Unanticipated Cardiotoxicity Associated with Targeted Anticancer Therapy in Patients with Hematologic Malignancies Patients: Natural History and Risk Factors

Our aim is to study unanticipated cardiotoxicity associated with the use of anticancer targeted agents, a problem that remains poorly understood. Using diagnosis codes, we retrospectively identified patients with both hematologic malignancies (HM) and cardiovascular diseases (n = 820 patients). Cardiotoxicity was defined per published criteria. The targeted agents of interest included tyrosine kinase inhibitors, proteasome inhibitors, monoclonal antibodies, and immunomodulatory agents. Patients found with cardiotoxicity (n = 29) were compared with 70 case-matched reference subjects. Median time from targeted therapy exposure to cardiotoxicity was 132 days. A higher percentage of patients had prior exposure to anthracyclines in study versus reference group (65.5 vs. 42.8%, P = 0.04), however, did not stay significant in multivariate analysis. Two variables were significant predictors, prior of DVT/PE and Karnofsky score of ≥ 80% (P ≤ 0.011). Only 2 study group patients died of cardiac causes. Most cardiotoxicity patients (23/29) had remained stable or improved, while 21 patients received further chemotherapy. OS was lower in the study group (P = 0.018) versus the reference group. In conclusion, a small number patients with HM experience unanticipated cardiotoxicity with low related mortality. Risk of cardiotoxicity was significantly associated with history of DVT/PE. Most patients do well, but despite that, their OS is significantly poorer.     

Effect of cytochrome P450 3A5 genotype on atorvastatin pharmacokinetics and its interaction with clarithromycin

Abstract Study Objective. To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin. Design. Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study. Setting. Clinical research center at a teaching hospital. Subjects. Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors). Intervention. In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days. Measurements and Main Results. Pharmacokinetic parameters of both forms of atorvastatin-atorvastatin acid and atorvastatin lactone-were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin's muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ng?hr/ml [interquartile range (IQR) 37.8-64.3 ng?hr/ml] vs 34.9 ng?hr/ml [IQR 21.6-42.2 ng?hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC(0-∞) of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049). Conclusion. Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant.     

Floppy eyelid syndrome is associated with obstructive sleep apnoea: a prospective study on 127 patients

A few investigations have raised the question of a possible relationship between obstructive sleep apnoea syndrome (OSAS) and floppy eyelid syndrome (FES). FES is an easily inverted floppy eyelid with papillary conjunctivis, and is a subset of the general pathology, lax eyelid syndrome. The aim of the current study is to determine whether OSAS severity is associated with FES. One hundred and 27 consecutive subjects (aged 25-75 years) referred to the Strasbourg University Sleep Clinic with suspicion of OSAS were included. All patients underwent overnight ambulatory respiratory polygraphy, comprehensive ophthalmological examination and completed standard sleep questionnaires. OSAS severity was defined based on the patient's obstructive apnoea-hypopnoea index (AHI). As expected, age, body mass index (BMI) and the proportion of males increased with OSAS severity. FES was observed in 15.8% of the subjects without OSAS, 25.8% of the total OSAS population and the frequency was significantly increased (40%) in patients with severe OSAS (AHI > 30 h(-1)). A significant correlation between OSAS severity and FES was found after adjustment for age, sex and BMI, using a principal component analysis (PCA). The multivariate analysis included clinical, polygraphic and comorbidity data and was followed by logistic regressions for the main components extracted from the PCA. In summary, our findings show an association between OSAS severity and FES and suggest that severe OSAS might be an independent risk factor for FES. These two disorders may share common biological determinants, such as tissue elasticity. Finally, clinicians should be aware of this association so that underlying OSAS or FES can be detected.     

Prevalence of human papillomavirus detection in ovarian cancer: a meta-analysis

European Journal of Clinical Microbiology & Infectious Diseases - We conducted a meta-analysis of published data to update and estimate the prevalence of HPV in ovarian cancer. A comprehensive...     

Circulation patterns and molecular epidemiology of human respiratory syncytial virus over five consecutive seasons in Morocco

Background

Respiratory syncytial virus (HRSV) is the leading cause of respiratory tract infections in infants and young children. we investigated the prevalence and characteristics of HRSV in Morocco and explored trends in circulating genotypes through partial G gene analysis of HRSV strains prevalent from 2012 to 2017.

