Adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomised trials.

BACKGROUND: To summarise specific adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir in patients with COVID-19. METHODS: We searched 32 databases through 27 October 2020. We included randomised trials comparing any of the drugs of interest to placebo or standard care, or against each other. We conducted fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the grading of recommendations assessment, development and evaluation approach. RESULTS: We included 16 randomised trials which enrolled 8152 patients. For most interventions and outcomes the certainty of the evidence was very low to low except for gastrointestinal adverse effects from hydroxychloroquine, which was moderate certainty. Compared with standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury (risk difference (RD) 8 fewer per 1000, 95% CI 27 fewer to 21 more) or cognitive dysfunction/delirium (RD 3 more per 1000, 95% CI 12 fewer to 19 more). Low certainty evidence suggests that hydroxychloroquine may increase the risk of cardiac toxicity (RD 10 more per 1000, 95% CI 0 more to 30 more) and cognitive dysfunction/delirium (RD 33 more per 1000, 95% CI 18 fewer to 84 more), whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI 23 more to 110 more) compared with standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea (RD 168 more per 1000, 95% CI 58 more to 330 more) and nausea and/or vomiting (RD 160 more per 1000, 95% CI 100 more to 210 more) compared with standard care or placebo. DISCUSSION: Hydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. Remdesivir may have no important effect on risk of acute kidney injury or cognitive dysfunction/delirium. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.

Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective.

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.

Efficacy and harms of remdesivir for the treatment of COVID-19: A systematic review and meta-analysis.

BACKGROUND: Efficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19. METHODS: Studies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed. RESULTS: We included four randomized controlled trials (RCTs) (n = 2296) [two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997)], and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed. CONCLUSIONS: There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19.

Remdesivir for the treatment of COVID-19: a living systematic review.

OBJECTIVE: Provide a timely, rigorous and continuously updated summary of the evidence on the role of remdesivir in the treatment of patients with COVID-19. METHODS: Eligible studies were randomized trials evaluating the effect of remdesivir versus placebo or no treatment. We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in databases, trial registries, preprint servers and websites relevant to COVID-19. All the searches covered the period until 25 August 2020. No date or language restrictions were applied. Two reviewers independently evaluated potentially eligible studies according to predefined selection criteria, and extracted data on study characteristics, methods, outcomes, and risk of bias, using a predesigned, standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic. RESULTS: Our search strategy yielded 574 references. Finally, we included three randomized trials evaluating remdesivir in addition to standard care versus standard care alone. The evidence is very uncertain about the effect of remdesivir on mortality (RR 0.7, 95% CI 0.46 to 1.05; very low certainty evidence) and the need for invasive mechanical ventilation (RR 0.69, 95% CI 0.39 to 1.24; very low certainty evidence). On the other hand, remdesivir likely results in a large increase in the incidence of adverse effects in patients with COVID-19 (RR 1.29, 95% CI 0.58 to 2.84; moderate certainty evidence). CONCLUSIONS: The evidence is insufficient for the outcomes critical for making decisions on the role of remdesivir in the treatment of patients with COVID-19, so it is impossible to balance potential benefits, if there are any, with the adverse effects and costs. PROSPERO REGISTRATION NUMBER: CRD42020183384.

Remdesivir para el tratamiento de COVID-19: una revisión sistemática viva / Remdesivir for the treatment of COVID-19: a living systematic review

