Cross-cultural equivalence of the Kessler Psychological Distress Scale (K10) across four African countries in a multi-national study of adults.

The Kessler Psychological Distress Scale (K10) has been widely used to screen psychological distress across many countries. However, its performance has not been extensively studied in Africa. The present study sought to evaluate and compare measurement properties of the K10 across four African countries: Ethiopia, Kenya, Uganda, and South Africa. Our hypothesis is that the measure will show equivalence across all. Data are drawn from a neuropsychiatric genetic study among adult participants (N = 9179) from general medical settings in Ethiopia (n = 1928), Kenya (n = 2556), Uganda (n = 2104), and South Africa (n = 2591). A unidimensional model with correlated errors was tested for equivalence across study countries using confirmatory factor analyses and the alignment optimization method. Results displayed 30 % noninvariance (i.e., variation) for both intercepts and factor loadings across all countries. Monte Carlo simulations showed a correlation of 0.998, a good replication of population values, indicating minimal noninvariance, or variation. Items "so nervous," "lack of energy/effortful tasks," and "tired" were consistently equivalent for intercepts and factor loadings, respectively. However, items "depressed" and "so depressed" consistently differed across study countries (R2 = 0) for intercepts and factor loadings for both items. The K10 scale likely functions equivalently across the four countries for most items, except "depressed" and "so depressed." Differences in K10 items were more common in Kenya and Ethiopia, suggesting cultural context may influence the interpretation of some items and the potential need for cultural adaptations in these countries.

Efficacy and tolerability of pharmacotherapy for obsessive-compulsive personality disorder: a systematic review of randomized controlled trials.

INTRODUCTION: Although obsessive-compulsive personality disorder (OCPD) is one of the most prevalent personality disorders, it is one of the least studied. There is debate as to whether pharmacotherapy is efficacious for OCPD. We aimed to systematically evaluate the efficacy and tolerability of pharmacotherapy for OCPD. AREAS COVERED: This systematic review found two randomized controlled trials investigating pharmacotherapy of OCPD. In a study of major depression (n = 308) with comorbid OCPD (n = 71), citalopram was more effective for OCPD than sertraline with fewer drop-outs from treatment. In a small study of OCPD (n = 24), fluvoxamine was more effective than placebo, and there was a low drop-out rate. Risk of bias and quality assessment of these studies was not possible, and findings have very low levels of certainty. EXPERT OPINION: Two studies provide preliminary evidence in support of citalopram and fluvoxamine for OCPD. Further randomized controlled trials are required before firm conclusions can be drawn regarding efficacy of pharmacotherapy for OCPD.

Construct validity and factor structure of the Kessler-10 in South Africa.

BACKGROUND: The Kessler Psychological Distress Scale (K-10) is a short screening tool developed to identify, with good sensitivity, non-specific psychological distress in the general population. Sensitivity and specificity of the K-10 have been examined in various clinical populations in South Africa; however, other psychometric properties, such as construct validity and factor structure, have not been evaluated. We present evidence of the prevalence and severity of psychological distress in an outpatient setting in South Africa and evaluate the internal reliability, construct validity, and factor structure of the K-10 in this population. METHODS: We explored prevalence estimates of psychological distress using previously established cutoffs and assessed the reliability (consistency) of the K-10 by calculating Cronbach's alpha, item-total correlations and omega total and hierarchical coefficients. Construct validity and factor structure of the K-10 were examined through split-sample exploratory factor analysis (EFA) followed by confirmatory factor analysis (CFA), comparing several theoretical models and the EFA. RESULTS: Overall, there was low prevalence of psychological distress in our sample of 2591 adults, the majority of whom were between the ages of 18-44 (77.7%). The K-10 showed good construct validity and reliability, with a Cronbach's alpha of 0.84 and omega total of 0.88. EFA yielded a four-factor solution with likely measurement artifacts. CFA showed that the four-factor model from EFA displayed the best comparative fit indices, but was likely overfitted. The unidimensional model with correlated errors was deemed the best fitting model based on fit indices, prior theory, and previous studies. CONCLUSION: The K-10 displays adequate psychometric properties, good internal reliability, and good fit with a unidimensional-factor structure with correlated errors. Further work is required to determine appropriate cutoff values in different populations and clinical subgroups within South Africa to aid in determining the K-10's clinical utility.

