Phase II Study of the Liposomal Formulation of Eribulin (E7389-LF) in Combination with Nivolumab: Results from the Small Cell Lung Cancer Cohort.

PURPOSE: E7389-LF is a liposomal formulation of eribulin that contributes to tumor vascular remodeling. The phase II part of this phase Ib/II study assessed the efficacy/safety of E7389-LF in combination with nivolumab in several disease cohorts; herein, we report results from the small cell lung cancer (SCLC) cohort. EXPERIMENTAL DESIGN: Patients with unresectable/measurable SCLC and disease progression with first-line platinum-based chemotherapy with/without an immune checkpoint inhibitor (ICI) were enrolled to receive E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously every 3 weeks. The primary objective of this part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory assessments included overall survival (OS) and biomarkers. RESULTS: Thirty-four patients were enrolled. By the data cut-off date (May 31, 2022), 29 (85.3%) had discontinued. Efficacy/biomarker analyses included 33 patients (1 had their diagnosis changed postenrollment); the ORR of E7389-LF plus nivolumab was 24.2% [95% confidence interval (CI): 11.1-42.3], the median PFS was 3.98 months (95% CI: 2.63-4.40), and, at a median follow-up of 10.6 months, the median OS was not reached (95% CI: not estimable). Notably, 27 of 33 patients (81.8%) had received an ICI as their prior first-line therapy. Treatment-related, treatment-emergent adverse events occurred in 97.1% (any grade) and 82.4% (grade ≥3) of enrolled patients; the most common event was neutropenia. Changes in vascular and immune-related plasma markers were observed. CONCLUSIONS: E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks showed notable antitumor activity as second-line therapy for SCLC; no new safety signals were observed compared with either agent as monotherapy. SIGNIFICANCE: This phase II part of a phase Ib/II study assessed liposomal eribulin (E7389-LF) plus nivolumab in 34 patients with pretreated SCLC; 8 of 33 evaluable patients (including 6/27 pretreated with ICIs) had objective responses. The combination was tolerable; increases in vasculature-related biomarkers tended to correlate with responses.

New insights on the potential effect of vinpocetine in Parkinson's disease: one of the neglected warden and baffling topics.

Vinpocetine (VPN) is an ethyl apovincaminate that has anti-inflammatory and antioxidant effects by inhibiting the expression of nuclear factor kappa B (NF-κB) and phosphodiesterase enzyme 1 (PDE-1). VPN is used in the management of stroke, dementia, and other neurodegenerative brain diseases. VPN may be effective in treating Parkinson's disease (PD). Therefore, this review aimed to clarify the mechanistic role of VPN in the management of PD. VPN has protective and restorative effects against neuronal injury by reducing neuroinflammation, and improvement of synaptic plasticity and cerebral blood flow. VPN protects dopaminergic neurons by reducing oxidative stress, lipid peroxidation, glutamate neurotoxicity, and regulation of Ca+ 2 overloads. VPN can alleviate PD neuropathology through its anti-inflammatory, antioxidant, antiapoptotic and neurogenic effects. VPN through inhibition of PDE1 improves cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) signaling in the dopaminergic neurons of the substantia nigra (SN). VPN improves PD neuropathology through PDE1 inhibition with a subsequent increase of the cAMP/cGMP signaling pathway. Therefore, increasing cAMP leads to antioxidant effects, while augmentation of cGMP by VPN leads to anti-inflammatory effects which reduced neurotoxicity and development of motor severity in PD. In conclusion, this review indicated that VPN could be effective in the management of PD.

Vinpocetine mitigates DMH-induce pre-neoplastic colon damage in rats through inhibition of pro-inflammatory cytokines.

