Severe reversible cardiac failure after bortezomib treatment combined with chemotherapy in a non-small cell lung cancer patient: a case report

BACKGROUND: Bortezomib (Velcade(®)), a dipeptide boronate proteasome inhibitor, is a novel anti-cancer agent registered for multiple myeloma (MM). It has also shown promising clinical activity in non-small cell lung cancer (NSCLC). Clinical experience with bortezomib so far indicates that overall incidence of cardiac failure associated with bortezomib therapy remains incidental. Nevertheless, acute development or exacerbation of congestive cardiac failure has been associated with bortezomib treatment. CASE PRESENTATION: We present here a case of severe, but reversible, congestive cardiac failure in a lung cancer patient who had no prior cardiac history, after receiving an experimental treatment of bortezomib combined with chemotherapy. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), as retrospectively measured in archived serum samples, were suggestive of pre-existent (sub-clinical) left ventricular dysfunction. CONCLUSION: Based on literature, we hypothesize that baseline presence of sub clinical cardiomyopathy, characterized by a dysregulation of the ubiquitin-proteasome system, could have predisposed this patient for a cardiac side effect induced by systemic proteasome inhibition. Patients with heart disease or risk factors for it should be closely monitored when being submitted to treatment with proteasome inhibition therapy such as bortezomib. Caution is therefore warranted in lung cancer patients who often present with cardiac comorbidities

Epidemic of illicit drug use, mechanisms of action/addiction and stroke as a health hazard

Drug abuse robs individuals of their jobs, their families, and their free will as they succumb to addiction; but may cost even more: a life of disability or even life lost due to stroke. Many illicit drugs have been linked to major cardiovascular events and other comorbidities, including cocaine, amphetamines, ecstasy, heroin, phencyclidine, lysergic acid diethylamide, and marijuana. This review focuses on available epidemiological data, mechanisms of action, particularly those leading to cerebrovascular events, and it is based on papers published in English in PubMed during 1950 through February 2011. Each drug's unique interactions with the brain and vasculature predispose even young, healthy people to ischemic or hemorrhagic stroke. Cocaine and amphetamines have the strongest association with stroke. However, the level of evidence firmly linking other drugs to stroke pathogenesis is weak. Large epidemiological studies and systematic evaluation of each drug's action on the brain and cardiovascular system are needed to reveal the full impact of drug use on the population

Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement

Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported

Pre-existing immunity to SARS-CoV-2 before the COVID-19 pandemic era in Cameroon: A comparative analysis according to HIV-status

BackgroundThe lower burden of COVID-19 in tropical settings may be due to preexisting cross-immunity, which might vary according to geographical locations and potential exposure to other pathogens. We sought to assess the overall prevalence of SARS-CoV-2 antibodies and determine SARS-CoV-2 seropositivity according to HIV-status before the COVID-19 pandemic era. MethodsA cross-sectional and comparative study was conducted at the Chantal BIYA International Reference Centre (CIRCB) on 288 stored plasma samples (163 HIV-positive versus 125 HIV-negative); all collected in 2017-2018, before the COVID-19 pandemic era. Abbott Panbio (TM) COVID-19 IgG/IgM assay was used for detecting SARS-CoV-2 immunoglobulin G (IgG) and M (IgM). Among people living with HIV (PLHIV), HIV-1 viral load and TCD4 cell count (LTCD4) were measured using Abbott Real Time PCR and BD FACSCalibur respectively. Statistical analyses were performed, with pResultsThe median [IQR] age was 25 [15-38] years. Overall seropositivity to SARS-CoV-2 antibodies was 13.5% (39/288) of which 7.3% (21) was IgG, 7.3% (21) IgM and 1.0% (3) IgG/IgM. According to HIV-status in the study population, SARS-CoV-2 seropositivity was 11.0% (18/163) among HIV-positive versus 16.8% (21/125) among HIV-negative respectively, p=0.21. Specifically, IgG was 6.1% (10/163) versus 8.8% (11/125), p=0.26; IgM was 5.5% (9/163) versus 9.6%, (12/125), p=0.13 and IgG/IgM was 0.6% (1/163) versus 1.6% (2/125) respectively. Among PLHIV, SARS-CoV-2 seropositivity according to CD4 count was 9.2% (>= 500 cells/mu L) versus 1.8% (200-499 cells/mu L), (OR=3.5; p=0.04) and 0.6% (<200 cells/mu L), (OR=17.7; p<0.01). According to viral load, SARS-CoV-2 seropositivity was 6.7% (>= 40 copies/mL) versus 4.9% (<40 copies/mL), (OR= 3.8; p<0.01). ConclusionBefore COVID-19 in Cameroon, cross-reactive antibodies to SARS-CoV-2 were in circulation, indicating COVID-19 preexisting immunity. This preexisting immunity may contribute in attenuating disease severity in tropical settings like Cameroon. Of relevance, COVID-19 preexisting immunity is lower with HIV-infection, specifically with viral replication and poor CD4-cell count. As poor CD4-count leads to lower cross-reactive antibodies (regardless of viral load), people living with HIV appear more vulnerable to COVID-19 and should be prioritized for vaccination

