A Review of the Dose Justification of Phase 3 Trials to Regulatory Authorities for Drugs Intended for the Treatment of Type 2 Diabetes in Europe

Aims: Cardiovascular outcome trials with anti-diabetic drugs suggest that additional cardiovascular benefit can be achieved independent of improving glycaemic control. Nonetheless, dose selection of anti-diabetic drugs is typically based solely on glycaemic effects. We evaluated whether off-target drug effects are currently considered for dose justification to regulatory agencies. Methods: In the European Union, anti-diabetic drugs are registered by the European Medicines Agency. We extracted available information regarding dose selection from public assessment reports and marketing application dossiers. Descriptive statistics were used to summarise the extracted information. Results: In total, 14 drugs of three drug classes were included; sodium-glucose co-transporter-2 inhibitors (n = 4), dipeptidyl peptidase-4 inhibitors (n = 4) and glucagon-like peptide-1 receptor agonists (n = 6). For these drugs, 21 dose-finding trials were submitted including results of multiple off-target effects, of which body weight (n = 18) and low-density lipoprotein cholesterol (n = 14) were most frequently reported. Dose-response curves for off-target effects appeared to be different compared to the glycaemic dose-response curve. Glycated hemoglobin (100%) and fasting plasma glucose (42.9%), were used most frequently for the dose justification, but generally off-target effects (<25%) were not. Conclusions: Dose justification to regulatory authorities was mainly based on glycaemic effects. The dose-response relationship for the off-target effects did not necessarily follow the dose-response relationship of the on-target effects suggesting that selection of the optimal anti-diabetic dose could benefit from including off-target effects in the dose selection process as well

An asymmetric junctional mechanoresponse coordinates mitotic rounding with epithelial integrity

Epithelia are continuously self-renewed, but how epithelial integrity is maintained during the morphological changes that cells undergo in mitosis is not well understood. Here, we show that as epithelial cells round up when they enter mitosis, they exert tensile forces on neighboring cells. We find that mitotic cell–cell junctions withstand these tensile forces through the mechanosensitive recruitment of the actin-binding protein vinculin to cadherin-based adhesions. Surprisingly, vinculin that is recruited to mitotic junctions originates selectively from the neighbors of mitotic cells, resulting in an asymmetric composition of cadherin junctions. Inhibition of junctional vinculin recruitment in neighbors of mitotic cells results in junctional breakage and weakened epithelial barrier. Conversely, the absence of vinculin from the cadherin complex in mitotic cells is necessary to successfully undergo mitotic rounding. Our data thus identify an asymmetric mechanoresponse at cadherin adhesions during mitosis, which is essential to maintain epithelial integrity while at the same time enable the shape changes of mitotic cells

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women

An asymmetric junctional mechanoresponse coordinates mitotic rounding with epithelial integrity

Epithelia are continuously self-renewed, but how epithelial integrity is maintained during the morphological changes that cells undergo in mitosis is not well understood. Here, we show that as epithelial cells round up when they enter mitosis, they exert tensile forces on neighboring cells. We find that mitotic cell–cell junctions withstand these tensile forces through the mechanosensitive recruitment of the actin-binding protein vinculin to cadherin-based adhesions. Surprisingly, vinculin that is recruited to mitotic junctions originates selectively from the neighbors of mitotic cells, resulting in an asymmetric composition of cadherin junctions. Inhibition of junctional vinculin recruitment in neighbors of mitotic cells results in junctional breakage and weakened epithelial barrier. Conversely, the absence of vinculin from the cadherin complex in mitotic cells is necessary to successfully undergo mitotic rounding. Our data thus identify an asymmetric mechanoresponse at cadherin adhesions during mitosis, which is essential to maintain epithelial integrity while at the same time enable the shape changes of mitotic cells

