Protection against Radiotherapy-Induced Toxicity

Radiation therapy is a highly utilized therapy in the treatment of malignancies with up to 60% of cancer patients receiving radiation therapy as a part of their treatment regimen. Radiation therapy does, however, cause a wide range of adverse effects that can be severe and cause permanent damage to the patient. In an attempt to minimize these effects, a small number of compounds have been identified and are in use clinically for the prevention and treatment of radiation associated toxicities. Furthermore, there are a number of emerging therapies being developed for use as agents that protect against radiation-induced toxicities. The aim of this review was to evaluate and summarise the evidence that exists for both the known radioprotectant agents and the agents that show promise as future radioprotectant agents

Molecular mechanisms underlying the effects of statins in the central nervous system

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly referred to as statins, are widely used in the treatment of dyslipidaemia, in addition to providing primary and secondary prevention against cardiovascular disease and stroke. Statins’ effects on the central nervous system (CNS), particularly on cognition and neurological disorders such as stroke and multiple sclerosis, have received increasing attention in recent years, both within the scientific community and in the media. Current understanding of statins’ effects is limited by a lack of mechanism-based studies, as well as the assumption that all statins have the same pharmacological effect in the central nervous system. This review aims to provide an updated discussion on the molecular mechanisms contributing to statins’ possible effects on cognitive function, neurodegenerative disease, and various neurological disorders such as stroke, epilepsy, depression and CNS cancers. Additionally, the pharmacokinetic differences between statins and how these may result in statin-specific neurological effects are also discussed

Provision of pharmaceutical care in patients with limited English proficiency: Preliminary findings

Objective: Overcoming language and cultural barriers is becoming ever challenging for pharmacists as the patient population grows more ethnically diverse. To evaluate the current practices used by the pharmacists for communicating with patients with limited English proficiency (LEP) and to assess pharmacists’ knowledge of, attitude toward, and satisfaction with accessing available services for supporting LEPs patients within their current practice settings. Methods: Semi-structured interviews were conducted with five pharmacists employed in pharmacies representing multiple practice settings Queensland, Australia. Thematic analysis was primarily informed by the general inductive approach. NVivo software (QSR International Pty Ltd.) was used to manage the data. Findings: Three interlinked themes emerged from the analysis of interview data: (1) Barriers to the provision of pharmaceutical care, (2) Strategies employed in dealing with LEP patients, and (3) Lack of knowledge about existing services. Pharmacists recognized their lack of skills in communicating with LEP patients to have potential negative consequences for the patient and discussed these in terms of uncertainty around eliciting patient information and the patient’s understanding of their instructions and or advice. Current strategies were inconsistent and challenging for LEP patient care. While the use of informal interpreters was common, a significant degree of uncertainty surrounded their actual competency in conveying the core message. Conclusion: The present study highlights a significant gap in the provision of pharmaceutical care in patients with LEP. Strategies are needed to facilitate quality use of medicines among this patient group

Reversal of dopamine inhibition of dopaminergic neurons of the ventral tegmental area is mediated by protein kinase C

Adaptation of putative dopaminergic (pDA) neurons in the ventral tegmental area (VTA) to drugs of abuse may alter information processing related to reward and reinforcement and is a key factor in the development of addiction. We have demonstrated that prolonged increases in the concentration of dopamine (DA) result in a time-dependent decrease in sensitivity of pDA neurons to DA, which we termed dopamine inhibition reversal (DIR). In the present study, we used extracellular recordings to examine factors mediating DIR. A 40 min administration of DA (2.5-10 μM), but not the DA D2 receptor agonist quinpirole (50-200 nM), resulted in inhibition of neuronal firing followed by DIR. In the presence of 100 nM cocaine, inhibition followed by DIR was seen with much lower DA concentrations. Reversal of quinpirole inhibition could be induced by an activator of protein kinase C, but not of protein kinase A. Inhibitors of protein kinase C or phospholipase C blocked the development of DIR. Disruption of intracellular calcium release also prevented DIR. Reduction of extracellular calcium or inhibition of store-operated calcium entry blocked DIR, but the L-type calcium channel blocker nifedipine did not. DIR was age-dependent and not seen in pDA VTA neurons from rat pups younger than 15 days postnatal. Our data indicate that DIR is mediated by protein kinase C, and implicate a conventional protein kinase C. This characterization of DIR gives insight into the regulation of autoinhibition of pDA VTA neurons, and the resulting long-term alteration in information processing related to reward and reinforcement

Laser assisted modified lip repositioning surgery for the treatment of excessive gingival display using Y V plasty: A case report

Excessive gingival display is matter of concern for a lot of patients and affects their psychological well-being. Various methods have been employed to reduce excessive gingival display but with variable results. Modified Lip repositioning is a surgical way to correct gummy smile by limiting the retraction of the elevator smile muscles and yet preserve the labial frenum using Y-V plasty using a method that gives long term results along with being non-invasive and has high patient compliance. After thorough disinfection and achieving adequate anaesthesia, the strip of mucosa which had to ablated was marked with a laser, which was twice the amount of gingival display seen in the patient. After carrying out laser ablation of the marked tissue, and performing Y-V plasty, the surgical area was evaluated and the wound margins were approximated with multiple interrupted sutures. The patient was put on a regular follow-up. The results revealed a marked reduction in gingival display at the 3-month follow-up. Overall gingival display reduced from 6 mm to 2 mm

Phorbol ester reduces ethanol excitation of dopaminergic neurons of the ventral tegmental area: Involvement of protein kinase C theta