OBJETIVO: Esta revisión sistemática viva tiene como objetivo entregar un resumen oportuno, riguroso y continuamente actualizado de la evidencia disponible sobre los efectos de remdesivir en pacientes con COVID-19. MÉTODOS: Se buscaron ensayos aleatorios que evaluaran el uso de remdesivir versus placebo o ningún tratamiento en pacientes con COVID-19. Se realizó una búsqueda en la plataforma L·OVE COVID-19 (Living OVerview of Evidence), un sistema que mantiene búsquedas regulares en bases de datos, registros de ensayos, servidores preprint y sitios web relevantes en COVID-19. Todas las búsquedas fueron realizadas hasta el 25 de agosto de 2020. No se aplicaron restricciones de fecha ni de idioma. Dos revisores evaluaron de forma independiente los artículos potencialmente elegibles, de acuerdo con criterios de selección predefinidos, y extrajeron los datos mediante un formulario estandarizado. Los resultados fueron combinados mediante un metanálisis utilizando modelos de efectos aleatorios y evaluamos la certeza de la evidencia utilizando el método GRADE. Una versión viva de esta revisión estará abiertamente disponible durante la pandemia de COVID-19. RESULTADOS: La búsqueda inicial arrojó 574 referencias. Finalmente, identificamos 3 ensayos aleatorios, que evaluaban el uso de remdesivir adicionado al tratamiento estándar versus tratamiento estándar. La evidencia es muy incierta acerca del efecto del remdesivir sobre la mortalidad (RR 0,7; IC del 95%: 0,46 a 1,05; certeza de la evidencia muy baja) y la necesidad de ventilación mecánica invasiva (RR 0,69; IC del 95%: 0,39 a 1,24; certeza de evidencia muy baja). Por otro lado, es probable que el uso de remdesivir produzca un aumento en la incidencia de efectos adversos en pacientes con COVID-19 (RR 1,29; IC del 95%: 0,58 a 2,84; evidencia de certeza moderada). CONCLUSIONES: La evidencia disponible sobre el papel del remdesivir en el tratamiento de pacientes con COVID-19 es insuficiente en relación a los desenlaces críticos para tomar decisiones, por lo que no es posible realizar un correcto balance entre los beneficios potenciales, los efectos adversos y los costos.

OBJECTIVE: Provide a timely, rigorous and continuously updated summary of the evidence on the role of remdesivir in the treatment of patients with COVID-19. METHODS: Eligible studies were randomized trials evaluating the effect of remdesivir versus placebo or no treatment. We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in databases, trial registries, preprint servers and websites relevant to COVID-19. All the searches covered the period until 25 August 2020. No date or language restrictions were applied. Two reviewers independently evaluated potentially eligible studies according to predefined selection criteria, and extracted data on study characteristics, methods, outcomes, and risk of bias, using a predesigned, standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic. RESULTS: Our search strategy yielded 574 references. Finally, we included three randomized trials evaluating remdesivir in addition to standard care versus standard care alone. The evidence is very uncertain about the effect of remdesivir on mortality (RR 0.7, 95% CI 0.46 to 1.05; very low certainty evidence) and the need for invasive mechanical ventilation (RR 0.69, 95% CI 0.39 to 1.24; very low certainty evidence). On the other hand, remdesivir likely results in a large increase in the incidence of adverse effects in patients with COVID-19 (RR 1.29, 95% CI 0.58 to 2.84; moderate certainty evidence). CONCLUSIONS: The evidence is insufficient for the outcomes critical for making decisions on the role of remdesivir in the treatment of patients with COVID-19, so it is impossible to balance potential benefits, if there are any, with the adverse effects and costs.

Alternating Rabacfosadine/Doxorubicin: Efficacy and Tolerability in Naïve Canine Multicentric Lymphoma.