Colorectal cancer (CRC) is currently recognized as the third most prevalent cancer worldwide. Vinpocetine is a synthetic derivative of the vinca alkaloid vincamine. It has been found effective in ameliorating the growth and progression of cancerous cells. However, its pharmacological effect on colon damage remains elusive. Hence, in this study, we have shown the role of vinpocetine in DMH-induced colon carcinogenesis. At first, male albino Wistar rats were administered with DMH consistently for four weeks to induce pre-neoplastic colon damage. Afterward, animals were treated with vinpocetine (4.2 and 8.4 mg/kg/day p.o.) for 15 days. Serum samples were collected to assess the physiological parameters, including ELISA and NMR metabolomics. Colon from all the groups was collected and processed separately for histopathology and western blot analysis. Vinpocetine attenuated the altered plasma parameters; lipid profile and showed anti-proliferative action as evidenced by suppressed COX-2 stimulation and decreased levels of IL-1ß, IL-2, IL-6, and IL-10. Vinpocetine is significantly effective in preventing CRC which may be associated with its anti-inflammatory and antioxidant potential. Accordingly, vinpocetine could serve as a potential anticancer agent for CRC treatment and thus be considered for future clinical and therapeutic research.

Phosphodiesterase1 inhibitor "Vinpocetine" ameliorates the inflammation, apoptosis and oxidative stress induced by cyclophosphamide in urinary bladder: an experimental study.

BACKGROUND: Hemorrhagic cystitis often develops in patients treated with cyclophosphamide (CP). Vincamine (vinca alkaloid) is the source of the synthetic derivative vinpocetine (Vinpo). Worldwide, Vinpo is used as a cerebroprotective drug. As it has anti-oxidant, anti-thrombotic and anti-inflammatory effects but the power of Vinpo to prevent CP induced cystitis has not been studied. AIM OF STUDY: This research was planned to explore the effect of Vinpo (10-30 mg/kg, orally) administered 1 or 4 h before inducing cystitis by CP injection (300 mg/kg, i.p.) on the urinary bladder of mice. RESULTS: Administration of Vinpo 30 mg/kg, 4 h before CP injection ameliorated inflammatory markers. It reduced inducible nitric oxide synthase (iNOS), tumor necrosis factor- α (TNF-α), and BCL2 Associated X (Bax) expression in the bladder and increased the total antioxidant capacity level. Histological examination of the bladder has further supported these results. The present study suggests a protective effect of Vinpo (30 mg/kg, 4 h before CP injection) against CP-induced bladder inflammation. CONCLUSION: This proposes that Vinpo 30 mg/kg may become a promising pharmacological drug to prevent urinary adverse effects in patients treated with chemotherapy using CP.

Photopharmacology of Antimitotic Agents.

Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell proliferation and promote cell death. Because these drugs target biological processes that are essential to all cells, they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing compounds that can be applied globally to cells in their inactive form, then be selectively induced to bioactivity in targeted cells or tissue during a defined time window. This review discusses photoswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or microtubule-destabilizing agents.

Magnetic resonance imaging patterns of tumor response to chemotherapy in desmoid-type fibromatosis.

BACKGROUND: We aimed to investigate changes in volume and MRI T2-weighted intensity in desmoid-type fibromatosis (DF) receiving methotrexate plus vinca-alkaloids (MTX-VA) at Istituto Nazionale dei Tumori, Milan. METHODS: All cases of sporadic DF treated with MTX-VA from 1999 to 2019 were reviewed. MRIs at baseline, 6 and 12 months of chemotherapy and at treatment withdrawal were retrospectively reviewed, contouring the tumor lesion and measuring diameters, volume, and mean T2-signal intensity (normalized to muscle) changes. These parameters were also evaluated according to clinical variables. RESULTS: Thirty-two DF patients were identified. Best RECIST response was: 25% partial response, 69% stable disease, 6% progression. A ≥65% tumor volume reduction was observed in 38%, <65% reduction in 53%, an increase in 9%. 22% had RECIST stable disease with a ≥65% tumor volume reduction. T2-signal intensity decreased by ≥50% in 47%, <50% in 41% and increased in 12%. In patients with symptomatic improvement while on therapy and in patients maintaining symptomatic improvement during follow-up, median T2-signal intensity showed a reduction along the time points (3.0, 1.9, 1.2, 1.1; 2.9, 2.0, 1.2, 1.2, respectively); in patients without symptomatic improvement and in those clinically progressing during follow-up, a reduction was not observed. High T2-signal intensity at baseline was observed in patients showing RECIST progression during follow-up. CONCLUSIONS: In this series, RECIST detected a lower proportion of responses as compared to volumetric and T2-signal changes. T2-signal reduction seemed to better reflect symptomatic improvement. High T2-signal intensity at baseline was related to a higher proportion of further progression.