Neurons of the ventral tegmental area (VTA) play a key role in the rewarding and reinforcing effects of drugs of abuse, including alcohol. Ethanol directly increases the firing rate of dopaminergic (DAergic) VTA neurons, but modulation of the firing rate of DAergic VTA neurons can be controlled by a number of factors, including some that are under the control of protein kinase C (PKC). Application of phorbol esters activates PKC and the present study assessed the effect of a phorbol ester, phorbol 12-myristate 13-acetate (PMA), on ethanol-induced excitation of DA VTA neurons. Ethanol-induced excitation of DAergic VTA neurons was reduced significantly in the presence of PMA. This action of PMA was antagonized by chelerythrine chloride, a non-selective antagonist of PKC, but not by moderate concentrations of antagonists of conventional PKC isoforms (Gö6976 and Gö6983). A PKC δ/θ inhibitor antagonized PMA-induced reduction of ethanol excitation. Since PKCδ antagonist Gö6983 did not antagonize the effect of PMA on ethanol excitation, the PMA reduction of ethanol excitation is most likely to be mediated by PKCθ. Antagonists of intracellular calcium pathways were ineffective in antagonizing PMA action on ethanol excitation, consistent with the lack of calcium dependence of PKCθ. In summary, ethanol-induced excitation of VTA neurons is attenuated in the presence of PMA, and this attenuation appears to be mediated by PKCθ. This novel mechanism for interfering with ethanol activation of reward-related neurons could provide a new target for pharmacotherapy to ameliorate alcoholism

Astrocytic Glutamatergic Transmission and Its Implications in Neurodegenerative Disorders

Several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is a predominant excitatory neurotransmitter where the astrocytes play a pivotal role in maintaining the extracellular levels through release and uptake mechanisms. Astrocytes modulate calcium-mediated excitability and release several neurotransmitters and neuromodulators, including glutamate, and significantly modulate neurotransmission. Accumulating evidence supports the concept of excitotoxicity caused by astrocytic glutamatergic release in pathological conditions. Thus, the current review highlights different vesicular and non-vesicular mechanisms of astrocytic glutamate release and their implication in neurodegenerative diseases. As in presynaptic neurons, the vesicular release of astrocytic glutamate is also primarily meditated by calcium-mediated exocytosis. V-ATPase is crucial in the acidification and maintenance of the gradient that facilitates the vesicular storage of glutamate. Along with these, several other components, such as cystine/glutamate antiporter, hemichannels, BEST-1, TREK-1, purinergic receptors and so forth, also contribute to glutamate release under physiological and pathological conditions. Events of hampered glutamate uptake could promote inflamed astrocytes to trigger repetitive release of glutamate. This could be favorable towards the development and worsening of neurodegenerative diseases. Therefore, across neurodegenerative diseases, we review the relations between defective glutamatergic signaling and astrocytic vesicular and non-vesicular events in glutamate homeostasis. The optimum regulation of astrocytic glutamatergic transmission could pave the way for the management of these diseases and add to their therapeutic value

A pilot study assessing the value of 3D printed molecular modelling tools for pharmacy student education

Background and purpose: Medicinal chemistry and pharmacology are difficult topics to both teach and learn given the complex nature of drug mechanisms and drug-receptor interactions. This highlights the need for innovative teaching methods to deliver this information to students. One such method is through three-dimensional (3D) printing of enzymes and ligands in the teaching of molecular modelling concepts relating to drug-receptor and enzyme interactions be ligands. This type of printing has been shown to be beneficial in several educational settings; however, to our knowledge, its effectiveness in pharmacy, medicinal chemistry and pharmacology learning and teaching is largely unknown. Therefore, the aim of this study was to evaluate pharmacy student perceptions and the educational benefits of 3D printed molecules in molecular modelling with regards to engagement and learning outcomes when used in a drug-target interaction topic. Educational activity and setting: This aim was achieved through administering students a short questionnaire designed to evaluate their engagement and learning outcomes with students also free to provide comments. Findings: This study found that nearly all (> 90%) students found the activity was useful in improving both student engagement and learning outcomes. Discussion and summary: In conclusion, 3D printing may provide an alternative learning activity to help pharmacy students understand the drug-target interaction.Griffith Health, School of PharmacyNo Full Tex

Suppression of Gq function using intra-pipette delivery of shRNA during extracellular recording in the ventral tegmental area

Selective suppression of protein function in the brain can be achieved using specific silencing RNAs administered in vivo. A viral delivery system is often employed to transfect neurons with small hairpin RNA (shRNA) directed against specific proteins, and intervals of several days are allowed between microinjection of the shRNA-containing virus into the brain and experiments to assess suppression of gene function. Here we report studies using extracellular recording of dopaminergic neurons of the ventral tegmental area (DA VTA neurons) recorded in brain slices in which lentivirus containing shRNA directed against Gq was included in the recording pipette, and suppression of Gq-related function was observed within the time frame of the recording. The action of neurotensin (NT) is associated with activation of Gq, and the firing rate of DA VTA neurons is increased by NT. With shRNA directed against Gq in the pipette, there was a significant reduction of NT excitation within 2h. Likewise, time-dependent dopamine desensitization, which we have hypothesized to be Gq-dependent, was not observed when shRNA directed against Gq was present in the pipette and dopamine was tested 2h after initiation of recording. As the time interval (2h) is relatively short, we tested whether blockade of protein synthesis with cycloheximide delivered via the recording pipette would alter Gq-linked responses similarly. Both NT-induced excitation and dopamine desensitization were inhibited in the presence of cycloheximide. Inclusion of shRNA in the recording pipette may be an efficient and selective way to dampen responses linked to Gq, and, more generally, the use of lentiviral-packaged shRNA in the recording pipette is a means to produce selective inhibition of the function of specific proteins in experiments