BACKGROUND: Standard of care treatment for multicentric lymphoma in dogs remains doxorubicin (DOX)-based combination chemotherapy, but owners may hesitate to commit the time and financial resources to complete such a protocol, typically requiring 12-16 visits. Rabacfosadine (RAB), a double prodrug of the nucleotide analog 9-(2-phosphonylmethoxyethyl) guanine, has substantial single-agent activity in dogs with lymphoma, and a different mechanism of action than DOX. HYPOTHESIS/OBJECTIVES: Our objective was to evaluate the efficacy and adverse effect (AE) profile of alternating doses of RAB and DOX in dogs with naïve multicentric lymphoma. ANIMALS: Fifty-four dogs with previously untreated lymphoma. METHODS: Open-label, multicenter prospective clinical trial. Dogs received alternating RAB (1.0 mg/kg IV weeks 0, 6, 12) and DOX (30 mg/m2 IV weeks 3, 9, 15). Dogs that achieved complete response (CR) were followed by monthly evaluations. Complete clinicopathological evaluation and assessment of remission and AEs were performed every 21 days. RESULTS: The overall response rate was 84% (68%; CR; 16%; partial response [PR)]. The overall median progression-free interval (PFI) was 194 days (216 for CR and 63 for PR). Most AEs were mild and self-limiting: gastrointestinal and hematologic AEs were most common. Thirteen dogs experienced dermatologic AEs, and 2 dogs developed grade 5 pulmonary fibrosis. CONCLUSIONS AND CLINICAL IMPORTANCE: Alternating RAB/DOX generally was well tolerated and resulted in PFIs comparable to standard DOX-based multi-agent protocols, with fewer treatment visits. Most adverse events were mild or moderate and self-limiting. Further studies are warranted to explore long-term outcome and other RAB chemotherapy combinations.

Efeito da suplementação com L-glutamina e L-alanina, livres ou como dipeptídeo, sobre a lesão, inflamação e citoproteção em modelos de estresse in vivo e in vitro / Effects of supplementation with L-glutamine and L-alanine, in their free form or as dipeptide, on muscle damage, inflammation and cytoprotection of in vivo and in vitro stress models

Subprojeto 1: Determinação do efeito anti-inflamatório e citoprotetor da suplementação com L-glutamina e L-alanina, ou com L-alanil-L-glutamina (DIP) em ratos submetidos a treinamento resistido. Exercícios intensos reduzem a disponibilidade de glutamina, comprometendo a função imune e a recuperação de atletas. O objetivo do estudo foi avaliar os efeitos da suplementação oral crônica com L-glutamina e L-alanina, nas formas livres ou como dipeptídeo (DIP), sobre parâmetros de lesão, inflamação e citoproteção em ratos Wistar adultos submetidos a treinamento resistido (TR). Neste estudo, o TR reduziu a concentração de glutamina no plasma e no músculo EDL. No entanto, este efeito foi atenuado pelos suplementos contendo L-glutamina, os quais aumentaram os conteúdos da proteína de resposta ao estresse (HSP70) em células do sistema imune (PBMC) e no EDL, concomitantemente à redução da ativação do NF-kB e a da concentração de citocinas no EDL. O efeito protetor das suplementações também foi evidenciado pela atenuação de marcadores de lesão (CK e LDH) e inflamação (TNF-α e IL-1ß), bem como pelo aumento nas concentrações de marcadores anti-inflamatórios (IL-6, IL-10 e MCP-1) no plasma. Nossos resultados sugerem que a suplementação oral crônica com L-glutamina (administrada com L-alanina livre ou como DIP) promoveu efeitos citoprotetores mediados pela HSP70 em resposta à lesão e inflamação induzidas pelo TR. Subprojeto 2: Efeitos da L-alanil-L-glutamina sobre as vias de sinalização da insulina e da mTOR/S6K, e citoproteção em células musculoesqueléticas C2C12. O dipeptídeo L-alanil-L-glutamina é conhecido por modular o metabolismo e a viabilidade celular. Contudo, os efeitos sobre os componentes clássicos das vias de sinalização da insulina e da mTOR/S6K, bem como o efeito citoprotetor em células musculares, são pouco esclarecidos. O objetivo deste estudo foi investigar o efeito do DIP sobre as vias de sinalização da insulina e da mTOR/S6K em miotubos C2C12, em condições normais ou resistentes à insulina. A exposição crônica à insulina (24h) promoveu resistência à insulina, reduzindo os conteúdos totais do receptor beta (IR-ß) e do substrato do receptor de insulina (IRS-1), e diminuindo a fosforilação de IRS-1, AKT e P44/42 MAPK. Adicionalmente, houve redução na expressão do transportador de glicose (GLUT4) e HSP70, redução da viabilidade celular e menor fosforilação de p70S6k e S6, proteínas relacionadas à síntese proteica. Em contraste, a suplementação com DIP aumentou os conteúdos totais de IR-ß e IRS-1 e a fosforilação de IRS-1 e AKT. A glicólise anaeróbia e a capacidade glicolítica, além da fosforilação de p70S6k e S6, foram aumentadas pelo DIP em condições normais e na resistência à insulina. Nestas condições experimentais, nossos resultados sugerem que a suplementação com DIP melhorou as vias de sinalizações da insulina e da mTOR/S6K, aumentou a captação e metabolização da glicose, independente da estimulação com insulina e, finalmente, promoveu citoproteção resgatando parcialmente as células de um estado resistente à insulina, por meio do aumento de HSP70 e ativação das etapas finais da via mTOR/S6K.

