Successful recovery from COVID‐19 in three kidney transplant recipients who received convalescent plasma therapy

Novel coronavirus disease 2019 (COVID‐19) is a highly infectious, rapidly spreading viral disease that typically presents with greater severity in patients with underlying medical conditions or those who are immunosuppressed. We present a novel case series of three kidney transplant recipients with COVID‐19 who recovered after receiving COVID‐19 convalescent plasma (CCP) therapy. Physicians should be aware of this potentially useful treatment option. Larger clinical registries and randomized clinical trials should be conducted to further explore the clinical and allograft outcomes associated with CCP use in this population.     

Reference region modeling approaches for amphetamine challenge studies with [11C]FLB 457 and PET

Detecting fluctuations in synaptic dopamine levels in extrastriatal brain regions with [¹¹C]FLB 457 and positron emission tomography (PET) is a valuable tool for studying dopaminergic dysfunction in psychiatric disorders. The evaluation of reference region modeling approaches would eliminate the need to obtain arterial input function data. Our goal was to explore the use of reference region models to estimate amphetamine-induced changes in [¹¹C]FLB 457 dopamine D2/D3 binding. Six healthy tobacco smokers were imaged with [¹¹C]FLB 457 at baseline and at 3 hours after amphetamine (0.4  to 0.5 mg/kg, per os) administration. Simplified reference tissue models, SRTM and SRTM2, were evaluated against the 2-tissue compartmental model (2TC) to estimate [¹¹C]FLB 457 binding in extrastriatal regions of interest (ROIs), using the cerebellum as a reference region. No changes in distribution volume were observed in the cerebellum between scan conditions. SRTM and SRTM2 underestimated binding, compared with 2TC, in ROIs by 26% and 9%, respectively, with consistent bias between the baseline and postamphetamine scans. Postamphetamine, [¹¹C]FLB 457 binding significantly decreased across several brain regions as measured with SRTM and SRTM2; no significant change was detected with 2TC. These data support the sensitivity of [¹¹C]FLB 457 for measuring amphetamine-induced dopamine release in extrastriatal regions with SRTM and SRTM2.     

GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice

Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control and weight loss compared with GLP-1R agonism in patients with type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine whether GIPR agonism contributes, we compared the effect of tirzepatide in obese WT and Glp-1r–null mice. In the absence of GLP-1R–induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support of this, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino acids (BCAAs) and ketoacids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid, and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual-receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.     

Studies of the metabotropic glutamate receptor 5 radioligand [11C]ABP688 with N‐acetylcysteine challenge in rhesus monkeys

Detecting changes in receptor binding at the metabotropic glutamate receptor 5 (mGluR5) with the PET allosteric antagonist, [¹¹C]ABP688, may be valuable for studying dysfunctional glutamate transmission associated with psychiatric illnesses. This study was designed to validate the findings of a recent pilot study in baboons which reported a significant global decrease from baseline [¹¹C]ABP688 binding after increasing endogenous glutamate with 50 mg/kg N‐acetylcysteine (NAC), with no change from test to retest. In rhesus monkeys (n = 5), paired [¹¹C]ABP688 scans were performed on the same day on the Focus‐220 as follows (n = 3 per group): test‐retest, baseline‐NAC (50 mg/kg), and baseline‐NAC (100 mg/kg). Multiple modeling methods were evaluated for kinetic analysis to estimate the total volume of distribution (V_T) and non‐displaceable binding potential (BP_ND) in regions‐of‐interest (ROIs), with the cerebellum gray matter (CGM) as the reference region. There was an increasing trend from test to retest BP_ND across ROIs (13%). NAC (50 mg/kg and 100 mg/kg) increased V_T (5% and 19%) and decreased BP_ND (3% and 10%), respectively, significant only for V_T in ROIs at the 100 mg/kg dose. High intersubject variability in BP_ND was comparable to that reported in the baboon study. However, interpretability of BP_ND is difficult with increases in V_T in the CGM reference region at the higher NAC dose. Additionally, the net reduction in BP_ND from the baseline‐NAC scans may be obscured due to observed increases in test‐retest BP_ND. Thus, we did not strictly replicate the findings in the baboon study based on BP_ND. Synapse 67:489–501, 2013. © 2013 Wiley Periodicals, Inc.     

Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor,in combination with gemcitabine in US patients with advanced solid tumors

Purpose

AZD7762 is a Chk1 kinase inhibitor which increases sensitivity to DNA-damaging agents, including gemcitabine. We evaluated the safety of AZD7762 monotherapy and with gemcitabine in advanced solid tumor patients.

Experimental design

In this Phase I study, patients received intravenous AZD7762 on days 1 and 8 of a 14-day run-in cycle (cycle 0; AZD7762 monotherapy), followed by AZD7762 plus gemcitabine 750–1,000 mg/m² on days 1 and 8, every 21 days, in ascending AZD7762 doses (cycle 1; combination therapy).

Results

Forty-two patients received AZD7762 6 mg (n = 9), 9 mg (n = 3), 14 mg (n = 6), 21 mg (n = 3), 30 mg (n = 7), 32 mg (n = 6), and 40 mg (n = 8), in combination with gemcitabine. Common adverse events (AEs) were fatigue [41 % (17/42) patients], neutropenia/leukopenia [36 % (15/42) patients], anemia/Hb decrease [29 % (12/42) patients] and nausea, pyrexia and alanine aminotransferase/aspartate aminotransferase increase [26 % (11/42) patients each]. Grade ≥3 AEs occurred in 19 and 52 % of patients in cycles 0 and 1, respectively. Cardiac dose-limiting toxicities occurred in two patients (both AZD7762 monotherapy): grade 3 troponin I increase (32 mg) and grade 3 myocardial ischemia with chest pain, electrocardiogram changes, decreased left ventricular ejection fraction, and increased troponin I (40 mg). AZD7762 exposure increased linearly. Gemcitabine did not affect AZD7762 pharmacokinetics. Two non-small-cell lung cancer patients achieved partial tumor responses (AZD7762 6 mg/gemcitabine 750 mg/m² and AZD7762 9 mg cohort).

Conclusions

The maximum-tolerated dose of AZD7762 in combination with gemcitabine 1,000 mg/m² was 30 mg. Although development of AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 remains an important therapeutic target.