TV-1380 (AlbuChE) is a novel recombinant fusion protein of mutated butyrylcholinesterase (BChE) that has increased catalytic efficiency for cocaine metabolism compared to wild-type BChE. Intra-muscular injections of TV-1380 (150mg or 300mg) or placebo were administered once weekly to participants (n=66-69 per group) in a randomized, double-blind study to evaluate the ability of TV-1380 to facilitate abstinence in treatment-seeking, cocaine-dependent individuals. The primary endpoint was the proportion of participants achieving abstinence from cocaine during the last three weeks of the 12 week treatment phase, based on daily self-report of "no use" confirmed by urine testing. Although there were no significant differences between the TV-1380 treatment groups and placebo for the primary endpoint, 6% of participants in the 150mg and 300mg TV-1380 groups and no participants in the placebo group achieved abstinence. For the only declared secondary endpoint, there was a dose-dependent increase in the group mean percentage of urine samples testing negative for cocaine metabolites during weeks 5-12 (8.1% and 14.6% for the 150mg and 300mg TV-1380 groups, respectively, compared to 4.7% for the placebo group; p=0.0056 for 300mg vs. placebo). No meaningful differences in adverse events were seen between treatment groups. While the apparent reduction in cocaine use may be of insufficient magnitude to justify further trials of TV-1380 in cocaine dependence, the results argue for development of improved enzymes with greater catalytic activity.

The blood-brain barrier (BBB) largely excludes antibodies from entering the central nervous system, thus limiting the potential of therapeutic antibodies to treat conditions such as neurodegenerative diseases and neuro-psychiatric disorders. Here, we demonstrate that the transport of human antibodies across the BBB in mice can be enhanced by modulating their interactions with the neonatal Fc receptor (FcRn). When M252Y/S254T/T246E substitutions are introduced on the antibody Fc domain, immunohistochemical assays reveal widespread distribution of the engineered antibodies throughout the mouse brain. These engineered antibodies remain specific for their antigens and retain pharmacological activity. We propose that novel brain-targeted therapeutic antibodies can be engineered to differentially engage FcRn for receptor-mediated transcytosis across the BBB in order to improve neurological disease therapeutics in the future.

A selective non-peptide endothelin A (ET_A) receptor antagonist, CI-1020, was administered to cynomolgus monkeys intravenously (iv) for 2 or 4 wk and orally for 4 wk. Groups consisting of 3 animals of each sex received CI-1020 at 1, 5, and 10 mg/kg/hr (iv) or orally at 250, 500, and 750 mg/kg body weight for 4 wk. Control animals received the vehicle only. In a separate experiment, 1 male was infused with 10 mg/kg/hr for 2 wk, and Monastral blue dye was administered iv to facilitate localization of lesions to the vascular walls. One female was administered saline and the dye and served as a control. One female at 1 mg/kg/hr was found dead at week 2, and 1 female at 5 mg/kg/hr was euthanatized during week 4 as a result of severe thigh swelling at the catheter site. Macroscopically, extramural coronary arteries appeared thickened and nodular in the 4-wk iv study in the female found dead at 1 mg/kg/hr, in 1 male and 1 female at 5 mg/kg/hr, and in 2 females at 10 mg/kg/hr. Histologically, Monastral blue pigment trapped in the walls of coronary arteries with arteriopathy was observed in the male treated with CI-1020 at 10 mg/kg/hr for 2 wk. Extramural coronary arteriopathy occurred at all doses in the 4-wk iv study, with higher incidence occurring in females than in males (7 of 9 treated females compared with 3 of 9 treated males). In the oral study, 1 female at 500 mg/kg/day and 1 male and 2 females at 750 mg/kg/day had coronary arteriopathy. Histological changes after 2 wk of treatment were characterized by intimal thickening, fragmentation of the internal elastic lamina, necrosis and edema of the media, and mixed inflammatory-cell infiltrates in the intima, media, and adventitia. After 4 wk of iv administration, arteriopathy was characterized by segmental disruption of the elastic lamina and intimal and medial fibrosis with complete replacement of smooth muscle with fibrous tissue. The adventitia was thickened as a result of fibrosis and mixed or mononuclear inflammatory-cell infiltrates. CI-1020 concentrations were higher in males (1.57 to 29 μg/ml) than in females (0.974 to 24.4 μg/ml) in the iv study. Transient systemic exposure with high maximum plasma concentration (Cmax) (120-352 μg/ml) in the oral study was insufficient to provoke arterial changes of the same magnitude as those noted with continuous iv administration. The regeneration of the media by fibrous tissue and the disruption of the elastic lamina may weaken the arterial wall and increase the susceptibility of the artery to the development of aneurysm.