Subproject 1: Determination of the anti-inflammatory and cytoprotective effects of supplementation with L-glutamine and L-alanine, or with L-alanyl-L-glutamine in rats submitted to resistance training. Intense exercise reduces glutamine availability, compromising immune function and recovery of athletes. The objective of the study was to evaluate the effects of chronic oral supplementation with L-glutamine and L-alanine, in their free form or as dipeptide (DIP), on muscle damage, inflammation and cytoprotection in adult Wistar rats submitted to resistance training (RT). In this study, RT reduced glutamine concentration in plasma and EDL muscle. However, this effect was attenuated by supplements containing L-glutamine, which increased the contents of the stress response protein (HSP70) in immune system cells (PBMC) and EDL, concomitantly with the reduction of NF-kB activation and the concentration of cytokines in EDL. The protective effect of supplementation was also evidenced by attenuation of lesion markers (CK and LDH) and inflammation (TNF-α and IL-1ß), as well as by the increase in anti-inflammatory plasma markers (IL-6, IL-10 and MCP-1). Our results suggest that chronic oral supplementation with L-glutamine (administered along with free L-alanine or as DIP) promoted HSP70-mediated cytoprotective effects in response to RT-induced injury and inflammation. Subproject 2: Effects of L-alanyl-L-glutamine on the components of insulin and mTOR/ S6K signaling pathways and cytoprotection in C2C12 musculoskeletal cells. The dipeptide L-alanyl-L-glutamine is known to modulate metabolism and cell viability. However, the effects on the classical components of insulin and mTOR/ S6K signaling pathways, as well as the cytoprotective effect on muscle cells, are poorly understood. The aim of this study was to investigate the effect of DIP on insulin and mTOR/ S6K signaling pathways in C2C12 myotubes, under normal or insulin resistant conditions. Chronic insulin exposure (24h) promoted insulin resistance, reducing the total contents of the insulin receptor (IR-ß) and the insulin receptor substrate (IRS-1), and decreasing the phosphorylation of IRS-1, AKT and P44/ 42 MAPK. In addition, there was a reduction in the expression of glucose transporter (GLUT4) and HSP70, reduction of cell viability and defective phosphorylation of p70S6k and S6, which are related to protein synthesis. On the other hand, DIP supplementation increased the total contents of IR-ß and IRS-1 and the phosphorylation of IRS-1 and AKT. Anaerobic glycolysis and glycolytic capacity, in addition to phosphorylation of p70S6k and S6, were increased by DIP under normal conditions and in insulin resistance. In our experimental conditions, our results suggest that DIP supplementation improved the signaling pathways of insulin and mTOR/ S6K, increased glucose uptake and metabolism, independent of insulin stimulation, and finally promoted cytoprotection by partially rescuing the cells of an insulin resistant state, by increasing HSP70 and activating the final stages of the mTOR/ S6K pathway.

The safety and efficacy of safinamide mesylate for the treatment of Parkinson's disease.