Pharmacotherapy for trichotillomania.

BACKGROUND: Trichotillomania (TTM; hair-pulling disorder) is a prevalent and disabling disorder characterised by recurrent hair-pulling. Here we update a previous Cochrane Review on the effects of medication for TTM. OBJECTIVES: To assess the effects of medication for trichotillomania (TTM) in adults, children and adolescents compared with placebo or other medication. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO, eleven other bibliographic databases, trial registries and grey literature sources (to 26 November 2020). We checked reference lists and contacted subject experts. SELECTION CRITERIA: We selected randomised controlled trials of medication versus placebo or other medication for TTM in adults, children and adolescents. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Twelve studies were included. We identified 10 studies in adults (286 participants) with a mean sample size of 29 participants per trial; one study in children and adolescents (39 participants); and, one study in adults and adolescents (22 participants: 18 adults and 4 adolescents). All studies were single-centre, outpatient trials. Eleven studies compared medication and placebo (334 participants); one study compared two medications (13 participants). Studies were 5 to 13 weeks duration. We undertook meta-analysis only for opioid antagonists as other comparisons contained a single study, or reported insufficient data. Antioxidants versus placebo in adults There was little to no difference in treatment response between antioxidant (35.7%) and placebo groups (28.6%) after six weeks, based on a single trial of silymarin (risk ratio (RR) 2.25, 95% confidence interval (CI) 0.84 to 5.99; 36 participants; low-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (18 participants; low-certainty evidence). Antioxidants versus placebo in adolescents There was little to no difference in treatment response between antioxidant (50%) and placebo groups (25%) after six weeks, based on a single trial of silymarin (RR 2.00, 95% CI 0.28 to 14.20; 8 participants; low-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (8 participants; low-certainty evidence). Antipsychotics versus placebo in adults There may be greater treatment response in the antipsychotic group (85%) compared to the placebo group (17%) after 12 weeks, based on a single trial of olanzapine (RR 5.08, 95% CI 1.4 to 18.37; 25 participants; low-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (25 participants; low-certainty evidence). Cell signal transducers versus placebo in adults There was little to no difference in treatment response between cell signal transducer (42.1%) and placebo groups (31.6%) after 10 weeks, based on a single trial of inositol (RR 1.33, 95% CI 0.57 to 3.11; 38 participants; low-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (38 participants; low-certainty evidence). Glutamate modulators versus placebo in adults There is probably greater treatment response in the glutamate modulator group (56%) compared to the placebo group (16%) after 12 weeks, based on a single trial of N-acetylcysteine (RR 3.5, 95% CI 1.34 to 9.17; 50 participants; moderate-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (50 participants; low-certainty evidence). Glutamate modulators versus placebo in children and adolescents There was little to no difference in treatment response between the glutamate modulator (25%) and placebo groups (21.1%) in children and adolescents, based on a single trial of N-acetylcysteine (RR 1.19, 95% CI 0.37 to 3.77; 39 participants; low-certainty evidence). There was little to no difference in dropouts due to adverse events between glutamate modulator (5%) and placebo (0%) groups, based on a single trial (RR 2.86, 95% CI 0.12 to 66.11; 39 participants; low-certainty evidence). Opioid antagonists versus placebo in adults There may be little to no difference in treatment response between opioid antagonist (37.5%) and placebo groups (25%) after six to eight weeks, based on two studies of naltrexone, but the evidence is very uncertain (RR 2.14, 95% CI 0.25 to 18.17; 2 studies, 68 participants; very low-certainty evidence). No data were available regarding dropouts due to adverse events. Selective serotonin reuptake inhibitors (SSRIs) versus placebo in adults There were no data available for treatment response to SSRIs. There was little to no difference in dropouts due to adverse events in the SSRI group (5.1%) compared to the placebo group (0%) after 6 to 12 weeks, based on two trials of fluoxetine (RR 3.00, 95% CI 0.33 to 27.62; 2 studies, 78 participants; low-certainty evidence). Tricyclic antidepressants (TCAs) with predominantly serotonin reuptake inhibitor (SRI) actions versus placebo in adults There may be greater treatment response in the TCAs with predominantly SRI actions group (40%) compared to the placebo group (0%) after nine weeks, but the evidence is very uncertain, based on a single trial of clomipramine (RR 5.73, 95% CI 0.36 to 90.83; 16 participants; very low-certainty evidence). There may be increased dropouts due to adverse events in the TCAs with predominantly SRI actions group (30%) compared to the placebo group (0%), but the evidence is very uncertain (RR 4.45, 95% CI 0.27 to 73.81; 16 participants; very low-certainty evidence). TCAs with predominantly SRI actions versus other TCAs in adults There may be greater treatment response in the TCAs with predominantly SRI actions group compared to the other TCAs group after five weeks, based on a single trial comparing clomipramine to desipramine (mean difference (MD) -4.00, 95% CI -6.13 to -1.87; 26 participants; low-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (26 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: There was insufficient evidence from meta-analysis to confirm or refute the efficacy of any agent or class of medication for the treatment of TTM in adults, children or adolescents. Preliminary evidence suggests there may be beneficial treatment effects for N-acetylcysteine, clomipramine and olanzapine in adults based on four trials, albeit with relatively small sample sizes.

