First-in-Human Study of the Reversible BTK Inhibitor Nemtabrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and B-Cell Non-Hodgkin Lymphoma.

Nemtabrutinib is an orally bioavailable, reversible inhibitor of Bruton tyrosine kinase (BTK) and C481S mutant BTK. We evaluated the safety, pharmacology, and antitumor activity of nemtabrutinib in relapsed/refractory hematologic malignancies. Forty-eight patients with chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (NHL), or Waldenström macroglobulinemia (WM), relapsed/refractory after ≥2 prior therapies were enrolled in the open-label, single-arm, phase I MK-1026-001 study (NCT03162536) to receive nemtabrutinib 5 to 75 mg once daily in 28-day cycles. Dose finding progressed using a 3 + 3 dose escalation design. Primary endpoints were safety and the recommended phase II dose (RP2D). Among 47 treated patients, 29 had CLL, 17 had NHL, and 1 had WM. Grade ≥3 treatment-emergent adverse events occurred in 37 (89%), most commonly neutropenia (11; 23.4%), febrile neutropenia (7; 14.9%), and pneumonia (7; 14.9%). The RP2D was 65 mg daily. An overall response rate of 75% was observed in patients with CLL at 65 mg daily. SIGNIFICANCE: This first-in-human phase I study demonstrates the safety and preliminary efficacy of nemtabrutinib in patients with relapsed/refractory B-cell malignancies. These data support further exploration of nemtabrutinib in larger clinical studies. This article is featured in Selected Articles from This Issue, p. 5.

Implementing the National Heart, Lung, and Blood Institute's Strategic Vision in the Division of Cardiovascular Sciences-2022 Update.

Spurred by the 2016 release of the National Heart, Lung, and Blood Institute's Strategic Vision, the Division of Cardiovascular Sciences developed its Strategic Vision Implementation Plan-a blueprint for reigniting the decline in cardiovascular disease (CVD) mortality rates, improving health equity, and accelerating translation of scientific discoveries into better cardiovascular health (CVH). The 6 scientific focus areas of the Strategic Vision Implementation Plan reflect the multifactorial nature of CVD and include (1) addressing social determinants of CVH and health inequities, (2) enhancing resilience, (3) promoting CVH and preventing CVD across the lifespan, (4) eliminating hypertension-related CVD, (5) reducing the burden of heart failure, and (6) preventing vascular dementia. This article presents an update of strategic vision implementation activities within Division of Cardiovascular Sciences. Overarching and cross-cutting themes include training the scientific workforce and engaging the extramural scientific community to stimulate transformative research in cardiovascular sciences. In partnership with other NIH Institutes, Federal agencies, industry, and the extramural research community, Division of Cardiovascular Sciences strategic vision implementation has stimulated development of numerous workshops and research funding opportunities. Strategic Vision Implementation Plan activities highlight innovative intervention modalities, interdisciplinary systems approaches to CVD reduction, a life course framework for CVH promotion and CVD prevention, and multi-pronged research strategies for combatting COVID-19. As new knowledge, technologies, and areas of scientific research emerge, Division of Cardiovascular Sciences will continue its thoughtful approach to strategic vision implementation, remaining poised to seize emerging opportunities and catalyze breakthroughs in cardiovascular sciences.

The Physiological and Evolutionary Ecology of Sperm Thermal Performance.

Ongoing anthropogenic climate change has increased attention on the ecological and evolutionary consequences of thermal variation. Most research in this field has focused on the physiology and behavior of diploid whole organisms. The thermal performance of haploid gamete stages directly tied to reproductive success has received comparatively little attention, especially in the context of the evolutionary ecology of wild (i.e., not domesticated) organisms. Here, we review evidence for the effects of temperature on sperm phenotypes, emphasizing data from wild organisms whenever possible. We find that temperature effects on sperm are pervasive, and that above normal temperatures in particular are detrimental. That said, there is evidence that sperm traits can evolve adaptively in response to temperature change, and that adaptive phenotypic plasticity in sperm traits is also possible. We place results in the context of thermal performance curves, and encourage this framework to be used as a guide for experimental design to maximize ecological relevance as well as the comparability of results across studies. We also highlight gaps in our understanding of sperm thermal performance that require attention to more fully understand thermal adaptation and the consequences of global change.

