Intra-Target Microdosing – A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans

Intra-target microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of ¹⁸F-fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well-tolerated. Results are consistent with ITM proof-of-concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach.

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Identification of OAT1/OAT3 as Contributors to Cisplatin Toxicity

Cisplatin is among the most widely used anticancer drugs and known to cause a dose-limiting nephrotoxicity, which is partially dependent on the renal uptake carrier OCT2. We here report a previously unrecognized, OCT2-independent pathway of cisplatin-induced renal injury that is mediated by the organic anion transporters OAT1 and OAT3. Using transporter-deficient mouse models, we found that this mechanism regulates renal uptake of a mercapturic acid metabolite of cisplatin that acts as a precursor of a potent nephrotoxin. The function of these two transport systems can be simultaneously inhibited by the tyrosine kinase inhibitor nilotinib through noncompetitive mechanisms, without compromising the anticancer properties of cisplatin. Collectively, our findings reveal a novel pathway that explains the fundamental basis of cisplatin-induced nephrotoxicity, with potential implications for its therapeutic management.

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The emotional and professional wellbeing of Australian midwives: A comparison between those providing continuity of midwifery care and those not providing continuity

Publication date: Available online 8 July 2017
Source:Women and Birth
Author(s): Jennifer Fenwick, Mary Sidebotham, Jenny Gamble, Debra K. Creedy
BackgroundContinuity of midwifery care contributes to significant positive outcomes for women and babies. There is a perception that providing continuity of care may negatively impact on the wellbeing and professional lives of midwives.AimTo compare the emotional and professional wellbeing as well as satisfaction with time off and work-life balance of midwives providing continuity of care with midwives not providing continuity.MethodOnline survey. Measures included; Copenhagen Burnout Inventory (CBI); Depression, Anxiety and Stress Scale-21; and Perceptions of Empowerment in Midwifery Scale (PEMS-Revised). The sample (n=862) was divided into two groups; midwives working in continuity (n=214) and those not working in continuity (n=648). Mann Whitney U tests were used to compare the groups.ResultsThe continuity group had significantly lower scores on each of the burnout subscales (CBI Personal p=.002; CBI Work p<.001; CBI Client p<.001) and Anxiety (p=.007) and Depression (p=.004) sub-scales. Midwives providing continuity reported significantly higher scores on the PEMs Autonomy/Empowerment subscale (p<.001) and the Skills and Resources subscale (p=.002). There was no difference between the groups in terms of satisfaction with time off and work-life balance.ConclusionOur results indicate that providing continuity of midwifery care is also beneficial for midwives. Conversely, midwives working in shift-based models providing fragmented care are at greater risk of psychological distress. Maternity service managers should feel confident that re-orientating care to align with the evidence is likely to improve workforce wellbeing and is a sustainable way forward.



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The influence of physical activity in water on sleep quality in pregnant women: A randomised trial

Publication date: Available online 8 July 2017
Source:Women and Birth
Author(s): R. Rodriguez-Blanque, J.C. Sánchez-García, A.M. Sánchez-López, N. Mur-Villar, M.J. Aguilar-Cordero
IntroductionSleep is a physiological state of self-regulation. The international classification of sleep disorders now includes as a new category those occurring during pregnancy. Regular physical activity is known to improve the quality of life, one aspect of which is sleep quality. During pregnancy, physical activity is decreased but should not be eliminated, as studies have reported a high correlation between sleep disorders and the absence of physical activity. Regular physical exercise during pregnancy, whether performed in water or out of it, provides greater control of gestational weight gain. Furthermore, the reduced weight gain during pregnancy, as a result of physical exercise, is associated with greater physical resistance to the demands of childbirth, combats the fatigue caused by pregnancy and reduces back pain. All of these outcomes tend to enhance sleep quality, among other beneficial effects.ObjectiveTo determine whether, in pregnant women, there is an association between moderate-intensity physical activity in an aquatic environment and sleep quality.Material and methodsA randomised clinical trial was conducted with a sample of 140 pregnant women aged 21–43 years, divided into two groups; Intervention Group and Control Group. The women were recruited in the twelfth week of gestation and took part in the [Study of] Water Exercise in Pregnancy programme from week 20 to week 37. Sleep quality was evaluated in the first and third trimesters of pregnancy, using the Pittsburgh Sleep Quality Index questionnaire.ResultsThe Mann–Whitney U test showed that the results obtained were statistically significant (p<0.05). In the Intervention Group, 44 of the women (65.67%) were classified as "poor sleepers" versus 62 women (92.54%) in the Control Group.ConclusionsThe [Study of] Water Exercise in Pregnancy method improves the quality of sleep in pregnant women, both subjectively and in terms of latency, duration and efficiency.



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Curcumin Induces p53-Null Hepatoma Cell Line Hep3B Apoptosis through the AKT-PTEN-FOXO4 Pathway

Objective. Curcumin (diferuloylmethane) is a yellow-colored polyphenol with antiproliferative and proapoptotic activities to various types of cancer cells. This study explored the mechanism by which curcumin induces p53-null hepatoma cell apoptosis. Results. AKT, FOXO1, and FOXO3 proteins were downregulated after curcumin treatment. Conversely, PTEN was upregulated. Subcellular fractionations revealed that the FOXO4 protein translocated from cytosol into the nucleus after curcumin treatment. Overexpression of FOXO4 increases the sensitivity of Hep3B cells to curcumin. Knockdown of the FOXO4 gene by siRNA inhibits the proapoptotic effects of curcumin on Hep3B cell. Conclusions. This study revealed the AKT/PTEN/FOXO4 pathway as a potential candidate of target for treatment of p53-null liver cancers.

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Binding Kinetics and Lateral Mobility of HSV-1 on End-Grafted Sulfated Glycosaminoglycans

Many viruses, including herpes simplex (HSV), are recruited to their host cells via interaction between their envelope glycoproteins and cell-surface glycosaminoglycans (GAGs). This initial attachment is of a multivalent nature, i.e., it requires the establishment of multiple bonds between amino acids of viral glycoproteins and sulfated saccharides on the GAG chain. To gain understanding of how this binding process is modulated, we performed binding kinetics and mobility studies using end-grafted GAG chains that mimic the end attachment of these chains to proteoglycans.

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Measuring Protein Binding to Lipid Vesicles by Fluorescence Cross-Correlation Spectroscopy

Fluorescence correlation spectroscopy has been previously used to investigate peptide and protein binding to lipid membranes, as it allows for very low amounts of sample, short measurement times and equilibrium binding conditions. Labeling only one of the binding partners, however, comes with certain drawbacks, as it relies on identifying binding events by a change in diffusion coefficient. Since peptide and protein aggregation can obscure specific binding, and since non-stoichiometric binding necessitates the explicit choice of a statistical distribution for the number of bound ligands, we additionally label the liposomes and perform dual-color fluorescence cross-correlation spectroscopy (dcFCCS).

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