Revisiting mouse minute virus inactivation by high temperature short time treatment.

In recent years, high temperature short time (HTST) treatment technology has been increasingly adopted for medium treatment to mitigate the potential risk of viral contamination in mammalian cell culture GMP manufacturing facilities. Mouse minute virus (MMV), also called minute virus of mice (MVM), implicated in multiple viral contamination events is commonly used as a relevant model virus to assess the effectiveness of HTST treatment of cell culture media. However, results from different studies vary broadly in inactivation kinetics as well as log reduction factors (LRFs) achieved under given treatment conditions. To determine whether the reported discrepancies stemmed from differences in MMV strains, laboratory-scale HTST devices, medium matrices, and/or experimental designs, we have taken a collaborative approach to systematically assess the effectiveness of HTST treatment for MMV inactivation. This effort was conceptualized based on a media treatment gap analysis conducted by the Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) under the MIT Center for Biomedical Innovation (CBI). Specifically, two different MMV strains were used to evaluate the effectiveness of HTST at various treatment conditions with regard to exposure temperature and hold time duration by two independent laboratories within two different companies. To minimize experimental variations, the two sites used the same batches of MMV stocks, the same commercially purchased medium, and the same model of thermocyclers as the laboratory-scale HTST device. The two independent laboratories yielded similar MMV inactivation kinetics and comparable LRF. No significant differences were observed between the two MMV strains evaluated, suggesting that the variations from prior studies were likely due to differences in equipment, medium matrices, or other factors. The data presented here indicate that MMV inactivation by HTST treatment obeys first-order kinetics and can be mathematically modeled using an Arrhenius equation. The model-based extrapolation provides a quantitative estimate of MMV inactivation by the current industry standard HTST condition (102°C for a hold time of 10 s) used for medium treatment. Finally, based on the data from the current study and the industry experience, it is recommended that any alternative virus barrier technologies adopted for medium treatment should provide a clearance of at least 3.0 LRF based on a worst-case model virus to effectively mitigate potential risks of viral contamination.

Dissolvable Template Nanoimprint Lithography: A Facile and Versatile Nanoscale Replication Technique.

Nanoimprinting lithography (NIL) is a next-generation nanofabrication method, capable of replicating nanostructures from original master surfaces. Here, we develop highly scalable, simple, and nondestructive NIL using a dissolvable template. Termed dissolvable template nanoimprinting lithography (DT-NIL), our method utilizes an economic thermoplastic resin to fabricate nanoimprinting templates, which can be easily dissolved in simple organic solvents. We used the DT-NIL method to replicate cicada wings which have surface nanofeatures of ∼100 nm in height. The master, template, and replica surfaces showed a >∼94% similarity based on the measured diameter and height of the nanofeatures. The versatility of DT-NIL was also demonstrated with the replication of re-entrant, multiscale, and hierarchical features on fly wings, as well as hard silicon wafer-based artificial nanostructures. The DT-NIL method can be performed under ambient conditions with inexpensive materials and equipment. Our work opens the door to opportunities for economical and high-throughput nanofabrication processes.

