Optimisation of abiraterone based non-steroidal lead molecules

Management of castration resistant prostate cancer is limited by androgen receptor reactivation resulting in loss of remission. A recent study indicated that abiraterone exhibits antagonist activity towards the androgen receptor in addition to CYP17A1 inhibition.Metribolone has demonstrable in vitro and in vivo high affinity for the AR thus it was established as a benchmark against which the affinity of abiraterone and de novo designed non-steroidal molecules could be compared. Binding affinities of abiraterone manually superimposed onto the steroid scaffold of metribolone (pKd 7.16) and abiraterone that was allowed limited rotation (pKd 7.23)were comparable to metribolone (pKd 7.44).The de novo study generated an 8 analogue molecular series with affinities ranging between 5.26 and 7.23. This study yielded sufficient analogues that may be proposed for further molecular optimisation to yield innovative non-steroidal high affinity molecules with superior side-effect profiles for the management of prostate cancer.peer-reviewe

Clinical pharmacist implementation of a medication assessment tool for long-term management of atrial fibrillation in older persons

Background: Optimisation of drug therapy is important in the older population and may be facilitated by medication assessment tools (MATs). Objective: The purpose of the study was to evaluate whether appropriateness of drug therapy and clinical pharmacist intervention documentation improved following implementation of a previously developed MAT for the long-term management of atrial fibrillation (MAT-AF). Methods: Adherence to MAT-AF review criteria and clinical pharmacist intervention documentation was assessed by the researcher pre-MAT implementation in 150 patients aged ≥60 years admitted to a rehabilitation hospital with a diagnosis of atrial fibrillation. MAT-AF was introduced as a clinical tool in the hospital for identification of pharmaceutical care issues in atrial fibrillation patients. Adherence to MAT-AF and pharmacist intervention documentation were assessed by the researcher post-MAT implementation for a further 150 patients with the same inclusion criteria. Logistic regression analysis and measurement of odds ratio was used to identify differences in adherence to MAT-AF pre- and post-MAT implementation. The differences between two population proportions z-test was used to compare pharmacist intervention documentation pre- and post-MAT implementation. Results: Adherence to MAT-AF criteria increased from 70.9% pre-implementation to 89.6% post-implementation. MAT-AF implementation resulted in a significant improvement in prescription of anticoagulant therapy (OR 4.07, p<0.001) and monitoring of laboratory parameters for digoxin (OR 10.40, p<0.001). Clinical pharmacist intervention documentation improved significantly post-implementation of MAT-AF (z-score 20.249, p<0.001). Conclusions: Implementation of MAT-AF within an interdisciplinary health care team significantly improved the appropriateness of drug therapy and pharmacist intervention documentation in older patients with atrial fibrillation

Pre‑operative pain sensitivity : a prediction of post‑operative outcome in the obstetric population

Context: Experimental assessments can determine pain threshold and tolerance, which mirror sensitivity to pain. This, in turn, influences the post‑operative experience. Aims: The study intended to evaluate whether the pre‑operative pressure and electrical pain tests can predict pain and opioid requirement following cesarean delivery. Settings and Design: Research was conducted on females scheduled for cesarean section at a tertiary care hospital of the state. Twenty women were enrolled, after obtaining written informed consent. Materials and Methods: Pain assessment was performed on the eve of cesarean sections using three devices: PainMatcher® determined electrical pain threshold while the algometers PainTest™ FPN100 (manual) and PainTest™ FPX 25 (digital) evaluated pressure pain threshold and tolerance. Post‑operative pain relief included intravenous morphine administered by patient‑controlled analgesia, diclofenac (100 mg, every 12 h, rectally, enforced) and paracetamol (1000 mg, every 4‑6 h, orally, on patient request). Pain scores were reported on numerical rating scales at specified time intervals. Statistical Analysis Used: Correlational and regression statistics were computed using IBM SPSS Statistics 21 software (IBM Corporation, USA). Results: A significant correlation was observed between morphine requirement and: (1) electrical pain threshold (r = –0.45, P = 0.025), (2) pressure pain threshold (r = –0.41 P = 0.036) and (3) pressure pain tolerance (r = –0.44, P = 0.026) measured by the digital algometer. The parsimonious regression model for morphine requirement consisted of electrical pain threshold (r2 = 0.20, P = 0.049). The dose of morphine consumed within 48 h of surgery decreases by 0.9 mg for every unit increment in electrical pain threshold. Conclusions: The predictive power of pain sensitivity assessments, particularly electrical pain threshold, may portend post‑cesarean outcomes, including opioid requirements.peer-reviewe

Adenosine preconditioning attenuates hepatic reperfusion injury in the rat by preventing the down-regulation of endothelial nitric oxide synthase

BACKGROUND: Previous work has suggested that in the liver, adenosine preconditioning is mediated by nitric oxide. Whether the endothelial isoform of nitric oxide synthase plays a part in this mechanism has however not yet been investigated. METHODS: Wistar rats were used (6 in each group) – Groups: (1) sham, (2) ischemia-reperfusion, (3) adenosine + ischemia-reperfusion, (4) endothelial isoform inhibitor + adenosine + ischemia-reperfusion. RESULTS: Using immunohistochemistry, this study has revealed a decrease in the expression of endothelial nitric oxide synthase following hepatic ischemia-reperfusion. This was prevented by adenosine pre-treatment. When an inhibitor of endothelial nitric oxide synthase was administered prior to adenosine pre-treatment, pre-conditioning did not occur despite normal expression of endothelial nitric oxide synthase. CONCLUSIONS: These findings suggest that adenosine attenuates hepatic injury by preventing the downregulation of endothelial nitric oxide synthase that occurs during ischemia-reperfusion

Liema....?