This randomized, blinded study tested the prophylactic effect of PD156707, a nonpeptide competitiveantagonist of endothelin A receptors, against vasospasm after subarachnoid hemorrhage in dogs.Twenty-two dogs were allocated on day 0 to undergo cerebral angiography followed by injection of arterialblood (0.5 ml/kg) into the cisterna magna. Dogs had central venous catheters implanted for continuousinfusion of drug vehicle (n=10) or PD156707 (n=12). Cisternal blood injection was repeatedon day 2. Drug levels were measured in plasma on days 2, 4, 6, and 7 and in cerebrospinal fluid (CSF) ondays 2 and 7. Angiography was repeated on day 7 to assess vasospasm. After angiography on day 7, acute effects of infusion of PD156707, 100 mg, or drug vehicle on established vasospasm were assessed.Analysis of physiological variables within (analysis of variance) groups across time and between (unpairedt-test) groups at each time showed that drug-treated animals had significantly increased heartrate on day 7 compared to day 0 (p<0.005). Comparison of basilar artery diameters at day 7 showedthat PD156707 significantly decreased the degree of basilar artery vasospasm (placebo: -47±5%reduction [mean±SE] versus PD156707: -28±7%, p<0.05, unpaired t-test). There was, however, significant vasospasm when comparing within groups (paired t-test, placebo: p<0.0001, PD156707: p<0.005). Mean plasma PD156707 levels (322±123 ng/ml) were adequate to block responses of endothelin-1 on endothelin A receptors in vitro although CSF levels (11±7 ng/ml) were substantially lower. Infusionof PD156707 into the basilar artery on day 7 caused a small but significant 10±3% (paired ttest, p<0.01) increase in diameter compared to placebo (3±3% increase, p=0.32). This infusionalso was associated with a substantial increase in CSF drug levels to 19±9 mg/ml. These results suggestthat endothelin A receptors mediate some of the vasospasm that occurs after SAH in dogs and thatblockade of these receptors may be a beneficial treatment for vasospasm.

The purpose of kidney transplantation is to improve the quality of life (QoL) for patients with end-stage renal disease. This study aims to measure QoL in renal transplant patients in Bethlehem and Hebron in Palestine. A descriptive, cross-sectional study was performed on 109 renal transplant patients referred to Palestinian Ministry of Health - primary health-care clinics of Bethlehem and Hebron in Palestine from December 2016 to April 2017, by using Kidney Transplant Questionnaire (KTQ-25) for the assessment of QoL and determining the effect of sociodemographic variables on QoL. The reliability of KTQ-25 was determined to be 0.74 by Cronbach’s alpha method. Data were analyzed by Statistical Package for Social Sciences version 19.0 and descriptive analytic statistics. The mean QoL for kidney transplant patients was 4.02 ± 0.84. The highest score of the KTQ was the appearance dimension (5.40 ± 1.23), whereas the lowest was related to the uncertainty/fear dimension (3.36 ± 1.23). The sample consisted of mostly males (79.8%), and their mean age was (41 ± 24) years. Most were married (81.7%), 45.9% were without work, and 66.1% of kidney donors’ type were biologically blood related. No statistically significant difference was observed (P ≥ 0.05) between the sociodemographic variables and QoL. Surprisingly, the majority of kidney transplant patients (83.3%) were on prednisone. The QoL for kidney transplant patients was moderate. The society, government, family, and medical staff need to support patients to alleviate fear and uncertainty they feel. Furthermore, high reliance on corticosteroids in treatment needs to be reconsidered.

The interest in the development and therapeutic application of long-acting injectable products for chronic or long-term treatments has experienced exponential growth in recent decades. TV-46000 (Uzedy, Teva) is a long-acting subcutaneous (sc) injectable formulation of risperidone, approved for the treatment of schizophrenia in adults. Following sc injection, the copolymers together with risperidone precipitate to form a sc depot under the skin to deliver therapeutic levels of risperidone over a prolonged period of either 1 month or 2 months, depending upon the dose. This work presents the strategy and the results of the physiologically-based pharmacokinetic (PBPK) modeling and establishing of in vitro–in vivo correlation (IVIVC) for the prediction of TV-46000 pharmacokinetic profile in humans, using in vitro release, intravenous (iv), and sc single-dose pharmacokinetic data in beagle dogs. The resulting simulated TV-46000 PK profile in humans showed that the shape of the predicted risperidone and its active metabolite 9-OH-risperidone PK profiles was different from the observed one, thus suggesting that the TV-46000 release profile was species-dependent and cannot be directly extrapolated from dog to human. In conclusion, while level A IVIVC cannot be claimed, this work combining PBPK and IVIVC modeling represents an interesting alternative approach for complex injectable formulations where classical methods are not applicable.