Evaluation of multitarget drugs on the expression of cocaine-induced locomotor sensitization in male rats: A comparative study.

Purpose: - Cocaine use disorder (CUD) is a complex disease. Several studies have shown the efficacy of multitarget drugs used to treat CUD. Here we compare the efficacy of mirtazapine (MIR), pindolol (PIN), fluoxetine (FLX), risperidone (RIS), trazodone (TRZ), ziprasidone (ZPR), ondansetron (OND), yohimbine (YOH), or prazosin (PRZ), to reduce long-term cocaine-induced locomotor activity and the expression of cocaine-induced locomotor sensitization in rats. Methods: - The study consists of four experiments, which were divided into four experimental phases. Induction (10 days), cocaine withdrawal (30 days), expression (10 days), and post-expression phase (10 days). Male Wistar rats were daily dosed with cocaine (10 mg/kg; i.p.) during the induction and post-expression phases. During drug withdrawal, the MIR, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ were administered 30 min before saline. In the expression, the multitarget drugs were administered 30 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min.During the agonism phase, in experiment four, 8-OH-DPAT, DOI, CP-809-101, SR-57227A, or clonidine (CLO) was administered 30 min before MIR and 60 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min. Results: -MIR, FLX, RIS, ZPR, OND, or PRZ attenuated the cocaine-induced locomotor activity and cocaine locomotor sensitization. PIN, TRZ, and YOH failed to decrease cocaine locomotor sensitization. At the optimal doses used, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ failed to attenuate long-term cocaine locomotor activation. MIR generated a decrease in cocaine-induced locomotor activity of greater magnitude and duration than the other multitarget drugs evaluated. Conclusion: - At the optimal doses of multitarget drugs evaluated, MIR was the multitarget drug that showed the greatest long-term cocaine-induced behavior effects compared to other multitarget drugs.

Prenatal and postnatal cocaine exposure enhances the anxiety- and depression-like behaviors in rats during cocaine withdrawal.

Prenatal drug exposure is a public health problem, which results in profound behavioral problems during childhood and adolescence, mainly represented by an increase in the risk of cocaine abuse at an early age. In rodents, prenatal and postnatal cocaine exposure enhanced locomotor activity and cocaine- or nicotine-induced locomotor sensitization. Various authors consider that the adverse emotional states (anxiety and depression) that occur during cocaine withdrawal are the main factors that precipitate, relapse, and increase chronic cocaine abuse, which could increase the risk of relapse of cocaine abuse. Therefore, the objective of this study was to characterize anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal in rats born to females exposed prenatally and postnatally to cocaine. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine preexposure group), and another group of pregnant female rats was administered daily with saline (saline preexposure group). Of the litters resulting from the cocaine-pre-exposed and saline-pre-exposed pregnant female groups, only the male rats were used for the recording of the anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal The study found that prenatal and postnatal cocaine exposure dose-dependent enhanced anxiety- and depression-like behaviors. This suggests that prenatal and postnatal cocaine exposure can result in enhanced vulnerability to cocaine abuse in young and adult humans.

COT-TT vaccine attenuates cocaine-seeking and cocaine-conditioned place preference in rats.

Vaccination active, promising alternative immunological strategy to treat of CUD. Various models of cocaine vaccines have been evaluated in animals and humans with relative success. In this sense, it is necessary to improve or optimize the cocaine vaccines already evaluated. Our laboratory previously reported the efficacy of the tetanus toxoid-conjugated morphine vaccine (M6-TT). The M6-TT vaccine can generate high titers of antibodies and reduce heroin-induced behavioral effects in rodents. So, it would be plausible to assume that if we modify the M6-TT vaccine by changing the hapten and maintaining the rest of the structural elements of the vaccine, we will maintain the properties of the M6-TT vaccine (high antibody titers). The objective of this study was to determine whether the antibodies generated by a tetanus toxoid-conjugated cocaine vaccine (COC-TT) can recognize and capture cocaine and decrease the cocaine-induced reinforcing effects. Male Wistar rats were immunized with the COC-TT. A solid-phase antibody-capture ELISA was used to monitor antibody titer responses after each booster dose in vaccinated animals. The study used cocaine self-administration and place-preference testing to evaluate the cocaine-reinforcing effects. The COC-TT vaccine could generate high levels of anti-cocaine antibodies. The antibodies reduced the cocaine self-administration and cocaine place preference. In addition, they decreased the cocaine-induced Fos protein expression. These findings suggest that the COC-TT vaccine generates a robust immunogenic response capable of reducing the reinforcing effects of cocaine, which supports its possible future use in clinical trials in patients with CUD.

Safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnant women with HIV from Gabon and Mozambique: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The cornerstone of malaria prevention in pregnancy, intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine, is contraindicated in women with HIV who are receiving co-trimoxazole prophylaxis. We assessed whether IPTp with dihydroartemisinin-piperaquine is safe and effective in reducing the risk of malaria infection in women with HIV receiving co-trimoxazole prophylaxis and antiretroviral drugs. METHODS: For this randomised, double-blind, placebo-controlled clinical trial, women with HIV attending the first antenatal care clinic visit, resident in the study area, and with a gestational age up to 28 weeks were enrolled at five sites in Gabon and Mozambique. Participants were randomly assigned (1:1) to receive either IPTp with dihydroartemisinin-piperaquine at each scheduled antenatal care visit plus daily co-trimoxazole (intervention group) or placebo at each scheduled antenatal care visit plus daily co-trimoxazole (control group). Randomisation was done centrally via block randomisation (block sizes of eight), stratified by country. IPTp was given over 3 days under direct observation by masked study personnel. The number of daily IPTp tablets was based on bodyweight and according to the treatment guidelines set by WHO (target dose of 4 mg/kg per day [range 2-10 mg/kg per day] of dihydroartemisinin and 18 mg/kg per day [range 16-27 mg/kg per day] of piperaquine given once a day for 3 days). At enrolment, all participants received co-trimoxazole (fixed combination drug containing 800 mg trimethoprim and 160 mg sulfamethoxazole) for daily intake. The primary study outcome was prevalence of peripheral parasitaemia detected by microscopy at delivery. The modified intention-to-treat population included all randomly assigned women who had data for the primary outcome. Secondary outcomes included frequency of adverse events, incidence of clinical malaria during pregnancy, and frequency of poor pregnancy outcomes. All study personnel, investigators, outcome assessors, data analysts, and participants were masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT03671109. FINDINGS: From Sept 18, 2019, to Nov 26, 2021, 666 women (mean age 28·5 years [SD 6·4]) were enrolled and randomly assigned to the intervention (n=332) and control (n=334) groups. 294 women in the intervention group and 308 women in the control group had peripheral blood samples taken at delivery and were included in the primary analysis. Peripheral parasitaemia at delivery was detected in one (<1%) of 294 women in the intervention group and none of 308 women in the control group. The incidence of clinical malaria during pregnancy was lower in the intervention group than in the control group (one episode in the intervention group vs six in the control group; relative risk [RR] 0·12, 95% CI 0·03-0·52, p=0·045). In a post-hoc analysis, the composite outcome of overall malaria infection (detected by any diagnostic test during pregnancy or delivery) was lower in the intervention group than in the control group (14 [5%] of 311 women vs 31 [10%] of 320 women; RR 0·48, 95% CI 0·27-0·84, p=0·010). The frequency of serious adverse events and poor pregnancy outcomes (such as miscarriages, stillbirths, premature births, and congenital malformations) did not differ between groups. The most frequently reported drug-related adverse events were gastrointestinal disorder (reported in less than 4% of participants) and headache (reported in less than 2% of participants), with no differences between study groups. INTERPRETATION: In the context of low malaria transmission, the addition of IPTp with dihydroartemisinin-piperaquine to co-trimoxazole prophylaxis in pregnant women with HIV did not reduce peripheral parasitaemia at delivery. However, the intervention was safe and associated with a decreased risk of clinical malaria and overall Plasmodium falciparum infection, so it should be considered as a strategy to protect pregnant women with HIV from malaria. FUNDING: European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) and Medicines for Malaria Venture. TRANSLATIONS: For the Portuguese and French translations of the abstract see Supplementary Materials section.

The effect of chronic stress on the immunogenicity and immunoprotection of the M6-TT vaccine in female mice.