Ġabra ta’ poeżiji u proża li tinkludi: Nhar l-Akkademja f’ġieħ il-wisq Rev. Mons. C. Psaila ta’ Albert M. Cassola – Inkwiet fil-Familja ta’ Ġużè Galea – F’Jum l-Ingress tal-maħbub Arċisqof Mons. Michael Gonzi D.D., l-ewwel Metropolita ta’ Malta tal-Kan. A. Copperstone – Dwiem ta’ Eric Serracino-Inglott – L-Imdina ta’ R. Briffa – Wenzu Jfittex lil Luċija ta’ Dun Pawl – Liema....? ta’ Dun Karm.N/

Strategies for Inhibiting Advanced Glycation Endproduct (Age) Induced Vascular Calcification in a Smooth Muscle Cell Culture Model

Vascular calcification is implicated in a range of cardiovascular disease mechanisms, leading to an associated increase in morbidity and mortality. One such trigger are advanced glycation endproducts (AGEs), the tissue accumulation of which increases with age and is more prevalent in diabetic subjects due to oxidative stress and poor glycaemic control. The aim of this study was to investigate the osteogenic potential of AGEs and elucidate mechanisms of inhibiting these processes in a smooth muscle cell (SMC) culture model. Osteogenic differentiation of SMCs was induced using β-glycerophosphate (β-GP), carboxymethyllysine (CML), carboxyethyllysine (CEL) methylglyoxal (MGO) and glycated low density lipoprotein (gly-LDL). The cells were subsequently treated with aminoguanidine (AG), an inhibitor of AGE formation, and novel glycomimetic compounds in order to determine their anti-calcification potential in vitro using qPCR, ELISA, Alkaline phosphatase (ALP) activity and Alizarin red staining. Gly-LDL (10 µg/ml) and CML (2.5nM) increased the level of calcification observed compared to the β-GP (5 mM) positive control after 21 days (p < 0.05), with gly-LDL induced calcification apparent after 14 days. Both AG (250 µM) and the novel glycomimetic compounds reduced the level of mineralisation observed at 21 days compared with osteogenic treatments (p < 0.05). CEL (2.5 nM) and MGO (0.1 mM) both induced calcification, however mineralization was not as extensive as with β-GP. When compared to the structure of CML, the side-chain of CEL contains an extra methyl group, suggesting this group impacts RAGE receptor binding. It was also shown that β-GP combined with increased glucose concentration induced more extensive calcification unlike low glucose levels and β-GP alone. ALP activity, when stimulated with β-GP, CML and gly-LDL was greater at day 4 than at day 7, with AG reducing ALP activity measurements at day 4. Gly-LDL increases gene expression of OCN at day 4 compared with β-GP and CML, however this was reduced at day 7, corresponding with an increased expression of OPN and OPG. NOTCH-3 gene expression was also reduced at day 7. Gene expression of OPN, OPG and NOTCH-3 were reduced at both day 4 and day 7 compared with osteogenic treatments (β-GP, CML and gly-LDL). In summary, we conclude that gly-LDL and CML are potent inducers of calcification compared with β-GP, and that their osteogenic potential can be modulated by both AG and novel glycomimetic compounds

Jien, Min Jien?

Ġabra ta’ poeżiji u proża li tinkludi: Il-Għanja ta’ Ċikkulata u Ċikkulatu ta’ Dun Karm – Mill-Qiegħ ta’ l-Imgħoddi ta’ Ġużè Chetcuti – Frak tad-Deheb ta’ P. Ġużeppi Meilak – Waqt ta’ Ġużè Ellul Mercer – “Għax Nibża’ Jiena fil-Jum Ħażin?” ta’ A. Copperstone – Ruħ il-Poeta ta’ Dun Frans Camilleri – Nisel ta’ Erin Serracino-Inglott – “Għanja” ta’ Ġużi Micallef Grimaud – Jien, Min Jien? ta’ Ġużè Galea.N/

Li kieku kont warda

Ġabra ta’ poeżiji u proża li tinkludi: Minn Betlehem għall-kalvarju ta’ A. Cremona – Mewt u ħajja ta’ Pawlu Cachia – Jahveh! ta’ Erin Serracino-Inglott – Ċinerama ta’ Charles Coleiro – F’lejl sajfi ta’ P. Feliċ Sammut – Ħbiberija ta’ Val. V. Barbara – Dubji ta’ Oliver Friggieri – Qiegħed jidlam ta’ Joe Mejlak – Zoo ta’ Albert M. Cassola – Li kieku kont warda ta’ Pawlu Mifsud.peer-reviewe