Conophylline Inhibits Hepatocellular Carcinoma by Inhibiting Activated Cancer-associated Fibroblasts Through Suppression of G Protein-coupled Receptor 68.

Treatment of hepatocellular carcinoma (HCC) is currently challenging. Cancer-associated fibroblasts (CAFs) promote the malignancy of HCC cells via production of cytokines. Conophylline (CnP), a vinca alkaloid obtained from Ervatamia microphylla leaves, has been reported to suppress activation of hepatic stellate cells and liver fibrosis in rats. We examined the efficacy of CnP in suppressing tumor growth in HCC. Specifically, we investigated whether CnP could inhibit CAFs, which were derived from HCC tissues in vitro and in vivo Same as previous reports, CAFs promoted proliferative and invasive ability of HCC cells. CnP suppressed α-smooth muscle actin expression of CAFs, and inhibited their cancer-promoting effects. CnP significantly suppressed CAFs producting cytokines such as IL6, IL8, C-C motif chemokine ligand 2, angiogenin, and osteopontin (OPN). Combined therapy with sorafenib and CnP against HCC cells and CAFs in vivo showed to inhibit tumor growth the most compared with controls and single treatment with CnP or sorafenib. Transcriptome analysis revealed that GPR68 in CAFs was strongly suppressed by CnP. The cancer-promoting effects of cytokines were eliminated by knockdown of GPR68 in CAFs. CnP inhibited the HCC-promoting effects of CAFs by suppressing several HCC-promoting cytokines secreted by CAFs expressing GPR68. Combination therapy with CnP and existing anticancer agents may be a promising strategy for treating refractory HCC associated with activated CAFs.

Combination of Vinpocetine and Dexamethasone Alleviates Cognitive Impairment in Nasopharyngeal Carcinoma Patients following Radiation Injury.

BACKGROUND: Nasopharyngeal carcinoma (NPC) originates in the nasopharyngeal epithelium. The most common treatments for NPC rT1-4 are radiotherapy and surgery. The pathogenesis of radiation-induced cognitive impairment is complex and includes oxidative stress, mitochondrial dysfunction, neuro-inflammation, and even apoptosis and cell death. Principally, toll-like receptors (TLRs) could regulate the inflammatory/anti-inflammatory balance in patients with radiation-induced brain injury. Vinpocetine has an anti-inflammatory effect as shown in both animal and in vitro studies. Also, dexamethasone is a widely used anti-inflammatory drug. Thus, it is important to test whether addition of vinpocetine could improve the anti-inflammatory properties of dexamethasone for the treatment of NPC patients with radiation-induced brain injuries. METHODS: A total of 60 NPC patients with radiation-related brain injury were recruited for this study. All subjects were randomly and blindly assigned to the following groups: the dexamethasone group (D group, n = 30) and the vinpocetine and dexamethasone group (VD group, n = 30). Both medicine treatments were uninterrupted for 14 days of administration. RESULTS: Combined administration of vinpocetine and dexamethasone lowered the expression levels of serum inflammatory cytokines, including TLR2, TLR4, interleukin (IL)-20, IL-8, tumor necrosis factor-α, interferon-γ, monocyte chemoattractant protein 2, and interferon-induced protein 20, when compared to dexamethasone monotherapy. Notably, combination therapy increased antioxidants (superoxide dismutase, glutathione, glutathione peroxidase, and glutathione reductase) and decreased oxidants (thiobarbituric acid reactive substances). Furthermore, combination therapy significantly increased the Mini Mental State Examination score, when compared to dexamethasone monotherapy. CONCLUSION: Administration of a combination of vinpocetine and dexamethasone may enhance the anti-inflammatory and anti-oxidative effects when compared to dexamethasone monotherapy, which leads to alleviated cognitive impairment in NPC patients with radiation injury.