Active vaccination is an effective therapeutic option to reduce the reinforcing effects of opioids. Several studies showed that chronic stress affects the immune system decreasing the efficiency of some vaccines. Heroin withdrawal is a stressor and it is a stage in which the patient who abuses heroin is vulnerable to stress affects the immune response and consequently its immunoprotective capacity, then, the objective was to determine the effect of heroin-withdrawal and heroin-withdrawal plus immobilization, on the immune (immunogenicity) and protective response (behavioral response) of morphine-6-hemisuccinate-tetanus toxoid (M6-TT) vaccine in animals of two inbred mice strains with different sensitivity to drug-opioid and stress. Female BALB/c and C57Bl/6 inbred mice were immunized with the M6-TT. A solid-phase antibody-capture ELISA was used to monitor antibody titer responses after each booster dose in vaccinated animals. During the vaccination period, the animals were subjected to two different stress conditions: drug-withdrawal (DW) and immobilization (IMM). The study used tail-flick testing to evaluate the heroin-induced antinociceptive effects. Additionally, heroin-induced locomotor activity was evaluated. Stress decreased the heroin-specific antibody titer generated by the M6-TT vaccine in the two inbred mouse strains evaluated. In the two stress conditions, the antibody titer was not able to decrease the heroin-induced antinociceptive effects and locomotor activity. These findings suggest that stress decreases the production of antibodies and the immunoprotective capacity of the M6-TT vaccine. This observation is important to determine the efficacy of active vaccination as a potential therapy for patients with opioid drug use disorder, since these patients during drug-withdrawal present stress disorders, which could affect the efficacy of therapy such as active vaccination.

Estradiol enhances the mirtazapine effects on the expression of cocaine-induced locomotor sensitization in female rats.

Epidemiological studies have mentioned that cocaine use disorder (CUD) has increased in the last decade among women; these show endocrine and reproductive disorders and a high propensity to stress and depression disorders. Mirtazapine-a tetracyclic antidepressant-decreases cocaine-induced locomotor activity and locomotor sensitization in male rats. The objective of this study was to evaluate if estradiol alters the efficacy of mirtazapine to decrease cocaine-induced locomotor activity in sham and ovariectomized female rats. Three hundred and twenty adult female Wistar rats were assigned to three experimental protocols. For experiments, 1-3, female rats were daily dosed with 10 mg/kg of cocaine during the 10 days of induction and expression of locomotor sensitization. During drug withdrawal (30 days), cocaine was withdrawn and the groups received daily mirtazapine, estradiol, or saline. In addition, the females underwent sham or ovariectomy surgery. Tamoxifen was administered during the antagonism phase. After each administration, locomotor activity for each animal was recorded for 30 min in activity chambers. The dosage of mirtazapine reduces estradiol-induced enhancement in cocaine-dependent locomotor activity during the expression of locomotor sensitization in sham and ovariectomized female rats. As well as they showed that estradiol co-dosed with mirtazapine enhances the efficacy of mirtazapine to decrease cocaine-induced locomotor activity. Finally, tamoxifen enhanced the estradiol and mirtazapine-induced decrease in the cocaine motor effect in female rats. Mirtazapine may be considered an effective therapeutic option for the treatment of CUD in women, even in those who are on hormonal treatment or antidepressant therapy with estradiol.

Mirtazapine attenuates the cocaine-induced locomotor sensitization in male and female C57BL/6J and BALBA/cJ mouse.