A facile synthesis of cysteine-based diketopiperazine from thiol-protected precursor.

l-Cysteine is one of the most promising biomass-based building blocks with great potential applications. Herein, we report a versatile synthetic route to produce cysteine-based 2,5-diketopiperazine (DKP) with good yield from the thiol-ene click reaction of l-cysteine and commercially available acrylates, followed by dimerization of the amino acid intermediates. The achieved DKP diastereomers were successfully separated and fully characterized by spectroscopic methods. Moreover, the chiroptical property of DKP in the presence of various metal ions was investigated by circular dichroism spectroscopy. The potential application of the optically active cysteine-based DKP as a chiral probe for detection of silver ion in water has been demonstrated.

Targeted transgenesis identifies Gαs as the bottleneck in ß2-adrenergic receptor cell signaling and physiological function in airway smooth muscle.

G protein-coupled receptors are the most pervasive signaling superfamily in the body and act as receptors to endogenous agonists and drugs. For ß-agonist-mediated bronchodilation, the receptor-G protein-effector network consists of the ß2-adrenergic receptor (ß2AR), Gs, and adenylyl cyclase, expressed on airway smooth muscle (ASM). Using ASM-targeted transgenesis, we previously explored which of these three early signaling elements represents a limiting factor, or bottleneck, in transmission of the signal from agonist binding to ASM relaxation. Here we overexpressed Gαs in transgenic mice and found that agonist-promoted relaxation of airways was enhanced in direct proportion to the level of Gαs expression. Contraction of ASM from acetylcholine was not affected in Gαs transgenic mice, nor was relaxation by bitter taste receptors. Furthermore, agonist-promoted (but not basal) cAMP production in ASM cells from Gαs-transgenic mice was enhanced compared with ASM from nontransgenic littermates. Agonist-promoted inhibition of platelet-derived growth factor-stimulated ASM proliferation was also enhanced in Gαs mouse ASM. The enhanced maximal ß-agonist response was of similar magnitude for relaxation, cAMP production, and growth inhibition. Taken together, it appears that a limiting factor in ß-agonist responsiveness in ASM is the expression level of Gαs. Gene therapy or pharmacological means of increasing Gαs (or its coupling efficiency to ß2AR) thus represent an interface for development of novel therapeutic agents for improvement of ß-agonist therapy.

Screening assay for blood vessel maturation inhibitors.

In cancer patients, the development of resistance to anti-angiogenic agents targeting the VEGF pathway is common. Increased pericyte coverage of the tumor vasculature undergoing VEGF targeted therapy has been suggested to play an important role in resistance. Therefore, reducing the pericytes coverage of the tumor vasculature has been suggested to be a therapeutic approach in breaking the resistance to and increasing the efficacy of anti-angiogenic therapies. To screen compound libraries, a simple in vitro assay of blood vessel maturation demonstrating endothelial cells and pericytes association while forming lumenized vascular structures is needed. Unfortunately, previously described 3-dimensional, matrix based assays are laborious and challenging from an image and data acquisition perspective. For these reasons they generally lack the scalability needed to perform in a high-throughput environment. With this work, we have developed a novel in vitro blood vessel maturation assay, in which lumenized, vascular structures form in one optical plane and mesenchymal progenitor cells (10T1/2) differentiate into pericyte-like cells, which associate with the endothelial vessels (HUVECs). The differentiation of the 10T1/2 cells into pericyte-like cells is visualized using a GFP reporter controlled by the alpha smooth muscle actin promoter (SMP-8). The organization of these vascular structures and their recruited mural cells in one optical plane allows for automated data capture and subsequent image analysis. The ability of this assay to screen for inhibitors of pericytes recruitment was validated. In summary, this novel assay of in vitro blood vessel maturation provides a valuable tool to screen for new agents with therapeutic potential.

Automatic event detection in lung transplant recipients based on home monitoring of spirometry and symptoms.