Attenuation of Oxidative Injury With Targeted Expression of NADPH Oxidase 2 Short Hairpin RNA Prevents Onset and Maintenance of Electrical Remodeling in the Canine Atrium: A Novel Gene Therapy Approach to Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal because they are not targeted to the molecular mechanisms underlying AF. Using a highly novel gene therapy approach in a canine, rapid atrial pacing model of AF, we demonstrate that NADPH oxidase 2 (NOX2) generated oxidative injury causes upregulation of a constitutively active form of acetylcholine-dependent K+ current (IKACh), called IKH; this is an important mechanism underlying not only the genesis, but also the perpetuation of electric remodeling in the intact, fibrillating atrium. METHODS: To understand the mechanism by which oxidative injury promotes the genesis and maintenance of AF, we performed targeted injection of NOX2 short hairpin RNA (followed by electroporation to facilitate gene delivery) in atria of healthy dogs followed by rapid atrial pacing. We used in vivo high-density electric mapping, isolation of atrial myocytes, whole-cell patch clamping, in vitro tachypacing of atrial myocytes, lucigenin chemiluminescence assay, immunoblotting, real-time polymerase chain reaction, immunohistochemistry, and Masson trichrome staining. RESULTS: First, we demonstrate that generation of oxidative injury in atrial myocytes is a frequency-dependent process, with rapid pacing in canine atrial myocytes inducing oxidative injury through the induction of NOX2 and the generation of mitochondrial reactive oxygen species. We show that oxidative injury likely contributes to electric remodeling in AF by upregulating IKACh by a mechanism involving frequency-dependent activation of PKCε (protein kinase C epsilon). The time to onset of nonsustained AF increased by >5-fold in NOX2 short hairpin RNA-treated dogs. Furthermore, animals treated with NOX2 short hairpin RNA did not develop sustained AF for up to 12 weeks. The electrophysiological mechanism underlying AF prevention was prolongation of atrial effective refractory periods, at least in part attributable to the attenuation of IKACh. Attenuated membrane translocation of PKCε appeared to be a likely molecular mechanism underlying this beneficial electrophysiological remodeling. CONCLUSIONS: NOX2 oxidative injury (1) underlies the onset, and the maintenance of electric remodeling in AF, as well, and (2) can be successfully prevented with a novel, gene-based approach. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.

Insights into virus inactivation by polysorbate 80 in the absence of solvent.

Triton X-100 has long been used either alone or in combination with solvent to inactivate enveloped viruses in biopharmaceutical manufacturing. However, European Chemicals Agency (ECHA) officially placed Triton X-100 on the Annex XIV authorization list in 2017 because 4-(1,1,3,3-tetramethylbutyl) phenol, a degradation product of Triton X-100, is of harmful endocrine disrupting activities. As a result, any use of Triton X-100 in the European Economic Area would require an ECHA issued authorization after the sunset date of January 4, 2021. In search of possible replacements for Triton X-100, we discovered that polysorbate 80 (PS80) in absence of any solvents was able to effectively inactive enveloped viruses such as xenotropic murine leukemia virus and pseudorabies virus with comparable efficacy as measured by log reduction factors. Interestingly, PS80 did not show any virucidal activities in phosphate buffered saline (PBS) while achieving robust virus inactivation in cell-free Chinese hamster ovary (CHO) bioreactor harvests. This intriguing observation led us to speculate that virus inactivation by PS80 involved components in the cell-free CHO bioreactor harvests that were absent in PBS. Specifically, we hypothesized that esterase and/or lipases in the cell-free bioreactor harvests hydrolyzed PS80 to yield oleic acid, a known potent virucidal agent, which in turn inactivated viruses. This theory was confirmed using purified recombinant lysosomal phospholipase A2 isomer (rLPLA2) in PBS. Subsequent characterization work has indicated that virus inactivation by PS80 is effective and robust within temperature and concentration ranges comparable to those of Triton X-100. Similar to Triton X-100, virus inactivation by PS80 is dually dependent on treatment time and temperature. Unlike Triton X-100, PS80 inactivation does not correlate with concentrations in a simple manner. Additionally, we have demonstrated that PS20 exhibits similar virus inactivation activities as PS80. Based on the findings described in the current work, we believe that PS80 is potentially a viable replacement for Triton X-100 and can be used in manufacturing processes for wide spectrum of biopharmaceuticals to achieve desirable virus clearance. Finally, the advantages and disadvantages of using PS80 for virus inactivation are discussed in the contexts of GMP manufacturing.