Analgesics use and ESRD in younger age: a case-control study

<p>Abstract</p> <p>Background</p> <p>An ad hoc peer-review committee was jointly appointed by Drug Authorities and Industry in Germany, Austria and Switzerland in 1999/2000 to review the evidence for a causal relation between phenacetin-free analgesics and nephropathy. The committee found the evidence as inconclusive and requested a new case-control study of adequate design.</p> <p>Methods</p> <p>We performed a population-based case-control study with incident cases of end-stage renal disease (ESRD) under the age of 50 years and four age and sex-matched neighborhood controls in 170 dialysis centers (153 in Germany, and 17 in Austria) from January 1, 2001 to December 31, 2004. Data on lifetime medical history, risk factors, treatment, job exposure and intake of analgesics were obtained in a standardized face-to-face interview using memory aids to enhance accuracy. Study design, study performance, analysis plan, and study report were approved by an independent international advisory committee and by the Drug Authorities involved. Unconditional logistic regression analyses were performed.</p> <p>Results</p> <p>The analysis included 907 cases and 3,622 controls who had never used phenacetin-containing analgesics in their lifetime. The use of high cumulative lifetime dose (3^rdtertile) of analgesics in the period up to five years before dialysis was not associated with later ESRD. Adjusted odds ratios with 95% confidence intervals were 0.8 (0.7 – 1.0) and 1.0 (0.8 – 1.3) for ever- compared with no or low use and high use compared with low use, respectively. The same results were found for all analgesics and for mono-, and combination preparations with and without caffeine. No increased risk was shown in analyses stratifying for dose and duration. Dose-response analyses showed that analgesic use was not associated with an increased risk for ESRD up to 3.5 kg cumulative lifetime dose (98 % of the cases with ESRD). While the large subgroup of users with a lifetime dose up to 0.5 kg (278 cases and 1365 controls) showed a significantly decreased risk, a tiny subgroup of extreme users with over 3.5 kg lifetime use (19 cases and 11 controls) showed a significant risk increase. The detailed evaluation of 22 cases and 19 controls with over 2.5 kg lifetime use recommended by the regulatory advisors showed an impressive excess of other conditions than analgesics triggering the evolution of ESRD in cases compared with controls.</p> <p>Conclusion</p> <p>We found no clinically meaningful evidence for an increased risk of ESRD associated with use of phenacetin-free analgesics in single or combined formulation. The apparent risk increase shown in a small subgroup with extreme lifetime dose of analgesics is most likely an indirect, non-causal association. This hypothesis, however, cannot be confirmed or refuted within our case-control study. Overall, our results lend support to the mounting evidence that phenacetin-free analgesics do not induce ESRD and that the notion of "analgesic nephropathy" needs to be re-evaluated.</p

Paleointensity Results From Pliocene Lavas of the Lesser Caucasus Obtained Using the Multispecimen Parallel Differential pTRM Method: A Comparison With Thellier- Thellier and IZZI Data

We report paleointensity results obtained with the multispecimen method (MSP) over the Pliocene sequence of Apnia (Georgia) which records a polarity reversal. Paleointensity determinations with the multispecimen technique were performed on 12 flows with the original (MSP-DB) and the domain-state corrected (MSP-DSC) protocol. Eight MSP-DSC determinations passed the proposed quality criteria. To obtain highly reliable data through the agreement between intensity values from different methods, MSP results were combined with paleointensities from a previous study with Thellier-type methods and especially strict selection criteria (RCRIT) on same flows (Sánchez-Moreno et al., 2020). Application of this multimethod procedure resulted in three new paleointensities including both MSP and Thellier-type results and an additional one obtained with two different Thellier-type methods, yielding one paleointensity of 36.9 µT in the normal-polarity, and three paleointensities between 19.2 and 24.1 µT in the reverse-polarity section. Additionally, Thellier-type data have been reinterpreted in this study with more flexible criteria (TTP) and the results combined with the MSP data. As a result, four flows yield paleointensities including MSP and Thellier-type determinations and seven include paleointensities obtained with two different Thellier-type methods. Results range from 37.2 and 44.3 μT in the normal-polarity and from 12.5 to 24.6 μT in the reverse-polarity section. Comparison of results from the four flows yielding multimethod determinations applying RCRIT criteria with those from the same flows under TTP criteria yields no significant difference in paleointensity values and their experimental uncertainty. Thus, application of a multimethod approach supports the possibility of using TTP criteria.Project PID2019-105796/10.13039/501100011033 (Agencia Estatal de Investigación, Spain), project BU066U16 (Junta de Castilla y León, Spain) and pre-doctoral grant BES-2013-064060 (MINECO, Spain). MCR acknowledges funding from the Fulbright Commission and the Spanish Ministry of Science, Innovation and Universities for a research stay at Hawaii University at Manoa. AG is grateful to the financial support given by DGAPA-PAPIIT IN101717. At Montpellier laboratory, the FUReMAG rapid furnace construction was supported by the French National Agency for Research (ANR-12-BS06-0015)