OBJECTIVE: The goal of this study was to develop, implement, and test an automated decision system to provide early detection of clinically important bronchopulmonary events in a population of lung transplant recipients following a home monitoring protocol. SUBJECTS AND METHODS: Spirometry and other clinical data were collected daily at home by lung transplant recipients and transmitted weekly to the study data center. Decision rules were developed using wavelet analysis of declines in spirometry and increases in respiratory symptoms from a learning set of patient home data and validated with an independent patient set. RESULTS: Using forced expiratory volume in 1 s or symptoms, the detection captured the majority of events (sensitivity, 80-90%) at an acceptable level of false alarms. On average, detections occurred 6.6-10.8 days earlier than the known event records. CONCLUSIONS: This approach is useful for early discovery of pulmonary events and has the potential to decrease the time required for humans to review large amount of home monitoring data to discover relatively infrequent but clinically important events.

TAS2R activation promotes airway smooth muscle relaxation despite ß(2)-adrenergic receptor tachyphylaxis.

Recently, bitter taste receptors (TAS2Rs) were found in the lung and act to relax airway smooth muscle (ASM) via intracellular Ca(2+) concentration signaling generated from restricted phospholipase C activation. As potential therapy, TAS2R agonists could be add-on treatment when patients fail to achieve adequate bronchodilation with chronic ß-agonists. The ß(2)-adrenergic receptor (ß(2)AR) of ASM undergoes extensive functional desensitization. It remains unknown whether this desensitization affects TAS2R function, by cross talk at the receptors or distal common components in the relaxation machinery. We studied intracellular signaling and cell mechanics using isolated human ASM, mouse tracheal responses, and human bronchial responses to characterize TAS2R relaxation in the context of ß(2)AR desensitization. In isolated human ASM, magnetic twisting cytometry revealed >90% loss of isoproterenol-promoted decrease in cell stiffness after 18-h exposure to albuterol. Under these same conditions of ß(2)AR desensitization, the TAS2R agonist chloroquine relaxation response was unaffected. TAS2R-mediated stimulation of intracellular Ca(2+) concentration in human ASM was unaltered by albuterol pretreatment, in contrast to cAMP signaling, which was desensitized by >90%. In mouse trachea, ß(2)AR desensitization by ß-agonist amounted to 92 ± 6.0% (P < 0.001), while, under these same conditions, TAS2R desensitization was not significant (11 ± 3.5%). In human lung slices, chronic ß-agonist exposure culminated in 64 ± 5.7% (P < 0.001) desensitization of ß(2)AR-mediated dilation of carbachol-constricted airways that was reversed by chloroquine. We conclude that there is no evidence for physiologically relevant cross-desensitization of TAS2R-mediated ASM relaxation from chronic ß-agonist treatment. These findings portend a favorable therapeutic profile for TAS2R agonists for the treatment of bronchospasm in asthma or chronic obstructive lung disease.

Cardiopulmonary exercise function among patients undergoing transcatheter pulmonary valve implantation in the US Melody valve investigational trial.

OBJECTIVES: We assessed the hypothesis that there is an improvement in clinical and physiologic parameters of cardiopulmonary exercise testing (CPET) after implantation of a transcatheter pulmonary valve (TPV). BACKGROUND: Transcatheter pulmonary valve provides a new tool for treating conduit stenosis and regurgitation in patients with right ventricle (RV) to pulmonary artery conduit dysfunction. METHODS: Patients who underwent a TPV placement between January 2007 and January 2010 (N = 150) were investigated with a standardized CPET protocol before and at 6 months after TPV placement. Cardiopulmonary exercise testing was performed on a mechanically braked cycle ergometer with respiratory gas exchange analysis. RESULTS: Six months post TPV, small but statistically significant improvements were observed in the maximum workload (65.0% ± 18.8% to 68.3% ± 20.3% predicted, P < .001) and the ratio of minute ventilation to CO(2) production at the anaerobic threshold (30.8 ± 4.7 to 29.1 ± 4.1, P < .001). There was no significant change in peak oxygen consumption (VO(2)). Patients with pre-TPV hemodynamics consistent with RV dysfunction and patients with a lower pre-TPV peak VO(2) tended to have the greatest improvement in peak VO(2). The correlation between TPV-related improvements in peak VO(2) and baseline clinical variables were weak, however, and these variables could not be used to reliably identify patients likely to have improved peak VO(2) after TPV. CONCLUSION: In patients with RV to pulmonary artery conduit dysfunction, TPV is associated with modest improvement in exercise capacity and gas exchange efficiency during exercise.

