Synthesis and leishmanicidal activity of cinnamic acid esters: structure–activity relationship

Several cinnamic acid esters were obtained via Fischer esterification of cinnamic acids derivatives with aliphatic alcohols. Structures of the products were elucidated by spectroscopic analysis. The synthesized compounds were evaluated for antileishmanial activity against L. (V) panamensis amastigotes and cytotoxic activity was evaluated against mammalian U-937 cells. The compounds 11, 15–17, and 23, were active against Leishmania parasite and although toxic for mammalian cells, they still are potential candidates for antileishmanial drug development. A SAR analysis indicates that first, while smaller alkyl chains lead to higher selectivity indices (10, 11 vs. 12–17); second, the degree of oxygenation is essential for activity, primarily in positions 3 and 4 (17 vs. 18–20 and 22); and third, hydroxyl groups increase both activity and cytotoxicity (14 vs. 23). On the other hand, the presence of a double bond in the side chain is crucial for cytotoxicity and leishmanicidal activity (12 vs. 21). However, further studies are required to optimize the structure of the promising molecules and to validate the in vitro activity against Leishmania demonstrated here with in vivo studies.     

Design and synthesis of tacrine-phenothiazine hybrids as multitarget drugs for Alzheimer’s disease

Tacrine is well-known drug for Alzheimer’s disease as an acetylcholinesterase inhibitor. Rember is a bright and promising AD drugs targeting tau protein, and it is currently in Phase III clinical trials. Phenothiazine, the key pharmacophore of Rember, can prevent tau filament formation. In this work, several tacrine-phenothiazine hybrids (T1–T26) were designed for inhibiting acetylcholinesterase and tau protein involved in Alzheimer’s disease. After initial screening with the help of computational chemistry software and Molegro Virtual Docker, three molecules (T5, T18, and T22) were selected for further synthesis and biological evaluation. Next, T5, T18, and T22 were synthesized and evaluated for their acetylcholinesterase and tau hyperphosphorylation inhibition. All the tested compounds had better acetylcholinesterase inhibitory activity compared with tacrine. Among them, compound T5 was found to be the most potent compound with IC₅₀ 89 nM. Meanwhile, T5 markedly prevented tau hyperphosphorylation induced by okadaic acid in N2α cell. Its P-tau level was decreased with 39.5 % inhibition when tested at 10^?5 M, lower than that Rember (55.7 %). Besides acetylcholinesterase and tau hyperphosphorylation inhibition, T5 can also interact with fibrill beta amyloid using surface plasmon resonance, the data of K_D were 5.51 × 10^?8 M. All the above results indicated that tacrine-phenothiazine hybrids are potential multitarget directed ligands targeting acetylcholinesterase, tau protein, and beta amyloid.     

The Effects of Moxifloxacin on QTc Interval in Healthy Korean Male Subjects

Background and objective

Moxifloxacin 400 mg is a widely used positive control in thorough QT (TQT) studies, but its QT-prolonging effects in Korean subjects have not been studied. The present study was conducted to collect pilot data in Korean subjects after moxifloxacin administration to evaluate the adequacy of moxifloxacin as a positive control.

Methods

Thirty-eight, healthy, Korean, male subjects were recruited for pharmacokinetic (PK) blood sampling and electrocardiography (ECG) recordings at three different study sites. On day 1, a baseline 12-lead ECG was recorded, and on day 2, ECG recordings were conducted after placebo, or moxifloxacin 400- or 800-mg administration. Baseline-corrected, placebo-adjusted, corrected QT (ΔΔQTc) values were calculated. Blood samples were collected after moxifloxacin administration and PK parameters were assessed.

Results

A total of 33 subjects completed the study. The largest time-matched ΔΔQTc occurred approximately 4 h after dosing, with ΔΔQTcI (QT interval corrected by individual QT-RR regression model) values of 11.66 ms (moxifloxacin 400 mg) and 20.96 ms (800 mg). The mean and 90 % confidence intervals of ΔΔQTcI did not include zero at any of the measurement time points. There was a positive correlation between plasma moxifloxacin concentration and ΔΔQTcI (r = 0.422). Dose-proportional PK profiles were observed.

Conclusion

Moxifloxacin 400 mg is an adequate positive control in Korean TQT studies. Our results indicate that moxifloxacin 400 mg can be used to evaluate the cardiac safety of a drug in Korean subjects.     

Acute and chronic toxic effects of bisphenol a on Chlorella pyrenoidosa and Scenedesmus obliquus

The acute and chronic toxic effects of Bisphenol A (BPA) on Chlorella pyrenoidosa (C. pyrenoidosa) and Scenedesmus obliquus (S. obliquus) were not well understood. The indoor experiments were carried out to observe and analyze the BPA‐induced changes. Results of the observations showed that in acute tests BPA could significantly inhibit the growth of both algae, whereas chronic exposure hardly displayed similar trend. Superoxide dismutase (SOD) and Catalase (CAT) activities of both algae were promoted in all the treatments. Chlorophyll a synthesis of the two algae exhibited similar inhibitory trend in short‐term treatments, and in chronic tests C. pyrenoidosa hardly resulted in visible influence, whereas in contrast, dose‐dependent inhibitory effects of S. obliquus could be clearly observed. The experimental results indicated that the growth and Chlorophyll a syntheses of S.obliquus were more sensitive in response to BPA than that of C. pyrenoidosa, whereas for SOD andCAT activities, C. pyrenoidosa was more susceptible. This research provides a basic understanding of BPA toxicity to aquatic organisms. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 714–722, 2014.     