Vinpocetine attenuates thioacetamide-induced liver fibrosis in rats.

Liver fibrosis is associated with increased mortality and morbidity. However, there is not effective treatment so far. Vinpocetine (Vinpo) is a synthetic derivative of vinca alkaloid vincamine. Limited previous reports have shown some beneficial effects of Vinpo in different organ fibrosis, but the ability of Vinpo to inhibit liver fibrosis induced by thioacetamide (TAA) has not been reported, that is why we investigate the potential ability of this vinca alkaloid derivative to attenuate liver fibrosis. Hepatic fibrosis was induced in male Sprague Dawley rats by TAA (200 mg/kg; ip; 3 times/week) for 6 weeks. Daily treatments with Vinpo (10-20 mg/kg/day; orally) ameliorated TAA-induced hepatic oxidative stress and histopathological damage as indicated by a decrease in liver injury markers, LDH, hepatic MDA, and NOx levels, as well as increase anti-oxidative parameters. Besides, the anti-fibrotic efficacy of Vinpo was confirmed by decreasing hydroxyproline, and α-SMA. Also, the anti-inflammatory effect of Vinpo was explored by decreasing IL-6 and TNF-α levels. Our novel findings were that Vinpo decreased VEGF/Ki-67 expression in the liver confirming its effect on angiogenesis and proliferation. These findings reveal the anti-fibrotic effect of Vinpo against TAA-induced liver fibrosis in rats, and suggest the modulation of oxidative stress, inflammation, angiogenesis and proliferation as mechanistic cassette underlines this effect.

Vinpocetine protects against the development of experimental abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA), commonly occurring in the aged population, is a degenerative disease that dilate and weaken infrarenal aorta due to progressive degeneration of aortic wall integrity. Vinpocetine, a derivative of alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment in the aged population. Recent studies have indicated that vinpocetine antagonizes occlusive vascular disorders such as intimal hyperplasia and atherosclerosis. However, its role in vascular degenerative disease AAA remains unexplored. Herein, we determined the effect of vinpocetine on the formation of AAA as well as the intervention of pre-existing moderate AAA. AAA was induced by periaortic elastase application in C57BL/6J mice. Systemic vinpocetine treatment was applied daily via intraperitoneal injection. We showed that vinpocetine pre-treatment remarkably attenuated aneurysmal dilation assessed by diameter and volume. More importantly, vinpocetine also significantly suppressed the progression of pre-existing moderate AAA in a post-intervention model. Vinpocetine improved multiple cellular and molecular changes associated with AAA, such as elastin degradation, media smooth muscle cell depletion, collagen fibers remodeling and macrophage infiltration in aneurysmal tissues. Vinpocetine potently suppressed tumor necrosis factor-α-induced nuclear factor kappa-light-chain-enhancer of activated B cells activation and proinflammatory mediator expression in primary cultured macrophages in vitro, as well as in the aorta wall in vivo, suggesting vinpocetine conferred anti-AAA effect at least partially via the inhibition of inflammation. Taken together, our findings reveal a novel role of vinpocetine in AAA formation, development and progression. Given the excellent safety profile of vinpocetine, the present study suggests vinpocetine may be a novel therapeutic agent for AAA prevention and treatment.

