Risk factors for an atherothrombotic event in patients with diabetic macular edema treated with intravitreal injections of bevacizumab

AIM: To identify risk factors for an atherothrombotic event (ATE) among patients who were treated for DME with intravitreal bevacizumab injections. METHODS: This retrospective study enrolled all consecutive patients with DME who were treated by intravitreal bevacizumab from 2009 through 2016 in a single center. They were divided into one group treated by bevacizumab and subsequently had an ATE and a second group also treated by bevacizumab and did not have an ATE. RESULTS: A total of 455 patients with DME were enrolled. Seventy-two of the patients had an ATE. A multivariate model adjusted for age, gender, smoking, body mass index, HbA1c, duration of diabetes, creatinine, and blood pressure revealed an increased risk for ATE in the patients with diabetic duration of more than 13y, a systolic blood pressure over 153 mm Hg at first treatment, or having been treated by more than 4 intravitreal bevacizumab injections. Additionally, patients that had an ATE within 3mo from the last intravitreal treatment underwent more bevacizumab injections (5.17±3.82 vs 3.08±1.96; P=0.0003). CONCLUSIONS: The risk factors for an ATE identified in this study were systolic blood pressure >153.5 mm Hg, a history of diabetic mellitus for more than 13y, and treatment with more than 4 intravitreal bevacizumab injections. These factors need to be borne in mind when bevacizumab is being considered in the management of patients with DME.     

Demographic and dietary predictors of urinary bisphenol A concentrations in adults in Israel

Background

To date, there is scarce data on levels of exposure to bisphenol A (BPA) in the general population in Israel and the region. The goal of the current study was to measure urinary levels of BPA in the general adult population in Israel and to determine the demographic and dietary predictors of exposure.

Methods

We recruited 249 individuals (ages 20–74) from five different regions in Israel. We collected urine samples and questionnaire data including detailed dietary data and analyzed urine samples for BPA concentrations.

Results

Eighty nine percent of the study population had urinary BPA concentrations equal to or above the level of quantification (0.3 μg/L). Median creatinine adjusted BPA urinary concentrations in the study population (2.3 μg/g) were slightly higher than those reported for the general population in the US (1.76 μg/g) and Canada (1.47 μg/g), and were comparable to those reported for the general population in Belgium (2.25 μg/g) and Korea (2.09 μg/g). BPA concentrations were higher in Jews compared to Arab and Druze (prevalence ratio (PR) = 2.34; 95%CI 1.56–3.49), in individuals with higher education (PR = 1.70, 1.11–2.62), in individuals consuming mushrooms (PR = 2.08, 1.07–4.05), and in smokers (PR = 1.43, 1.00–2.05).

Conclusions

We found that the general adult population in Israel is widely exposed to BPA. Our findings on higher BPA levels in Jews compared to Arabs and Druze and in individuals with higher education highlights the fact that predictors of BPA exposure vary across populations.     

Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins

We have recently shown that drug conjugation catalysed by UDP-glucuronosyltransferases (UGTs) functions as an intrinsic mechanism of resistance to the topoisomerase I inhibitors 7-ethyl-10-hydroxycamptothecin and NU/ICRF 505 in human colon cancer cells and now report on the role of drug transport in this mechanism. The ability of transport proteins to recognise NU/ICRF 505 as a substrate was evaluated in model systems either transfected with breast cancer-resistance protein 1 (Bcrp1), multidrug-resistance protein 2 (Mrp2) or Mrp3, or overexpressing MRP1 or P-170 glycoprotein. Results from chemosensitivity assays suggested that NU/ICRF 505 was not a substrate for any of the above proteins. In drug accumulation studies in human colon cancer cell lines NU/ICRF 505 was taken up avidly and retained in cells lacking UGTs (HCT116), whereas, following equally rapid uptake, it was cleared rapidly from cells displaying UGT activity (HT29) as glucuronide metabolites. HT29 cells were shown to express MRP1 and 3, but not P-170 glycoprotein, MRP2 or breast cancer-resistance protein. The major glucuronide of NU/ICRF 505 inhibited ATP-dependent transport of estradiol 17-beta-glucuronide in Sf9 insect cell membrane vesicles containing MRP1 or MRP3, while co-incubation of HT29 cells with the MRP antagonist, MK571, significantly restored intracellular concentrations of NU/ICRF 505. These data lead us to conclude that the presence of a glucuronide transporter is essential for glucuronidation to represent a major de novo resistance mechanism and that UGTs will contribute more as a primary resistance mechanism when the parent drug (e.g. NU/ICRF 505) is not itself recognised by transport proteins.     

Evolving brand-name and generic drug competition may warrant a revision of the Hatch-Waxman Act

The evolution of pharmaceutical competition since Congress passed the Hatch-Waxman Act in 1984 raises questions about whether the act's intended balance of incentives for cost savings and continued innovation has been achieved. Generic drug usage and challenges to brand-name drugs' patents have increased markedly, resulting in greatly increased cost savings but also potentially reduced incentives for innovators. Congress should review whether Hatch-Waxman is achieving its intended purpose of balancing incentives for generics and innovation. It also should consider whether the law should be amended so that some of its provisions are brought more in line with recently enacted legislation governing approval of so-called biosimilars, or the corollary for biologics of generic competition for small-molecule drugs.     