Evaluating the safety and dosing of drugs in patients with liver cirrhosis by literature review and expert opinion

INTRODUCTION: Liver cirrhosis can have a major impact on drug pharmacokinetics and pharmacodynamics. Patients with cirrhosis often suffer from potentially preventable adverse drug reactions. Guidelines on safe prescribing for these patients are lacking. The aim of this study is to develop a systematic method for evaluating the safety and optimal dosage of drugs in patients with liver cirrhosis. METHODS AND ANALYSIS: For each drug, a six-step evaluation process will be followed. (1) Available evidence on the pharmacokinetics and safety of a drug in patients with liver cirrhosis will be collected from the Summary of Product Characteristics (SmPC) and a systematic literature review will be performed. (2) Data regarding two outcomes, namely pharmacokinetics and safety, will be extracted and presented in a standardised assessment report. (3) A safety classification and dosage suggestion will be proposed for each drug. (4) An expert panel will discuss the validity and clinical relevance of this suggested advice. (5) Advices will be implemented in all relevant Clinical Decision Support Systems in the Netherlands and published on a website for patients and healthcare professionals. (6) The continuity of the advices will be guaranteed by a yearly check of new literature and comments on the advices. This protocol will be applied in the evaluation of a selection of drugs: (A) drugs used to treat (complications of) liver cirrhosis, and (B) drugs frequently prescribed to the general population. ETHICS AND DISSEMINATION: Since this study does not directly involve human participants, it does not require ethical clearance. Besides implementation on a website and in clinical decision support systems, we aim to publish the generated advices of one or two drug classes in a peer-reviewed journal and at conference meetings

An Integrated Paleomagnetic, Multimethod- Paleointensity, and Radiometric Study on Cretaceous and Paleogene Lavas From the Lesser Caucasus: Geomagnetic and Tectonic Implications

Sixteen rhyolitic and dacitic Cretaceous and Paleocene-Eocene lavas from the Lesser Caucasus have been subjected to paleomagnetic and multimethod paleointensity experiments to analyze the variations of the Earth's magnetic field. Paleointensity experiments were performed with two methods. Thellier-type experiments with the IZZI method on 65 specimens (nine flows) yielded 15 successful determinations and experiments with the multispecimen method on 14 samples (seven flows) yielded two successful determinations. The joint analysis of the results obtained with both methods produced a mean FuK = (19.9 ± 3.7) µT for upper Cretaceous and FPg = (20.7 ± 3.3) µT for Paleogene sites. Low virtual axial dipole moments for the Cretaceous (3.4 × 1022 Am2) and Paleogene (3.5 × 1022 Am2) samples support the idea of a lower average dipole moment during periods of stable polarity of the Earth magnetic field. Mean flow paleomagnetic directions did not match expected upper Cretaceous to Paleogene directions calculated from the European Apparent Polar Wander Path. While inclination results roughly agreed with expected values, a group of sites showed nearly North-South paleodeclinations (D = 1.1° ± 14.2°), and another group displayed eastward deviated paleodeclinations (D = 72.9° ± 26.6°). These results suggest the occurrence of nearly vertical-axis rotations, probably as a result of continental collision since Oligocene. In addition to paleomagnetic and palaeointensity analyses, new K-Ar absolute age determinations have been performed on three of the studied sites, yielding Late Cretaceous ages (78.7 ± 1.7, 79.7 ± 1.6, and 83.4 ± 1.8 Ma (2σ)).Project PID2019-105796GB-100/AEI/10.13039/501100011033 (Agencia Estatal de Investigación, Spain). M. Calvo-Rathert acknowledges funding from the Fulbright Commission and the Spanish Ministry of Science, Innovation, and Universities for a research stay at Hawaii University at Manoa. A. Goguitchaichvili acknowledges financial support from UNAM-PAPIIT no. IN101920. N. García-Redondo acknowledges financial support from Junta de Castilla y León and the European Research Development Fund (ERDF). EHB acknowledges financial support for laboratory maintenance and measurements to SOEST-HIGP and National Science Foundation grants. These is SOEST 11143 and HIGP 2420 contribution