BACKGROUND: Clinical studies have described the efficacy of various therapeutic approaches. Results are inconsistent and clinical application is limited. Clinical trials have suggested that individual variability in the response to pharmacological therapies and sex affects the efficacy of some antidepressant drugs. Mouse strain-dependent variability influenced the response to antidepressant drugs. Some mouse strains respond faster and better to antidepressants than other mouse strains. We recently reported a series of preclinical studies that showed that dosing of mirtazapine, a noradrenergic and serotonergic antidepressant, in male and female Wistar rats decreased cocaine-induced locomotor activity and attenuated the induction and expression of cocaine-induced locomotor sensitization. Therefore, the aim of this study was to evaluate the mirtazapine effects, on cocaine-induced locomotor activity and cocaine-induced locomotor sensitization in male and female mice of the C57BL/6J and BALB/cJ strains, which differ in sensitivity to the cocaine motor effects and response to antidepressant drugs. METHODS: Male and female BALB/cJ and C57BL/6J inbred mice (20-25 g) were daily dosed with 10 mg/kg of cocaine during the induction and expression of locomotor sensitization. During drug withdrawal, cocaine was withdrawn, and the groups received daily mirtazapine (30 mg/kg, i.p.) or saline. Mirtazapine was administered 30 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min in transparent Plexiglass activity chambers. RESULTS: Cocaine-induced locomotor activity were greater in C57BL/6J strain mice than BALB/cJ strain mice during the induction and expression phase of locomotor sensitization. The female mice of both strains showed a higher cocaine locomotor response than males and mirtazapine significantly decreased cocaine-induced locomotor activity, as well as the induction and expression of locomotor sensitization, regardless of mouse strain or sex. CONCLUSION: The results suggest mirtazapine may be considered an effective therapeutic option to treat cocaine use disorder in men and women with very diverse genetic backgrounds.

Agomelatine decreases cocaine-induced locomotor sensitisation and dopamine release in rats.

BACKGROUND: Agomelatine is a melatoninergic antidepressant approved to treat the major depressive disorder. Agomelatine exerts its behavioural, pharmacological, and physiological effects through the activation of MT1 and MT2 melatonin receptors and the blockade of 5-HT2B and 5-HT2C serotonin receptors. Some studies have reported that the activation of the MT1 and MT2 melatonin receptors decreased cocaine-induced locomotor activity and cocaine self-administration. These findings from another study showed that agomelatine decreased alcohol consumption. This study aimed to evaluate the effects of agomelatine administration on cocaine-induced behavioural (cocaine-induced locomotor activity and cocaine-induced locomotor sensitisation) and neurochemical (dopamine levels) effects. METHODS: Male Wistar rats (250-280 g) received cocaine (10 mg/kg) during the induction and expression of locomotor sensitisation. Agomelatine (10 mg/kg) was administered 30 minutes before cocaine. After each treatment, locomotor activity was recorded for 30 minutes. Dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) by high-performance liquid chromatographic (HPLC) in animals treated with agomelatine and cocaine. Luzindole (30 mg/kg) was administered to block the agomelatine effect. RESULTS: In this study, we found that agomelatine decreased cocaine-induced locomotor activity and the induction and expression of locomotor sensitisation. In addition, agomelatine decreased cocaine-induced dopamine levels. Luzindole blocked the agomelatine-induced decrease in the expression of locomotor sensitisation in rats. CONCLUSION: Our results suggest (1) that agomelatine showed efficacy in decreasing cocaine psychostimulant effects and (2) that agomelatine can be a useful therapeutic agent to reduce cocaine abuse.

Vortioxetine treatment decreases cocaine-induced locomotor sensitization in rats.

Vortioxetine is a serotoninergic multi-target antidepressant, approved to treat major depressive disorder, and carries out its behavioral, pharmacological, and physiological effects through the blocking of serotonin 5-HT1D, 5-HT3, and 5-HT7 receptors and by activating 5-HT1A receptors. Some studies report that the simultaneous activation of the 5-HT1A serotonin receptors or blockade of 5-HT3 serotonin receptors decreased cocaine-induced locomotor activity and cocaine self-administration. Recent studies showed that vortioxetine decreased alcohol consumption. This studio aimed to evaluate the effects of vortioxetine dosing on cocaine-induced behavioral (cocaine-induced locomotor activity and cocaine-induced locomotor sensitization) and neurochemical (dopamine levels) effects. Male Wistar rats received cocaine during the induction and expression of locomotor sensitization. Vortioxetine was administered 30 min before cocaine. After each treatment, the locomotor activity was recorded for 30 min. Dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) by high-performance liquid chromatographic (HPLC) in animals treated with vortioxetine and cocaine. In this study, we found that vortioxetine decreased cocaine-induced locomotor activity, as well as the induction and expression of locomotor sensitization. As well as the amount of cocaine-induced dopamine decreased. Vortioxetine can be a useful therapeutic agent to reduce cocaine abuse.

Prenatal and Postnatal Cocaine Enhances the Induction and Expression of Locomotor Sensitization to Nicotine in Male Rats.