Vinpocetine reduces cisplatin-induced acute kidney injury through inhibition of NF-κB pathway and activation of Nrf2/ARE pathway in rats.

Acute kidney injury is a complex clinical disease that is associated with a high incidence of morbidity and mortality. Drug-induced acute kidney injury occurs in approximately 19-33% of hospitalized patients. Cisplatin, one of the most commonly used and effective chemotherapeutic drugs not only exerts anti-tumor effects but also causes renal toxicity damage, affecting its clinical application. Vinpocetine is an anti-inflammatory and antioxidant drug that predominately acts in the nervous system. In this study, we investigated the effects and mechanisms of vinpocetine in an animal model of cisplatin-induced acute renal injury. Rats were randomly divided into three experimental groups. During a 10-day trial, rats in the control group were administered a physiological saline solution; rats in the model group received a 5 mg/kg intraperitoneal injection of cisplatin; and rats in the cisplatin + vinpocetine group received a 5 mg/kg intraperitoneal injection of cisplatin as well as a 5 mg/kg dose of vinpocetine via gavage. We observed that following cisplatin administration, the rats exhibited an increase in blood urea and creatinine levels as well as an increase in their inflammation and oxidative stress levels. In renal tissue, cisplatin caused the morphological changes typical of acute tubular injury. Vinpocetine reduced the cisplatin-induced acute renal function damage and tubular injury. In both in vivo and in vitro experiments, we found that vinpocetine can confer protection of rat renal cells by inhibiting the NF-κB signaling pathway and activating the Nrf2/ARE signaling pathway. Therefore, vinpocetine is a promising therapeutic drug for the treatment of cisplatin-induced acute kidney injury.

Peripheral neuropathy in hematologic malignancies - Past, present and future.

Neurotoxic treatments (including proteasome inhibitors, immunomodulatory drugs and vinca-alkaloids) are often used in the treatment of hematologic malignancy. Peripheral neuropathy can be part of a paraneoplastic syndrome accompanying the disease but more commonly is a consequence of treatment with neurotoxic therapies, and produces sensory, motor, autonomic nerve dysfunction or a combination, leading to pain, loss of sensation and functional disability. This review provides an update on peripheral neuropathy in hematologic malignancy, including risk factors, mechanisms and treatment options. We examine the clinical features and risk factors for peripheral neuropathy following bortezomib, thalidomide, brentuximab vedotin and vinca alkaloid treatment, as well as related compounds. We review the current data on pharmacogenetic risk factors for the development of toxicity and highlight areas of future research.

Vinpocetine Suppresses Streptococcus pneumoniae-Induced Inflammation via Inhibition of ERK1 by CYLD.

Otitis media (OM) is the most common bacterial infection in children. It remains a major health problem and a substantial socioeconomic burden. Streptococcus pneumoniae (S. pneumoniae) is one of the most common bacterial pathogens causing OM. Innate inflammatory response plays a critical role in host defense against bacterial pathogens. However, if excessive, it has a detrimental impact on the middle ear, leading to middle ear inflammation, a hallmark of OM. Currently, there has been limited success in developing effective therapeutic agents to suppress inflammation without serious side effects. In this study, we show that vinpocetine, an antistroke drug, suppressed S. pneumoniae-induced inflammatory response in cultured middle ear epithelial cells as well as in the middle ear of mice. Interestingly, vinpocetine inhibited S. pneumoniae-induced inflammation via upregulating a key negative regulator cylindromatosis (CYLD). Moreover, CYLD suppressed S. pneumoniae-induced inflammation via inhibiting the activation of ERK. Importantly, the postinfection administration of vinpocetine markedly inhibited middle ear inflammation induced by S. pneumoniae in a well-established mouse OM model. These studies provide insights into the molecular mechanisms underlying the tight regulation of inflammation via inhibition of ERK by CYLD and identified vinpocetine as a potential therapeutic agent for suppressing the inflammatory response in the pathogenesis of OM via upregulating negative regulator CYLD expression.