MicroRNA let-7 establishes expression of beta2-adrenergic receptors and dynamically down-regulates agonist-promoted down-regulation.

Although ß(2)-adrenergic receptors (ß(2)AR) are expressed on most cell types, mechanisms that establish expression levels and regulate expression by chronic agonist remain unclear. The 3' UTR of ADRB2 has a conserved 8-nucleotide seed region that we hypothesized is targeted by the let-7 family of miRNAs leading to translational repression. In luciferase assays with transfected cells, luc-ß(2)WT3'UTR had decreased expression when cotransfected with let-7f, but a mutated luc-ß(2)3'UTR lacking the seed was unaffected by let-7f; a mutated let-7f also had no effect on luc-ß(2)WT3'UTR expression. ADRB2 mRNA was in greater abundance in immunoprecipitates of Ago2, a core component of the miRNA-induced silencing complex, when cells were transfected with let-7f, but not with a mutated let-7f, indicating a direct interaction with the silencing mechanism. H292 cells transfected with let-7f caused ∼60% decrease in native ß(2)AR expression, but transfection with let-7f-specific locked nucleic acid anti-miRNA increased ß(2)AR expression by ∼twofold. We considered that an increase in let-7f leading to greater repression of translation contributes to agonist-promoted down-regulation. Paradoxically, in cells and in lungs from mice treated in vivo, an ∼50% decrease in let-7f occurs during long-term agonist exposure, indicating a counterregulatory event. Consistent with this notion, let-7f locked nucleic acid transfection caused depressed agonist-promoted down-regulation. Thus, let-7f miRNA regulates baseline ß(2)AR expression and decreases in let-7f evoked by agonist attenuate down-regulation. This positive feedback loop has not previously been described for a G protein-coupled receptor and its miRNA. Methods to decrease let-7f expression in targeted cells may increase therapeutic responses to ß-agonist by increasing ß(2)AR expression or minimizing tachyphylaxis.

Paradoxical attenuation of ß2-AR function in airway smooth muscle by Gi-mediated counterregulation in transgenic mice overexpressing type 5 adenylyl cyclase.

The limiting component within the receptor-G protein-effector complex in airway smooth muscle (ASM) for ß(2)-adrenergic receptor (ß(2)-AR)-mediated relaxation is unknown. In cardiomyocytes, adenylyl cyclase (AC) is considered the "bottleneck" for ß-AR signaling, and gene therapy trials are underway to increase inotropy by increasing cardiac AC expression. We hypothesized that increasing AC in ASM would increase relaxation from ß-agonists, thereby providing a strategy for asthma therapy. Transgenic (TG) mice were generated with approximately two- to threefold overexpression of type 5 AC (AC5) in ASM. cAMP and airway relaxation in response to direct activation of AC by forskolin were increased in AC5-TG. Counter to our hypothesis, isoproterenol-mediated airway relaxation was significantly attenuated (∼50%) in AC5-TG, as was cAMP production, suggesting compensatory regulatory events limiting ß(2)-AR signaling when AC expression is increased. In contrast, acetylcholine-mediated contraction was preserved. G(αi) expression and ERK1/2 activation were markedly increased in AC5-TG (5- and 8-fold, respectively), and ß-AR expression was decreased by ∼40%. Other G proteins, G protein-coupled receptor kinases, and ß-arrestins were unaffected. ß-agonist-mediated airway relaxation of AC5-TG was normalized to that of nontransgenic mice by pertussis toxin, implicating ß(2)-AR coupling to the increased G(i) as a mechanism of depressed agonist-promoted relaxation in these mice. The decrease in ß(2)-AR may account for additional relaxation impairment, given that there is no enhancement over nontransgenic after pertussis toxin, despite AC5 overexpression. ERK1/2 inhibition had no effect on the phenotype. Thus perturbing the ratio of ß(2)-AR to AC in ASM by increasing AC fails to improve (and actually decreases) ß-agonist efficacy due to counterregulatory events.

Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction.