INTRODUCTION: Several studies mention that early consumption of cannabis, alcohol, or even cocaine is related to an increase in the prevalence of daily consumption of tobacco in adulthood. However, other factors, such as genetic comorbidity, social influences, and even molecular, neurochemical, and behavioral alterations induced by prenatal and postnatal cocaine exposure, could also explain these observations, since these factors together increase the vulnerability of the offspring to the reinforcing effects of nicotine. The objective of this study was to determine the effect of prenatal and postnatal exposure to cocaine on nicotine-induced locomotor sensitization in young and adult rats. AIMS AND METHODS: The study was divided into two stages: prenatal and postnatal. In the prenatal stage, a group of pregnant female Wistar rats was administered cocaine daily from day GD0 to GD21 (cocaine preexposure group), and another group of pregnant female rats was administered saline daily (saline preexposure group). Of the litters resulting from the cocaine preexposed and saline preexposed pregnant female groups, in the postnatal stage, only the male rats were used for the recording of the locomotor activity induced by different doses of nicotine (0.2, 0.4, and 0.6 mg/kg) during the induction and expression of locomotor sensitization at different postnatal ages (30, 60, 90, and 120 days). RESULTS: Prenatal and postnatal cocaine exposure enhanced nicotine-induced locomotor activity and locomotor sensitization. CONCLUSIONS: This suggests that prenatal and postnatal cocaine exposure can result in increased vulnerability to other drugs of abuse, such as nicotine, in humans. IMPLICATIONS: Several studies have shown that the abuse of a drug, such as cannabis, alcohol, or even cocaine, at an early age can progress to more severe levels of use of other drugs, such as nicotine, to adulthood. Our data are consistent with this hypothesis, since prenatal and postnatal cocaine exposure enhanced the nicotine-induced increase in locomotor activity and locomotor sensitization. This suggests that prenatal and postnatal exposure to cocaine enhances the drug's salience.

Higher mortality and intubation rate in COVID-19 patients treated with noninvasive ventilation compared with high-flow oxygen or CPAP.

The effectiveness of noninvasive respiratory support in severe COVID-19 patients is still controversial. We aimed to compare the outcome of patients with COVID-19 pneumonia and hypoxemic respiratory failure treated with high-flow oxygen administered via nasal cannula (HFNC), continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV), initiated outside the intensive care unit (ICU) in 10 university hospitals in Catalonia, Spain. We recruited 367 consecutive patients aged ≥ 18 years who were treated with HFNC (155, 42.2%), CPAP (133, 36.2%) or NIV (79, 21.5%). The main outcome was intubation or death at 28 days after respiratory support initiation. After adjusting for relevant covariates and taking patients treated with HFNC as reference, treatment with NIV showed a higher risk of intubation or death (hazard ratio 2.01; 95% confidence interval 1.32-3.08), while treatment with CPAP did not show differences (0.97; 0.63-1.50). In the context of the pandemic and outside the intensive care unit setting, noninvasive ventilation for the treatment of moderate to severe hypoxemic acute respiratory failure secondary to COVID-19 resulted in higher mortality or intubation rate at 28 days than high-flow oxygen or CPAP. This finding may help physicians to choose the best noninvasive respiratory support treatment in these patients.Clinicaltrials.gov identifier: NCT04668196.

Determinants of early antibody responses to COVID-19 mRNA vaccines in a cohort of exposed and naïve healthcare workers.