Methods

Respiratory samples were gathered from both outpatients and inpatients meeting ILI or SARI case definitions. The patients' ages varied from 1 month to 99 years old. Nucleic acids were extracted and HRSV type/subtype was detected by RT-qPCR. A subset of positive samples was randomly selected in each epidemic year, the complete viral genome was sequenced, phylogenetic analysis was performed using the MEGA7 program and the genotypes were confirmed.

Results

The 3679 specimens were collected from 2012 to 2017, of which 726 (19.7%) were positive for HRSV. The 35% (257/726) of HRSV-positives were of the HRSV-A subtype, while the HRSV-B subtype accounted for 61% (442/726). The co-infection rate was 3.7% (27/726). The virus circulates in a periodic pattern, where epidemics occur during the fall months through early spring. HRSV genotype was confirmed in 127 specimens (56 HRSV-A and 71 HRSV-B). Based on phylogenetic analysis, all HRSV-A were ON1 genotype, and HRSV-B were mostly BA9 genotype. HRSV-B belonging to the BA10 genotype was detected in 2012 exclusively.

Conclusions

BA9, BA10, and ON1 were the only HRSV genotypes detected between 2012 and 2017. Variations in the G gene amino acid chain were identified in local strains, which suggests an increased need for continuous genomic surveillance.     

Semisynthetic Derivatives of the Verticillin Class of Natural Products through Acylation of the C11 Hydroxy Group

The verticillins, a class of epipolythiodioxopiperazine alkaloids (ETPs) first described 50 years ago with the discovery of verticillin A (1), have gained attention due to their potent activity against cancer cells, noted both in vitro and in vivo. In this study, the complex scaffold afforded through optimized fermentation was used as a feedstock for semisynthetic efforts designed to explore the reactivity of the C11 and C11′ hydroxy substituents. Functionality introduced at these positions would be expected to impact not only the potency but also the pharmacokinetic properties of the resulting compound. With this in mind, verticillin H (2) was used as a starting material to generate nine semisynthetic analogues (4–12) containing a variety of ester, carbonate, carbamate, and sulfonate moieties. Likewise, verticillin A succinate (13) was synthesized from 1 to demonstrate the successful application of this strategy to other ETPs. The synthesized compounds and their corresponding starting materials (i.e., 1 and 2) were screened for activity against a panel of melanoma, breast, and ovarian cancer cell lines: MDA-MB-435, MDA-MB-231, and OVCAR3. All analogues retained IC₅₀ values in the nanomolar range, comparable to, and in some cases more potent than, the parent compounds.     

Phytochemical Composition,Antioxidant and Antibacterial Activities of Crude Extracts from the Species Euphorbia Atlantica Coss.

Pharmaceutical Chemistry Journal - A phytochemical study of crude extracts obtained from Euphorbia atlantica Coss. led to the isolation and structure identification of ten known compounds by...     

高效液相色谱-质谱联用分析磷酸可待因及其精氨酸布洛芬复方中的有关物质

建立了高效液相色谱法检查磷酸可待因、磷酸可待因与精氨酸布洛芬复方的有关物质,并采用HPLC-TOF／MS和LC—MS／MS对磷酸可待因及两种复方药物产生的降解产物进行了结构鉴定。色谱柱为ClR（250mm×4．6mm,5μm）,柱温50℃,流速1mL／min,检测波长245nm,醋酸铵（0．04M,用醋酸调pH6．0）-乙腈（92：8,v／v）为流动相A,乙腈为流动相B,梯度洗脱。磷酸可待因在氧化条件下很不稳定产生了两个N-氧可待因异构体,在碱性破坏中得到了新的杂质,其结构可能为6-羟基-3-甲氧基-17-甲基-7,8-双脱氢吗啡-5-醇。在酸性破坏条件下磷酸可待因和精氨酸布洛芬可发生酯化反应。所建立的HPLC方法灵敏、准确,可有效测定磷酸可待因、磷酸可待因与精氨酸布洛芬复方的有关物质,并对产生的降解产物进行了结构鉴定,为更好的控制磷酸可待因与磷酸可待因复方药物的质量提供了依据。