Gene therapy for atrial fibrillation - How close to clinical implementation?

In this review we examine the current state of gene therapy for the treatment of cardiac arrhythmias. We describe advances and challenges in successfully creating and incorporating gene vectors into the myocardium. After summarizing the current scientific research in gene transfer technology we then focus on the most promising areas of gene therapy, the treatment of atrial fibrillation and ventricular tachyarrhythmias. We review the scientific literature to determine how gene therapy could potentially be used to treat patients with cardiac arrhythmias.

Ultrascalable Multifunctional Nanoengineered Copper and Aluminum for Antiadhesion and Bactericidal Applications.

Biofouling disrupts the surface functionality and integrity of engineered substrates. A variety of natural materials such as plant leaves and insect wings have evolved sophisticated physical mechanisms capable of preventing biofouling. Over the past decade, several reports have pinpointed nanoscale surface topography as an important regulator of surface adhesion and growth of bacteria. Although artificial nanoengineered features have been used to create bactericidal materials that kill adhered bacteria, functional surfaces capable of synergistically providing antiadhesion and bactericidal properties remain to be developed. Furthermore, fundamental questions pertaining to the need for intrinsic hydrophobicity to achieve bactericidal performance and the role of structure length scale (nano vs micro) are still being explored. Here, we demonstrate highly scalable, cost-effective, and efficient nanoengineered multifunctional surfaces that possess both antiadhesion and bactericidal properties on industrially relevant copper (Cu) and aluminum (Al) substrates. We characterize antiadhesion and bactericidal performance using a combination of scanning electron microscopy (SEM), atomic force microscopy (AFM), live/dead bacterial staining and imaging, as well as solution-phase and Petrifilm measurements of bacterial viability. Our results showed that nanostructures created on both Cu and Al were capable of physical deformation of adhered Escherichia coli bacteria. Bacterial viability measurements on both Cu and Al indicated a complex interaction between the antiadhesion and bactericidal nature of these materials and their surface topography, chemistry, and structure. Increased superhydrophobicity greatly decreased bacterial adhesion while not significantly influencing surface bactericidal performance. Furthermore, we observed that more densely packed nanoscale structures improved antiadhesion properties when compared to larger features, even over extended time scales of up to 24 h. Our data suggests that the superhydrophobic Al substrate possesses superior antiadhesion and bactericidal effects, even over long time courses. The techniques and insights presented here will inform future work on antiadhesion and bactericidal multifunctional surfaces and enable their rational design.

Transformation of Sintered CsPbBr3 Nanocrystals to Cubic CsPbI3 and Gradient CsPbBrxI3-x through Halide Exchange.

All-inorganic cesium lead halide (CsPbX3, X = Br(-), I(-)) perovskites could potentially provide comparable photovoltaic performance with enhanced stability compared to organic-inorganic lead halide species. However, small-bandgap cubic CsPbI3 has been difficult to study due to challenges forming CsPbI3 in the cubic phase. Here, a low-temperature procedure to form cubic CsPbI3 has been developed through a halide exchange reaction using films of sintered CsPbBr3 nanocrystals. The reaction was found to be strongly dependent upon temperature, featuring an Arrhenius relationship. Additionally, film thickness played a significant role in determining internal film structure at intermediate reaction times. Thin films (50 nm) showed only a small distribution of CsPbBrxI3-x species, while thicker films (350 nm) exhibited much broader distributions. Furthermore, internal film structure was ordered, featuring a compositional gradient within film. Transient absorption spectroscopy showed the influence of halide exchange on the excited state of the material. In thicker films, charge carriers were rapidly transferred to iodide-rich regions near the film surface within the first several picoseconds after excitation. This ultrafast vectorial charge-transfer process illustrates the potential of utilizing compositional gradients to direct charge flow in perovskite-based photovoltaics.

Perceptions and knowledge of voluntary medical male circumcision for HIV prevention in traditionally non-circumcising communities in South Africa.