BACKGROUND: Two doses of mRNA vaccination have shown >94% efficacy at preventing COVID-19 mostly in naïve adults, but it is not clear if the second dose is needed to maximize effectiveness in those previously exposed to SARS-CoV-2 and what other factors affect responsiveness. METHODS: We measured IgA, IgG and IgM levels against SARS-CoV-2 spike (S) and nucleocapsid (N) antigens from the wild-type and S from the Alpha, Beta and Gamma variants of concern, after BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna) vaccination in a cohort of health care workers (N=578). Neutralizing capacity and antibody avidity were evaluated. Data were analyzed in relation to COVID-19 history, comorbidities, vaccine doses, brand and adverse events. FINDINGS: Vaccination induced robust IgA and IgG levels against all S antigens. Neutralization capacity and S IgA and IgG levels were higher in mRNA-1273 vaccinees, previously SARS-CoV-2 exposed, particularly if symptomatic, and in those experiencing systemic adverse effects (p<0·05). A second dose in pre-exposed did not increase antibody levels. Smoking and comorbidities were associated with 43% (95% CI, 19-59) and 45% (95% CI, 63-18) lower neutralization, respectively, and 35% (95% CI, 3-57%) and 55% (95% CI, 33-70%) lower antibody levels, respectively. Among fully vaccinated, 6·3% breakthroughs were detected up to 189 days post-vaccination. Among pre-exposed non-vaccinated, 90% were IgG seropositive more than 300 days post-infection. INTERPRETATION: Our data support administering a single-dose in pre-exposed healthy individuals as primary vaccination. However, heterogeneity of responses suggests that personalized recommendations may be necessary depending on COVID-19 history and life-style. Higher mRNA-1273 immunogenicity would be beneficial for those expected to respond worse to vaccination and in face of variants that escape immunity such as Omicron. Persistence of antibody levels in pre-exposed unvaccinated indicates maintenance of immunity up to one year. FUNDING: This work was supported by Institut de Salut Global de Barcelona (ISGlobal) internal funds, in-kind contributions from Hospital Clínic de Barcelona, the Fundació Privada Daniel Bravo Andreu, and European Institute of Innovation and Technology (EIT) Health (grant number 20877), supported by the European Institute of Innovation and Technology, a body of the European Union receiving support from the H2020 Research and Innovation Programme. We acknowledge support from the Spanish Ministry of Science and Innovation and State Research Agency through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. L. I. work was supported by PID2019-110810RB-I00 grant from the Spanish Ministry of Science & Innovation. Development of SARS-CoV-2 reagents was partially supported by the National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance (contract number HHSN272201400008C). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.

Accumulation of heavy metals (Cd, Cr, Cu, Mn, Pb, Ni, Zn) in sediments, macroalgae (Cryptonemia crenulata) and sponge (Cinachyrella kuekenthali) of a coral reef in Moín, Limón, Costa Rica: An ecotoxicological approach.

Moín, on the Caribbean coast of Costa Rica, is a multi-use coastal zone with a variety of human activities that can cause metal pollution. With the purpose of assessing the current environmental burden due to heavy metal presence in the marine environment of Moín, and their bioaccumulation in organisms of the nearby coral reef, we determined seven metals in samples of bottom sediments, macroalgae (Cryptonemia crenulata) and sponge (Cinachyrella kuekenthali). The results were compared with samples from the southern Caribbean, an area with little human activity. Using ICP-MS, results showed a concentration range for sediments Mn > Cu > Zn > Cr > Ni > Pb > Cd, algae Mn > Cu > Zn > Ni > Cr > Pb > Cd and sponge Mn > Cu > Zn > Ni > Cr > Cd > Pb, relatively low concentrations overall and no differences observed between sites. Bioconcentration factor > 1 was determined for Cd, Cu, Ni and Zn, while concentrations in sediments were below the SQG thresholds. Our study provides the first data on metal concentrations in a macroalgae and a sponge from the Costa Rican Caribbean.

Seven-month kinetics of SARS-CoV-2 antibodies and role of pre-existing antibodies to human coronaviruses.

Unraveling the long-term kinetics of antibodies to SARS-CoV-2 and the individual characteristics influencing it, including the impact of pre-existing antibodies to human coronaviruses causing common cold (HCoVs), is essential to understand protective immunity to COVID-19 and devise effective surveillance strategies. IgM, IgA and IgG levels against six SARS-CoV-2 antigens and the nucleocapsid antigen of the four HCoV (229E, NL63, OC43 and HKU1) were quantified by Luminex, and antibody neutralization capacity was assessed by flow cytometry, in a cohort of health care workers followed up to 7 months (N = 578). Seroprevalence increases over time from 13.5% (month 0) and 15.6% (month 1) to 16.4% (month 6). Levels of antibodies, including those with neutralizing capacity, are stable over time, except IgG to nucleocapsid antigen and IgM levels that wane. After the peak response, anti-spike antibody levels increase from ~150 days post-symptom onset in all individuals (73% for IgG), in the absence of any evidence of re-exposure. IgG and IgA to HCoV are significantly higher in asymptomatic than symptomatic seropositive individuals. Thus, pre-existing cross-reactive HCoVs antibodies could have a protective effect against SARS-CoV-2 infection and COVID-19 disease.