Effects of VIP on antigen-induced bronchoconstriction and thromboxane release in guinea-pig lung

1. Exogenous vasoactive intestinal polypeptide (VIP) infused into the pulmonary artery of isolated and ventilated lungs of guinea-pigs decreased, in a dose-dependent fashion (1.0-10.0 nmol), airway resistance and thromboxane B2 (TXB2, the stable hydrolysis product of TXA2) release in the perfusion medium. Prostacyclin (PGI2) synthesis, as reflected by the release of its stable hydrolysis product 6-oxo-PGF1 alpha, was unaffected. Pretreatment with the 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) M) did not modify the bronchodilatory effect of VIP or its inhibitory action on TXB2 release. 2. Basal release of immunoreactive VIP from perfused lungs decreased from an initial value of 0.96 +/- 0.10 ng min-1 (mean +/- s.e.mean) in the first 2 min to an average of 0.58 +/- 0.10 ng min-1 in the following 15-20 min. 3. Antigen challenge with ovalbumin (0.1%) in sensitized lungs caused an anaphylactic reaction in 45% of tested lungs, concomitant with a 5 fold increase in both VIP and TXB2 release. Tetrodotoxin pretreatment (10(-6) M) reduced basal VIP release by > 80% and abolished the VIP increase observed during anaphylaxis, without modifying TXB2 release or the bronchoconstrictor response. 4. Indomethacin (10(-6) M) inhibited TXB2 synthesis and release by > 90%, delayed the bronchoconstrictor response and blunted the increased VIP release during lung anaphylaxis, without influencing basal VIP release. 5. The 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) M) blunted the increase of TXB2 and VIP release from guinea-pig lung and attenuated the bronchoconstrictor response following ovalbumin challenge. 6. The administration of exogenous VIP as a continuous infusion (10-8 M) attenuated the bronchoconstriction and the release of cyclo-oxygenase metabolites following antigen challenge.7. Acetylcholine (10-6-l0-5 M) infused into the pulmonary artery induced a dose-dependent bronchoconstriction not associated with enhanced VIP or TXB2 release.8. The TXA2 mimetic U-46619 (0.1-1.0 nmol) caused dose-dependent increases in airway resistance,concomitant with an up to 10 fold increase in VIP release. VIP inhibited arachidonate-induced in vitro aggregation of washed rabbit platelets in a dose-dependent manner over a dose range 10-8 10-6 M.Despite the antiaggregatory effect of VIP, TXB2 and PGE2 synthesis was reduced only to a minor extent,and there was no redirection of arachidonate metabolism from TXA2 to PGE2, indicating that VIP does not act as a TX synthase inhibitor in vitro.9. We conclude that VIP may play a role in regulating bronchial smooth muscle reactivity in lung anaphylaxis by inhibiting the synthesis and release of TXA2, a potent vasoactive and bronchoconstrictor agent. TXA2, on the other hand, strongly enhances neuronal VIP release