Voluntary medical male circumcision (VMMC) has been recommended for the prevention of HIV transmission, particularly in sub-Saharan Africa. Uptake of the campaign has been relatively poor, particularly in traditionally non-circumcising regions. This study evaluates the knowledge, attitudes and practices of medical male circumcision (MC) of 104 community members exposed to promotional campaigns for VMMC for five years. Results show that 93% of participants have heard of circumcision and 72% have heard of some health benefit from the practice. However, detailed knowledge of the relationship with HIV infection is lacking: 12.2% mistakenly believed you could not get HIV after being circumcised, while 75.5% believe that a circumcised man is still susceptible and another 12.2% do not know of any relationship between HIV and MC. There are significant barriers to the uptake of the practice, including misperceptions and fear of complications commonly attributed to traditional, non-medical circumcision. However, 88.8% of participants believe circumcision is an acceptable practice, and community-specific promotional campaigns may increase uptake of the service.

Update: Causes and symptoms of sudden cardiac death in young athletes.

Abstract Sudden cardiac death (SCD) is the leading cause of death during exercise. While initial reports suggested that the most common cause of SCD in young athletes was due to hypertrophic cardiomyopathy (HCM), a critical review of investigations in several populations (athletes, non-athletes, military, national, and international) supports that the most common finding at autopsy of young individuals with SCD is actually a structurally normal heart (SNH). This information is vital for sports medicine clinicians, especially with regard to the pre-participation evaluation (PPE) since cardiac death associated with a SNH is likely attributed to disorders such as arrhythmia or ion channel diseases. This comprehensive review explores the causes of SCD, along with the symptoms preceding death, which ultimately may help refine the PPE and maximize the ability to detect potentially lethal disease prior to competition.

A photocleavable masked nuclear-receptor ligand enables temporal control of C.†elegans development.

The development and lifespan of C. elegans are controlled by the nuclear hormone receptor DAF-12, an important model for the vertebrate vitamin D and liver X receptors. As with its mammalian homologues, DAF-12 function is regulated by bile acid-like steroidal ligands; however, tools for investigating their biosynthesis and function in vivo are lacking. A flexible synthesis for DAF-12 ligands and masked ligand derivatives that enable precise temporal control of DAF-12 function was developed. For ligand masking, photocleavable amides of 5-methoxy-N-methyl-2-nitroaniline (MMNA) were introduced. MMNA-masked ligands are bioavailable and after incorporation into the worm, brief UV irradiation can be used to trigger the expression of DAF-12 target genes and initiate development from dauer larvae into adults. The in vivo release of DAF-12 ligands and other small-molecule signals by using photocleavable MMNA-masked ligands will enable functional studies with precise spatial and temporal resolution.

An allosteric Akt inhibitor effectively blocks Akt signaling and tumor growth with only transient effects on glucose and insulin levels in vivo.

The PI3K-Akt pathway is dysregulated in the majority of solid tumors. Pharmacological inhibition of Akt is a promising strategy for treating tumors resistant to growth factor receptor antagonists due to mutations in PI3K or PTEN. We have developed allosteric, isozyme-specific inhibitors of Akt activity and activation, as well as ex vivo kinase assays to measure inhibition of individual Akt isozymes in tissues. Here we describe the relationship between PK, Akt inhibition, hyperglycemia and tumor efficacy for a selective inhibitor of Akt1 and Akt2 (AKTi). In nude mice, AKTi treatment caused transient insulin resistance and reversible, dose-dependent hyperglycemia and hyperinsulinemia. Akt1 and Akt2 phosphorylation was inhibited in mouse lung with EC50 values of 1.6 and 7 µM, respectively, and with similar potency in other tissues and xenograft tumors. Weekly subcutaneous dosing of AKTi resulted in dose-dependent inhibition of LNCaP prostate cancer xenografts, an AR-dependent tumor with PTEN deletion and constitutively activated Akt. Complete tumor growth inhibition was achieved at 200 mpk, a dose that maintained inhibition of Akt1 and Akt2 of greater than 80% and 50%, respectively, for at least 12 hours in xenograft tumor and mouse lung. Hyperglycemia could be controlled by reducing C(max), while maintaining efficacy in the LNCaP model, but not by insulin administration. AKTi treatment was well tolerated, without weight loss or gross toxicities. These studies supported the rationale for clinical development of allosteric Akt inhibitors and provide the basis for further refining of pharmacokinetic properties and dosing regimens of this class of inhibitors.

Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model.

A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecule in particular, compound 17, has potent inhibitory activity against Akt1 and 2 in vivo in a mouse lung and efficacy in a tumor xenograft model.