Mirtazapine-induced decrease in cocaine sensitization is enhanced by environmental enrichment in rats.

Several studies have reported that mirtazapine attenuated the induction and expression of cocaine-induced locomotor sensitization. Animals placed in enriched housing environments have shown a decrease in cocaine-induced locomotor activity and sensitization. In addition, it has been suggested that a pharmacological treatment combined with a behavioral intervention increases the efficacy of the former. Thus, the objective of this study was to determine if dosing of mirtazapine in an enriched housing environment enhanced the mirtazapine-induced decrease on the induction and expression of cocaine-induced locomotor sensitization. Wistar male rats were dosed with cocaine (10 mg/kg, i.p.). During the drug-withdrawal phase, mirtazapine (30 mg/kg, i.p.) was administered under standard and enriched housing environmental conditions. The environmental enrichment consisted of housing the animals in enclosures with plastic toys, tunnels, and running wheels. After each administration, locomotor activity for each animal was recorded for 30 min. The study found that treatment with mirtazapine in an enriched housing environment produced an enhanced and persistent attenuation of the induction and expression of cocaine-induced locomotor sensitization. Additionally, it reduced the duration of cocaine-induced locomotor activity in the expression phase of locomotor sensitization. Dosing of mirtazapine in an enriched housing environment enhanced the effectiveness of mirtazapine to decrease cocaine-induced locomotor sensitization. This suggests the potential use of enriched environments to enhance the effect of mirtazapine.

The morphine/heroin vaccine decreased the heroin-induced antinociceptive and reinforcing effects in three inbred strains mouse.

Clinical trials have indicated that a vaccine must be immunogenic in genetically diverse human populations and that immunogenicity and protective efficacy in animal models are two key indices required for the approval of a new vaccine. Additionally, the immune response (immunogenicity) and immunoprotection are dependent on the mouse strain. Therefore, the objective of the present study was to determine the immune response (immunogenicity) and the protective efficacy (behavioral response) in three inbred mouse strains immunized with the M6TT vaccine. Female BALB/c, C57Bl/6, and DBA/2 inbred mice were immunized with the M6-TT vaccine. A solid-phase antibody-capture ELISA was used to monitor antibody titer responses after each booster dose in vaccinated animals. The study used tail-flick testing to evaluate the antinociceptive effects induced by heroin. Additionally, heroin-induced locomotor activity and place preference were evaluated. The M6-TT vaccine was able to generate a specific antibody titer in the three inbred mouse strains evaluated. The antibodies reduced the antinociceptive effect of different doses of heroin. In addition, they decreased the heroin-induced locomotor activity and place preference. These findings suggest that the M6-TT vaccine generates a powerful immunogenic response capable of reducing the antinociceptive and reinforcing effects of heroin in different inbred mouse strains, which supports its possible future use in clinical trials in genetically diverse human populations.

Synergistic immune and antinociceptive effects induced from the combination of two different vaccines against morphine/heroin in mouse.

Animal studies have reported the use of different opioid-vaccine formulations with relative success These studies have suggested that new opioid-vaccine formulations are required, which are capable of triggering a robust humoral response. One strategy that has been used is the co-administration of two or more vaccines with different but complementary properties, which are capable of generating a robust immune response. We have developed two formulations of opioid-vaccine, the M6-TT, and M3-TT, which generate a robust immune response capable of recognizing heroin and morphine. In this work, we evaluate the combination of two vaccine formulations, which we call the M3/6-TT vaccine, to elicit a robust immune response and protection against heroin and morphine. Balb/c mice were immunized simultaneously with M6-TT vaccine and with M3-TT vaccine. A solid-phase antibody-capture ELISA was used for monitoring antibody titer responses after each booster dose in vaccinated animals. The study used tail-flick and hot-plate testing to evaluate the antinociceptive effects induced by heroin or morphine. Immunization with M3-TT and M6-TT vaccine elicits a robust immune response with an antibody titer of 1: 590 000 able to recognize heroin and morphine. These antibodies are capable of reducing the antinociceptive effects induced by doses of up to 40 mg/Kg. of morphine or 10 mg/kg of heroin. This suggests that the combination of two vaccine formulations that generate antibodies with different but complementary characteristics would be a new therapeutic strategy aimed at reducing drug relapses.