Targeted Delivery of Doxorubicin via Sterically Stabilized Immunoliposomes: Pharmacokinetics and Biodistribution in Tumor-bearing Mice

Purpose. To evaluate benefits in tumor localization, availability, and noncancerous organ distribution of doxorubicin (DOX) delivered via small (120 nm) sterically stabilized immunoliposomes targeted against a tumor-associated antigen in fibrosarcoma-bearing mice. Methods. DOX-loaded liposomes were prepared with (i) specific monoclonal IgG₃ antibody (32/2, D-SSIL-32/2); (ii) non-specific IgG₃ (D-SSIL-IgG); or (iii) no IgG (D-SSL) on their surface. Equal DOX amounts were injected intravenously via each type of liposome into BALB/c mice carrying experimental lung metastases of a polyoma virus-induced fibrosarcoma (A9 etc 220) expressing a polyoma virus-induced tumor-associated antigen (PAA) on their surface. Metastases occurred mainly in lung. Mice were treated at 3 stages of tumor development (micrometastases, medium-size metastases, and large, necrotic metastases). Performance evaluation was based on time-dependent quantification of DOX and DOX metabolites (DOX-M) in lung tumor, noncancerous organs, and plasma. Results. (i) DOX delivered via both SSIL retained the prolonged circulation time typical of DOX delivered via D-SSL. (ii) DOX accumulation in noncancerous organs was similar for all preparations. Low levels of DOX-M were obtained for all three preparations in all organs except liver, suggesting a similar processing, (iii) Preparations differed in behavior in lung tumor depending on tumor size and microanatomy. Only at the micrometastases stage were the specifically targeted D-SSIL-32/2 superior to D-SSL and D-SSIL-IgG, delivering 2–4 times more drug into the tumor, (iv) DOX-M level in all three tumor stages was in the following order: D-SSIL-32/2 >> D-SSL >> D-SSIL-IgG, suggesting that DOX delivered as D-SSIL-32/2 is most available to tumor cells. Conclusions. The advantage of specific targeting of sterically stabilized liposomes is expressed mainly in increasing availability of DOX to tumor cells in a way which is dependent on tumor microanatomy. The impact of this advantage to therapeutic efficacy remains to be determined.     

Lymphocyte subpopulation before and after operation in patients with benign vs malignant breast disease.

Multiple parameters of immune function were measured serially before and one and five weeks following operation in 14 patients with fibrocystic disease of the breast (Group A) and in 20 patients with stage 1-2 infiltrating duct carcinoma (Group B). These parameters included the following: WBC, total number and percentage of lymphocytes, numbers of B cells, T cells, T-active, T-helper and T-suppressor cells and the ratio between the latter as well as spontaneous suppressor or helper activity and the graft-versus-host reaction. Prior to operation no statistically significant difference was found between the two groups except for the number of T-helper cells, which was higher in Group B (p less than 0.05), and the spontaneous suppressor activity, which was higher in Group B (p less than 0.05). The finding of such a high percentage (80%) of negative graft-versus-host reactions five weeks after operation together with the high suppressor activity may indicate the presence of tumor micrometastases. The burden of surgery and general anesthesia was stronger in Group B, with a pronounced difference found between the groups (p = 0.0005), but the interaction between the influence of time (surgery and anesthesia) and the groups was not as great (p = 0.4864) and was found to be different for each group.     

Ego development and treatment requests

Ego development theory suggests that patients might differ in the forms of psychiatric treatment they find helpful, depending on the maturity of their ego functioning. In our study, 100 adults beginning outpatient psychiatric treatment completed the Sentence Completion Test of ego development and the Patient Request Form, which measures treatment modality preference. Ego development was related to treatment requests in patterns predicted from theory: higher ego stage patients were more likely to request insight therapy, while lower stage patients were more likely to request reality checks, social intervention, and triage. We argue that the ego development construct can help treaters match patients to treatment modalities that are compatible with their frames of reference.     

Blocking antibodies and T cell subsets in long-term survivors of renal allografts

Fc-receptor blocking antibodies as well as T cell subsets were studied in a group of 12 long-term survivors of renal allografts. The absolute number of T suppressor cells was similar to that found in a control group, but there was a significant decrease in the total number of T helper lymphocytes and a decreased helper/suppressor ratio. Sera from all patients tested showed inhibitory activity in the erythrocyte antibody model against leukemic B lymphocytes, demonstrating the presence of Fc-receptor blocking antibodies. Also inhibited was the ability of normal human lymphocytes to form E rosettes and to induce a local xenogeneic graft-versus-host reaction. These findings indicate that the Fc blocking antibodies are beneficial to the patient, possibly by abrogating the cellular and humoral immune mechanism that is detrimental to the kidney allograft.