Safinamide (brand name Xadago®, Zambon S.p.A) is a third-generation reversible MAO-B inhibitor, which also blocks sodium voltage-sensitive channels and modulates stimulated release of glutamate. Safinamide was recently licensed by EMA for the treatment of PD as add-on therapy to a stable dose of levodopa alone or in combination with other PD medicinal products in mid-to advanced-stage fluctuating patients. It is also under review by the US FDA. Studies in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and 6OHDA-lesioned rats suggest antiparkinsonian efficacy and antidyskinesic effects. Randomized, double-blind, placebo-controlled trials have shown efficacy for the treatment of motor symptoms in stable PD patients on dopamine agonists and in fluctuating PD patients on levodopa. Significant improvement in daily ON time was also observed in the latter. This effect was maintained for at least 2 years in double-blind conditions and, interestingly, without significant worsening of dyskinesia. Clinical studies have not detected any specific safety issue other than those already known with MAO-B inhibitors.

Estudo do metaboloma salivar e sua associação com a doença periodontal em pacientes com síndrome de Down / Saliva metabolome in patients with Down syndrome and its association with periodontal disease

Os pacientes com Síndrome de Down (SD) possuem grande incidência de doença periodontal (DP), caracterizada por um curso precoce e com maior severidade. O estudo de metaboloma pode contribuir para o entendimento deste curso da doença, identificando possíveis metabólitos como biomarcadores nestes indivíduos. Para entender o perfil metabolômico dos indivíduos com síndrome de Down e a sua relação com a doença periodontal, realizamos a identificação de metabólitos salivares de adolescentes e adultos jovens, entre 12 e 21 anos, ambos os gêneros. Foram coletados dados sobre o estado geral de saúde e realizados exames clínicos bucais, como índice de higiene oral simplificado, sangramento e profundidade de sondagem. Para a análise do metaboloma foi coletada amostra de saliva não estimulada, analisadas por meio de cromatografia gasosa acoplada á espectrometria de massas. Saliva e fluido crevicular gengival também foram coletados para identificação microbiana através do MALDI-TOF. Os dados encontrados foram submetidos a análise estátisca por meio da Análise dos Componentes Principais (PCA) e quantificação relativa dos metabólitos foi avaliada por testes não paramétricos, Mann-Whitney

e Kruskal-Wallis. Foi possível observar através dos modelos de PCA separação dos indivíduos com SD e controles, independente da doença periodontal. A quantificação relativa revelou maiores níveis de glicina, lprolina, l-leucina, l-serina, ácido palmítico, ácido pentanóico, ácido tetradecanóico, tirosina e l-fenilalanina nos grupos SD quando comparados aos controles. Controles com DP também apresentaram níveis elevados de glicina, l-alanina, l-serina e manopiranose quando comparados com controles saudáveis. A microbiota de indivíduos com SD apresentous diferenças siginificantes em relação aos individuos controles, principalmente para Rothia dentocariosa, Staphylococcus epidermidis, Tannerella forsythia quando avaliado a saliva e A. Actinomycetemcomitans, Micrococcus luteus, Rothia aeria, Treponema denticola no fluido crevicular gengival. Em conclusão, o perfil metabolômico impresso nos indivíduos com SD difere significativamente dos indivíduos controles, independente da doença periodontal. Entretanto, os metabólitos que diferenciam indivíduos controles com e sem DP, apresentam-se elevados em todos indivíduos com SD, promovendo novos "insights" para o perfil metabólico relacionado a DP na SD.

Down Syndrome (DS) patients have a high incidence of periodontal disease (PD), characterized by an early course and greater severity. The metabolome study may contribute to the understanding of the disease course, identifying possible metabolites as biomarkers in these individuals. To understand the metabolomic profile of the DS and their relationship with PD, we conducted the identification of salivary metabolites of adolescents and young adults between 12 and 21 years, both genders. Data were collected on general health and was performed oral clinical examination, as the IHOS, bleeding index and probing depth. For metabolome analysis was collected unstimulated saliva sample, analyzed by gas chromatography coupled to mass spectrometry. Saliva and gingival crevicular fluid were also collected for microbial identification by MALDI-TOF. Data were submitted to analysis-statistic by PCA and relative quantification