Serological reactivity against T. cruzi-derived antigens: Evaluation of their suitability for the assessment of response to treatment in chronic Chagas disease.

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects more than 6 million people worldwide. Following a mostly asymptomatic acute phase, the disease progresses to a long-lasting chronic phase throughout which life-threatening disorders to the heart and/or gastrointestinal tract will manifest in about 30% of those chronically infected. During the chronic phase, the parasitemia is low and intermittent, while a high level of anti-T. cruzi antibodies persist for years. These two features hamper post-chemotherapeutic follow-up of patients with the tools available. The lack of biomarkers for timely assessment of therapeutic response discourages a greater use of the two available anti-parasitic drugs, and complicates the evaluation of new drugs in clinical trials. Herein, we investigated in a blinded case-control study the serological reactivity over time of a group of parasite-derived antigens to potentially address follow up of T. cruzi chronically infected subjects after treatment. We tested PFR2, KMP11, HSP70, 3973, F29 and the InfYnity multiplexed antigenic array, by means of serological assays on a multi-national retrospective collection of samples. Some of the antigens exhibited promising results, underscoring the need for further studies to determine their potential role as treatment response biomarkers.

Community delivery of malaria intermittent preventive treatment in pregnancy: protocol of a quasi-experimental evaluation through multistage cluster sampling household surveys in four sub-Saharan African countries.

BACKGROUND: In sub-Saharan Africa (SSA), millions of pregnant women are exposed to malaria infection. The cornerstone of the WHO strategy to prevent malaria in pregnancy in moderate to high-transmission areas is the administration of intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine at each scheduled antenatal care (ANC) visit. However, overall coverage remains low. 'Transforming IPT for Optimal Pregnancy' (TIPTOP) project aims at delivering IPTp at the community level (C-IPTp) to complement ANC provision with the goal of increasing IPTp coverage and improving maternal and infant's health. This protocol describes the approach to measure the effect of this strategy through household surveys (HHS) in four SSA countries: Democratic Republic of Congo (DRC), Madagascar, Mozambique and Nigeria. METHODS AND ANALYSIS: A quasi-experimental evaluation has been designed. Delivery of C-IPTp will start first in one area per country, and later it will be extended to two more areas per country. HHS will be carried out before C-IPTp implementation in all study sites, at midterm in initial implementation areas, and after the implementation in all project areas. A multistage cluster sampling method will be followed for the selection of participants. Women of reproductive age who had a pregnancy that ended in the 6 or 12 months prior to the interview, depending on the survey, will be invited to participate by responding to a questionnaire. The main indicators will be coverage of three or more doses of IPTp and attendance to at least four ANC visits. A difference-in-difference analysis will be performed to evaluate the effectiveness of C-IPTp. ETHICS AND DISSEMINATION: The project has been reviewed by the ethics committees of WHO, Hospital Clinic of Barcelona and all project country boards. Project results will be disseminated to in-country stakeholders and at regional and international meetings. TIPTOP project aims to develop and disseminate global recommendations for C-IPTp delivery. TRIAL REGISTRATION NUMBER: NCT03600844; Pre-results.

Visualizing the dynamics of tuberculosis pathology using molecular imaging.

Nearly 140 years after Robert Koch discovered Mycobacterium tuberculosis, tuberculosis (TB) remains a global threat and a deadly human pathogen. M. tuberculosis is notable for complex host-pathogen interactions that lead to poorly understood disease states ranging from latent infection to active disease. Additionally, multiple pathologies with a distinct local milieu (bacterial burden, antibiotic exposure, and host response) can coexist simultaneously within the same subject and change independently over time. Current tools cannot optimally measure these distinct pathologies or the spatiotemporal changes. Next-generation molecular imaging affords unparalleled opportunities to visualize infection by providing holistic, 3D spatial characterization and noninvasive, temporal monitoring within the same subject. This rapidly evolving technology could powerfully augment TB research by advancing fundamental knowledge and accelerating the development of novel diagnostics, biomarkers, and therapeutics.