon monoxide (CO) at low dose could be involved in cardiovascular disorders in patients with chronic hypoxic pulmonary hypertension secondary to chronic hypoxia. Ten-week-old male and female healthy Dark Agouti rats were randomly divided into two series--untrained (U) and trained (T)--of four groups of 18 animals each. Both U and T series were continuously exposed to ambient air (U(AIR), and T(AIR); n = 16) or air plus 50 ppm CO (U(AIR+CO) and T(AIR+CO); n = 18). Similarly, rats initially subjected to right ventricle hypertrophy secondary to chronic hypoxia (H) were continuously exposed to ambient air (TH(AIR), and UH(AIR); n = 18) or air plus 50 ppm CO (UH(AIR+CO), and TH(AIR+CO); n = 18). Doppler-echocardiography and hemodynamic studies performed at rest both indi-cated that CO had no significant effect on cardiac morphology or functions in control rats (U(AIR+CO) vs U(AIR)). In contrast, cardiac dilation and large decreases in left ventricular ejection fraction, mitral early diastolic rapid inflow (E) deceleration, E/atrial contraction filling (A) ratio, +dP/dt, and -dP/dt were found in TH(AIR+CO) compared with TH(AIR). After exposure, heart rate variability was unaffected in U(AIR+CO), whereas total power spectra were markedly decreased and low frequency/high frequency power ratio was increased in TH(AIR+CO) rats. CO pollution could be directly involved in cardiac disorders of patients with pre-existent hypertrophic cardiomyopathies.

Increased levels of superoxide in brains from old female rats.

Hypertension, aging and a range of neurodegenerative diseases are associated with increased oxidative damage. The present study examined whether superoxide (O2*-) levels in brain are increased during aging in female rats, and the role of superoxide dismutase (SOD) and oestrogen in regulating O2*- levels. Young adult (3 month) and old (11 month) female spontaneously hypertensive stroke prone rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY) were studied. O2*- levels were measured in brain homogenates by lucigenin chemiluminescence and SOD expression by Western blotting. Ageing significantly increased brain O2*- levels in WKY (cortex +216%, hippocampus +320%, striatum +225%) and to a greater extent in SHRSP (cortex +540%, hippocampus +580%, striatum +533%). Older SHRSP showed a decline in cortical Cu/Zn SOD expression compared to young adult SHRSP. Oestrogen did not attenuate O2*- levels. The results show a significant age-dependent increase in brain O2*- levels which is exaggerated in SHRSP. The excess cortical O2*- levels in the SHRSP may be associated with a down-regulation of Cu/Zn SOD but are not related to a decrease in oestrogen.

Computer-assisted management of unconsumed drugs as a cost-containment strategy in oncology.

BACKGROUND: Cost-containment strategies are required to deal with rising drug expenditure, also in oncology. Drug wastage related to the preparation of chemotherapy drugs for patients is costly, but solutions exist for optimizing the use of unconsumed anticancer drugs. OBJECTIVE: Our pharmacy department makes use of a computerized drug storage bank, which records stability data and the amounts of unconsumed drugs available, and is connected to prescription software via an interface. We aimed to evaluate the real cost savings generated by this system. METHOD: We assessed the cost savings achieved with this system, for 37 different anticancer drugs, over a 1-year period. French drug pricing and the amounts of drugs from the storage bank potentially re-used were assessed. RESULTS: The re-use of unconsumed anticancer drugs generated substantial cost savings, for nine drugs in particular: azacitidine, bevacizumab, bortezomib, cetuximab, docetaxel, liposomal doxorubicin, rituximab, topotecan and trastuzumab. Overall cost savings accounted for about 5 % of total anticancer drug expenditure at our hospital (8.5 M). CONCLUSION: In medical hematology-oncology, drug wastage reduction and a computerized physician order entry system could be applied in routine practice at centralized drug-processing units, with significant financial benefits.

Oxidative stress is related to the deleterious effects of heme oxygenase-1 in an in vivo neuroinflammatory rat model.

Heme oxygenase-1 (HO-1) induction is associated with beneficial or deleterious effects depending on the experimental conditions adopted and the neurodegenerative rodent models used. The present study aimed first to evaluate the effects of cerebral HO-1 induction in an in vivo rat model of neuroinflammation by intrastriatal injection of quinolinic acid (QA) and secondly to explore the role played by reactive oxygen species (ROS) and free iron (Fe(2+)) derived from heme catabolism promoted by HO-1. Chronic I.P. treatment with the HO-1 inductor and substrate hemin was responsible for a significant dose-related increase of cerebral HO-1 production. Brain tissue loss, microglial activation, and neuronal death were significantly higher in rats receiving QA plus hemin (H-QA) versus QA and controls. Significant increase of ROS production in H-QA rat brain was inhibited by the specific HO-1 inhibitor ZnPP which supports the idea that ROS level augmentation in hemin-treated animals is a direct consequence of HO-1 induction. The cerebral tissue loss and ROS level in hemin-treated rats receiving the iron chelator deferoxamine were significantly decreased, demonstrating the involvement of Fe(2+)in brain ROS production. Therefore, the deleterious effects of HO-1 expression in this in vivo neuroinflammatory model were linked to a hyperproduction of ROS, itself promoted by free iron liberation.