Bitter taste receptors (TAS2Rs) on the tongue probably evolved to evoke signals for avoiding ingestion of plant toxins. We found expression of TAS2Rs on human airway smooth muscle (ASM) and considered these to be avoidance receptors for inhalants that, when activated, lead to ASM contraction and bronchospasm. TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased intracellular calcium ([Ca²(+)](i)) in ASM in a Gßγ-, phospholipase Cß (PLCß)- and inositol trisphosphate (IP3) receptor-dependent manner, which would be expected to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM and dilation of airways that was threefold greater than that elicited by ß-adrenergic receptor agonists. The relaxation induced by TAS2Rs is associated with a localized [Ca²(+)](i) response at the cell membrane, which opens large-conductance Ca²(+)-activated K(+) (BK(Ca)) channels, leading to ASM membrane hyperpolarization. Inhaled bitter tastants decreased airway obstruction in a mouse model of asthma. Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants.

A yeast-based recombinogenic targeting toolset for transgenic analysis of human disease genes.

Transgenic mouse models are valuable resources for analyzing functions of genes involved in human diseases. Mouse models provide critical insights into biological processes, including in vivo visualization of vasculature critical to our understanding of the immune system. Generating transgenic mice requires the capture and modification of large-insert DNAs representing genes of interest. We have developed a methodology using a yeast-bacterial shuttle vector, pClasper, that enables the capture and modification of bacterial artificial chromosomes (BAC)-sized DNA inserts. Numerous improvements and technical advances in the original pClasper vector have allowed greater flexibility and utility in this system. Examples of such pClasper mediated gene modifications include: Claspette-mediated capture of large-insert genomic fragments from BACs-human polycystic kidney disease-1 (PKD1); modification of pClasperA clones by the RareGap method-PKD1 mutations; Claspette-mediated modification of pClasper clones-mouse albumin-1 gene; and, of most relevance to our interest in lymph node vasculature-Claspimer-mediated modification of pClasper clones-high endothelial venule and lymphatic vessel genes. Mice that have been generated with these methods include mice with fluorescent high endothelial venules.

Common ADRB2 haplotypes derived from 26 polymorphic sites direct beta2-adrenergic receptor expression and regulation phenotypes.

BACKGROUND: The beta2-adrenergic receptor (beta2AR) is expressed on numerous cell-types including airway smooth muscle cells and cardiomyocytes. Drugs (agonists or antagonists) acting at these receptors for treatment of asthma, chronic obstructive pulmonary disease, and heart failure show substantial interindividual variability in response. The ADRB2 gene is polymorphic in noncoding and coding regions, but virtually all ADRB2 association studies have utilized the two common nonsynonymous coding SNPs, often reaching discrepant conclusions. METHODOLOGY/PRINCIPAL FINDINGS: We constructed the 8 common ADRB2 haplotypes derived from 26 polymorphisms in the promoter, 5'UTR, coding, and 3'UTR of the intronless ADRB2 gene. These were cloned into an expression construct lacking a vector-based promoter, so that beta2AR expression was driven by its promoter, and steady state expression could be modified by polymorphisms throughout ADRB2 within a haplotype. "Whole-gene" transfections were performed with COS-7 cells and revealed 4 haplotypes with increased cell surface beta2AR protein expression compared to the others. Agonist-promoted downregulation of beta2AR protein expression was also haplotype-dependent, and was found to be increased for 2 haplotypes. A phylogenetic tree of the haplotypes was derived and annotated by cellular phenotypes, revealing a pattern potentially driven by expression. CONCLUSIONS/SIGNIFICANCE: Thus for obstructive lung disease, the initial bronchodilator response from intermittent administration of beta-agonist may be influenced by certain beta2AR haplotypes (expression phenotypes), while other haplotypes may influence tachyphylaxis during the response to chronic therapy (downregulation phenotypes). An ideal clinical outcome of high expression and less downregulation was found for two haplotypes. Haplotypes may also affect heart failure antagonist therapy, where beta2AR increase inotropy and are anti-apoptotic. The haplotype-specific expression and regulation phenotypes found in this transfection-based system suggest that the density of genetic information in the form of these haplotypes, or haplotype-clusters with similar phenotypes can potentially provide greater discrimination of phenotype in human disease and pharmacogenomic association studies.

Targeted transgenesis reveals discrete attenuator functions of GRK and PKA in airway beta2-adrenergic receptor physiologic signaling.