of metabolites was evaluated by Mann-Whitney and Kruskal-Wallis tests. It can be observed through the PCA models separation of DS groups and controls groups, regardless of periodontal disease. Relative quantification showed higher levels of glycine, L-proline, L-leucine, L-serine, palmitic acid, pentanoic acid, tetradecanoic acid, tyrosine and L-phenylalanine in the SD groups when compared to controls groups. Controls with PD also showed high levels of glycine, L-alanine, L-serine and mannopyranose compared with healthy controls. The microbiota of individuals with DS groups show significant differences compared to control groups, especially for Rothia dentocariosa, Staphylococcus epidermidis, Tannerella forsythia when evaluated saliva and A. actinomycetemcomitans, Micrococcus luteus, Rothia aeria, Treponema denticola in gingival crevicular fluid. In conclusion, the printed metabolomic profile in individuals with Down syndrome differs significantly from control subjects, regardless of periodontal disease. However, the metabolites that distinguish controls group with and without PD, show up high in all DS individuals, promoting new "insights" to the metabolic profile related to PD in DS.

Phase II evaluation of VDC-1101 in canine cutaneous T-cell lymphoma.

BACKGROUND: Canine cutaneous T-cell lymphoma (CTCL) is an uncommon disease for which efficacious therapies are lacking. The novel anticancer nucleotide prodrug VDC-1101 (formerly known as GS-9219) has shown efficacy in dogs with multicentric lymphoma. One of the observed adverse effects with this drug was a skin change characterized by hair loss, erythema, and pruritus, implying delivery of VDC-1101 to the skin. HYPOTHESIS/OBJECTIVES: The primary study objective was to identify the objective response rate (ORR) to VDC-1101 in canine CTCL; secondary objectives included characterization of progression-free survival (PFS) and adverse events (AEs). ANIMALS: Twelve dogs with chemotherapy-naïve or relapsed, histologically and immunohistochemically confirmed CTCL. METHODS: Dogs received VDC-1101 as a 30-minute IV infusion once every 21 days. Prednisone (1 mg/kg PO q48h) was administered concurrently. RESULTS: In 11 evaluable patients, responses included 1 complete response (CR), 4 partial responses (PR), 2 stable disease (SD), and 4 progressive disease for an ORR of 45% and biologic response rate (CR/PR/SD) of 64%. The median PFS was 37.5 days (26 to >399 days), which includes 1 durable and ongoing CR (>1 year). Gastrointestinal and hematologic AEs were mild; no dogs developed grade 3 or 4 AEs. Three dogs developed dermatopathies and 1 of these dogs was removed from the study as a result of this AE. CONCLUSIONS AND CLINICAL IMPORTANCE: VDC-1101 has activity against canine CTCL and could provide another treatment option in a disease process with a poor prognosis.

Role of oral blockade of platelet glycoprotein IIb/IIIa on neutrophil activation in patients with acute coronary syndromes.

Orbofiban is a unique antiplatelet agent that inhibits the binding of fibrinogen to gycoprotein (GP) IIb/IIIa integrin receptors and thus prevents platelet aggregation induced by various agents. However, recent studies indicate that treatment with orbofiban does not reduce the incidence of recurrent ischemic events. The mechanisms underlying the lack of benefit of orbofiban in patients with acute coronary syndromes are not completely clear. The purpose of this study was to characterize the effects of orbofiban on cellular activation (neutrophil superoxide generation) and surface expression of adhesion molecules of circulating neutrophils (CD18, CD11b, and L-selectin) and platelets (P-selectin and GP IIb/IIIa) in patients with acute coronary syndromes. After 5-7 days, orbifiban (50 mg BID) did not reduce PMN adhesion molecule expression and ex vivo-stimulated PMN superoxide generation--as was observed in the placebo group, without orbofiban. In contrast, orbofiban induced marked reductions in GP IIb/IIIa and P-selectin expressions after 5-7 days of treatment. The sustained neutrophil activation observed with orbofiban may have a role on the recurrent thrombotic events observed with orbofiban treatment in the OPUS-TIMI 16 trial.