Vinpocetine mitigates aluminum-induced cognitive impairment in socially isolated rats.

Several reports have highlighted the role of vinpocetine in Alzheimer's disease (AD). However, the role of vinpocetine in AD under social isolation conditions has not yet been elucidated. Henceforth, this study aimed to investigate the potential neuroprotective effect of vinpocetine in aluminum-induced AD model associated with social isolation. Social isolation increased the escape latency in Morris water maze (MWM) test, elevated the immobility score and decreased swimming score in forced swimming test (FST) in aluminum treated rats. However, vinpocetine enhanced acquisition in MWM test and exerted anti-depressive effect in FST. The histopathological examination showed marked deterioration in the cerebral cortex and hippocampus of AD isolated rats, while vinpocetine revealed overt improvement. In addition, the levels of amyloid-ß protein (Aß), phosphorylated-tau (Ser396), malondialdehyde (MDA), interleukin 1-beta (IL-1ß), tumor necrosis alpha (TNFα), p- Glycogen synthase kinase-3ß (p-GSK3ß) (Tyr216), and ß-secretase (BACE1) gene expression were increased in socially isolated aluminum treated rats, yet, vinpocetine treatment reversed these deteriorating effects. Hence, this study provides profound insights into the role of vinpocetine in AD particularly in the conditions of social isolation. The effects of vinpocetine might be attributed not only to its antioxidant and anti-inflammatory properties, but also to its suppressing effect on GSK3ß activity and its downstream BACE1.

Phosphodiestrase-1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of cAMP/CREB/TLR4 inflammatory and fibrogenic pathways.

BACKGROUND: Phosphodiestrase (PDE) enzymes are suggested to play a leading role in fibrogenesis of liver where studies showed the possible implication of PDE 1 & 4 in liver injury proposing them as possible targets for treating liver fibrosis. AIM: The present study was designed to investigate, for the first time, the possible therapeutic effects of selective inhibitors of PDE-1 (vinpocetine) and PDE-4 (roflumilast) in liver fibrosis induced by diethylnitrosamine (DEN) in rats. MAIN METHODS: Rats were given DEN (100 mg/kg, i.p.) once weekly for 6 weeks to induce liver fibrosis. Vinpocetine (10 mg/kg/day) or roflumilast (0.5 mg/kg/day) was then orally administered for 2 weeks. KEY FINDINGS: Vinpocetine significantly suppressed the contents of hydroxyproline, transforming growth factor-beta 1 (TGF-ß1), nuclear factor-kappa B (NF-κB) whereas roflumilast normalized them. Moreover, tumor necrosis factor-alpha (TNF-α) content and protein expressions of toll-like receptor 4 (TLR4) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly decreased whereas cAMP response element binding (CREB) protein expression was significantly elevated by both treatments. Additionally, vinpocetine and roflumilast up-regulated the gene expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) receptor where roflumilast showed better results. PDE1 and 4 activities were inhibited by vinpocetine and roflumilast, respectively. The superior results offered by roflumilast could be related to the higher cAMP level obtained relative to vinpocetine. SIGNIFICANCE: Our study manifested the up-regulation of PDE enzymes (1 & 4) in liver fibrosis and addressed the therapeutic role of vinpocetine and roflumilast as PDEIs through a cAMP-mediated TLR4 inflammatory and fibrogenic signaling pathways.

Vinca alkaloids and analogues as anti-cancer agents: Looking back, peering ahead.