Olecranon fractures: factors influencing re-operation

Purpose

We evaluated factors influencing re-operation in tension band and plating of isolated olecranon fractures.

Methods

Four hundred eighty-nine patients with isolated olecranon fractures who underwent tension band (TB) or open reduction internal fixation (ORIF) from 2003 to 2013 were identified at an urban level 1 trauma centre. Medical records were reviewed for patient information and complications, including infection, nonunion, malunion, loss of function or hardware complication requiring an unplanned surgical intervention. Electronic radiographs of these patients were reviewed to identify Orthopaedic Trauma Association (OTA) fracture classification and patients who underwent TB or ORIF.

Results

One hundred seventy-seven patients met inclusion criteria of isolated olecranon fractures. TB was used for fixation in 43 patients and ORIF in 134. No statistical significance was found when comparing complication rates in open versus closed olecranon fractures. In a multivariate analysis, the key factor in outcome was method of fixation. Overall, there were higher rates of infection and hardware removal in the TB compared with the ORIF group.

Conclusions

Our results demonstrate that the dominant factor driving re-operation in isolated olecranon fractures is type of fixation. When controlling for all variables, there is an increased chance of re-operation in patients with TB fixation.     

Monitoring of Intrasplenic Hepatocyte Transplantation for Acute-on-Chronic Liver Failure: A Prospective Five-Year Follow-Up Study

Background

Acute-on-chronic liver failure (ACLF) is defined as an acute deterioration of chronic liver disease. Intrasplenic hepatocyte transplantation is increasingly recognized as a treatment for liver failure and genetic metabolic liver diseases. We describe our experience of intrasplenic hepatocyte transplantation in a small cohort of patients as bridge therapy or as an alternative to orthotopic liver transplantation (OLT).

Methods

Seven patients with ACLF with an expected survival of less than 8 weeks were enrolled into the study. The donor hepatocytes were collected from 2 healthy males and cryopreserved. Donor hepatocytes were transplanted into the spleen of recipients via catheterization of the femoral artery. All patients were followed up for 5 years or to death.

Results

A total of (4.2–6.0) × 10¹⁰ hepatocytes were harvested from the 2 donors' livers and their survival after recovery from the frozen stock was 63% ± 2.8% and 73.5% ± 3.2%, respectively. Following intrasplenic hepatocyte transplantation, 3 patients fully recovered from liver failure, 1 survived and subsequently underwent OLT, and the remaining 3 patients died between 2.5 and 12 months after intrasplenic hepatocyte transplantation. At month 48 post–intrasplenic hepatocyte transplantation, living hepatocyte signals were observed in the spleen using magnetic resonance imaging (MRI) with gadobenate dimeglumine (Gd-BOPTA).

Conclusions

Intrasplenic hepatocyte transplantation is a promising therapy for liver failure that may reduce mortality rates among patients with end-stage liver disease awaiting OLT. Conceivably, intrasplenic hepatocyte transplantation may be considered an alternative to OLT for patients with acute liver failure. MRI (Gd-BOPTA) is a useful tool for detecting living hepatocytes in the spleen after intrasplenic hepatocyte transplantation.     

Holmium laser enucleation of the prostate versus transurethral resection of the prostate: a randomized clinical trial

Objective

To evaluate the efficacy and safety of holmium laser enucleation of the prostate (HoLEP) and transurethral resection of the prostate (TURP), for treatment of benign prostatic hyperplasia (BPH).

Methods

A total of 164 cases of BPH were selected from patients who were hospitalized between January 2010 and December 2011. Patients had received either HoLEP or TURP treatment. Clinical data were collected from the perioperative period, 1 month after surgery, and 12 months after surgery.

Results

There was no significant difference between the two groups in the maximum urinary flow rate (Q _max), postvoid residual volume (PVR), international prostate symptom score (IPSS), or quality-of-life score (QOL score) at 1 month after surgery (p = 0.56, p = 0.346, p = 0.536 and p = 0.145, respectively). However, after 12 months, patients from the HoLEP group demonstrated better scores in Q _max, PVR, IPSS, and QOL than those from the TURP group (p = 0.037, p = 0.003, p < 0.001 and p = 0.019, respectively). The two groups had comparable operation time (p = 0.105), catheterization time (p = 0.173), and length of hospital stay (p = 0.395), but were statistically different in the weight of resected prostate tissue (p < 0.001), bladder irrigation time (p < 0.001), hemoglobin levels (p = 0.011), and blood sodium levels (p = 0.002) after surgery.

Conclusions

Compared to TURP, HoLEP was safer and had better long-term efficacy as assessed by multiple quantitative measures. Therefore, HoLEP may present a better option in the treatment of BPH.