Phosphorylation by protein kinase A (PKA) and G protein-coupled receptor kinases (GRKs) desensitize beta2-adrenergic receptor (beta2AR) signaling, and these are thought to be mechanisms involved with cell and organ homeostasis and tolerance to agonists. However, there is little direct evidence that these events are relevant to beta2AR physiological function, such as airway smooth muscle (ASM) relaxation leading to bronchodilation. To maintain cell- and receptor-specificity without altering the natural complement of kinases/arrestins, transgenic mice were generated expressing the human WT and mutated beta2ARs lacking PKA and/or GRK phosphorylation sites on ASM at approximately 4-fold over background. Functional gains in response to beta-agonist from the selective loss of these mechanisms were determined in mouse airways. Relaxation kinetics were altered in all mutant airways compared with beta2WT. At low receptor occupancy, beta2PKA(-) had enhanced agonist-promoted relaxation, while beta2GRK(-) airways were unaffected. In contrast, at saturating agonist concentrations, the greatest relaxation enhancement was with beta2GRK(-), with no evidence for additivity when PKA sites were also removed. For the full range of responses, the beta2PKA(-)/GRK(-) airways had the greatest relaxation efficiency, indicating a graded effect of GRKs as agonist concentration increased. ASM cAMP levels paralleled relaxation phenotypes. No interaction between PKA phosphorylation of beta2AR and GRK-promoted events was identified by beta-arrestin-2 recruitment. Thus, these two mechanisms indeed impact a relevant beta2AR physiologic function, acting as attenuators of the acute response, and represent specific interfaces where adjunct therapy or biased ligands may improve beta-agonist treatment of obstructive lung disease.

Genital and perianal herpes simplex simulating neoplasia in patients with AIDS.

Genital and perianal herpetic ulcers are common in HIV-infected patients and chronic mucocutaneous ulcers persisting for more than 1 month are the hallmark of active AIDS status. However, atypical clinical manifestations of herpes simplex virus (HSV) may occur in immunocompromised patients presenting as tumor-like nodules or condylomatous or hypertrophic lesions, rather than a classic ulcer. Such unusual presentations raise the risk of misdiagnosis and a delay in appropriate treatment. Here we describe nine immunocompromised HIV-positive patients with CD 4 count ranging from 14-362/mm(3) (mean 170/mm(3)), with unusual tumoral presentation of anogenital herpes. There were six male and three female patients with AIDS with mean duration of HIV infection of 14 years. All of the patients had history of highly active antiretroviral therapy (HAART), with five patients compliant with the therapy at the time of biopsy. Six patients presented with scrotal or vulvar masses and three with perianal nodules. Five patients had adjacent human papilloma virus (HPV)-related lesions. Prior to excision, herpetic lesion was clinically suspected in only three patients and in the rest of the patients a malignant growth was the main clinical concern. The predominant histopathologic finding was dense dermal plasmacytic infiltration with overlying pseudoepitheliomatous hyperplasia, superficial ulcers and classic herpetic inclusions. Patients with AIDS may experience excessive number and size of both primary and reactivated herpetic lesions. The tumoral presentations discussed here are less common, but are often clinically misdiagnosed. It is important to be aware of these unusual presentations to provide a correct diagnosis and prompt, effective treatment for HSV. Several studies suggest that aggressive treatment of HSV in combination with HAART therapy provides a significant survival benefit. Pathobiology mechanisms of unusual and exaggerated tumor-like inflammatory response are not completely elucidated.

Formation and characterization of solid dispersions of piroxicam and polyvinylpyrrolidone using spray drying and precipitation with compressed antisolvent.

Solid dispersions of a poorly water-soluble drug piroxicam in polyvinylpyrrolidone (PVP) were prepared by precipitation with compressed antisolvent (PCA) and spray drying techniques. Physicochemical properties of the products and drug-polymer interactions were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry, etc. Piroxicam was found amorphously dispersed in both solid dispersion systems with the drug to polymer weight ratio of 1:4. Spectra data indicated the formation of hydrogen bonding between the drug and the polymer. Both techniques evaluated in this work resulted in improved dissolution of piroxicam. By comparison, PCA-processed solid dispersions showed distinctly superior performance in that piroxicam dissolved completely within the first 5 min and the dissolution rate was at least 20 times faster than raw drug did within the first 15 min. PCA processing could provide an effective pharmaceutical formulation technology to improve the bioavailability of poorly water-soluble drug.