Cancer still represents a "nightmare" worldwide, causing annually millions of victims. Several antiproliferative molecules are currently used as drugs market and offer a pharmaceutical opportunity for attenuating and treating tumor manifestations. In this context, natural sources have a relevant role, since they provide the 60% of currently-used anticancer agents. Among the numerous natural products, acting via different mechanisms of action, microtubule-targeting agents (MTAs) have a high therapeutic potential, since they disrupt the abnormal cancer cell growth, interfering with the continuous mitotic division. Vinca alkaloids (VAs) are the earliest developed MTAs and approved for clinical use (Vincristine, Vinblastine, Vinorelbine, Vindesine, and Vinflunine) as agents in the treatment of hematological and lymphatic neoplasms. Here, we review the state-of-art of VAs, discussing their mechanism of action and pharmacokinetic properties and highlighting their therapeutic relevance and toxicological profile. Additionally, we briefly disclosed the technological approaches faced so far to ameliorate the pharmacological properties, as well as to avoid the drug resistance. Lastly, we introduced the recent advances in the discovery of new derivatives.

Recent advances in peptidomimetics antagonists targeting estrogen receptor α-coactivator interaction in cancer therapy.

Estrogen receptor α (ERα) is a crucial target for ERα positive breast cancer treatment. Previous drug discovery efforts were focused on developing inhibitors that targeted the canonical ligand binding pockets of the ligand binding domain (LBD) of ERα. However, significant percentage of patients developed cancer relapse with drug-resistance. ERα peptidomimetic modulators have been considered as promising treatments for drug resistant breast cancers as they are targeting ERα-coactivator interacting interface instead of the ligand binding pocket of ERα. Herein, we reviewed the recent development of ERα peptidomimetics antagonists.

[Peripheral neuropathy as a side effect of chemotherapy and targeted therapy]. / Chemotherapie-induzierte periphere Neuropathie.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and common side effect induced by a variety of anticancer drugs. CIPN presents as a sensory, motor, and sometimes autonomic dysfunction with a large variability, from a mild tingling sensation and hyperesthesia, to severe neuropathic pain. Up to 40 % of patients will develop CIPN which may lead to dose-reduction or discontinuation of their current treatment and largely affects their quality of life (QoL). This review presents specific clinical features and pathomechanisms and discusses current preventive strategies and therapeutic options.

Novel action of vinpocetine in the prevention of paraquat-induced parkinsonism in mice: involvement of oxidative stress and neuroinflammation.

Parkinson's disease (PD) is a multifactorial chronic progressive neurodegenerative disease caused by age, genetic and environmental factors such as paraquat (PQT). PQT (a quartenary nitrogen herbicide) is implicated in some form of idiopathic PD. This study sought to investigate the protective effect of vinpocetine on paraquat-induced Parkinsonism in mice. Forty-eight male albino mice were randomly divided into 6 groups and treated orally as follows for 21 days; Group 1: vehicle normal (10 ml/kg), group 2: vehicle control (10 ml/kg); groups 3-5: vinpocetine (5, 10 or 20 mg/kg); group 6: vinpocetine (20 mg/kg). Animals in groups 2-5 were given PQT (10 mg/kg, i.p.) every 3 days for 3 weeks. The effect of treatments on spontaneous motor activity (open field test), muscle coordination (rotarod tests), cataleptic behaviour (bar test), and working memory (Y-maze test) were assayed. After the behavioural assay on day 21, the midbrain was isolated for estimation of oxidative stress and TNF-α. Intraperitoneal injection of paraquat significantly induced motor deficits, muscle incoordination, catalepsy and working memory impairment which was ameliorated by the pretreatment of mice with vinpocetine. In addition, paraquat injection caused marked increase in nitroso-oxidative stress markers with concomitant deficits in antioxidant enzymes activities (GSH and SOD) as well as induction of tumour necrotic factor-α (TNF-α) in the mid-brain which were attenuated by the pretreatment of mice with vinpocetine. Findings from this study showed that vinpocetine prevented paraquat-induced motor deficits, memory impairment, oxidative stress and neuroinflammation through enhancement of antioxidant defense system and inhibition of neuroinflammatory cytokine. Thus, could be a potential drug in the management of Parkinsonism.