Medical students' perceptions of an artificial intelligence (AI) assisted diagnosing program.

As artificial intelligence (AI) assisted diagnosing systems become accessible and user-friendly, evaluating how first-year medical students perceive such systems holds substantial importance in medical education. This study aimed to assess medical students' perceptions of an AI-assisted diagnostic tool known as 'Glass AI.' Data was collected from first year medical students enrolled in a 1.5-week Cell Physiology pre-clerkship unit. Students voluntarily participated in an activity that involved implementation of Glass AI to solve a clinical case. A questionnaire was designed using 3 domains: 1) immediate experience with Glass AI, 2) potential for Glass AI utilization in medical education, and 3) student deliberations of AI-assisted diagnostic systems for future healthcare environments. 73/202 (36.10%) of students completed the survey. 96% of the participants noted that Glass AI increased confidence in the diagnosis, 43% thought Glass AI lacked sufficient explanation, and 68% expressed risk concerns for the physician workforce. Students expressed future positive outlooks involving AI-assisted diagnosing systems in healthcare, provided strict regulations, are set to protect patient privacy and safety, address legal liability, remove system biases, and improve quality of patient care. In conclusion, first year medical students are aware that AI will play a role in their careers as students and future physicians.

Development of a rapid, sensitive, and selective LC-MS/MS method for quantifying curcumin levels in healthy human urine: Effect of pepper on curcumin bioavailability.

Curcumin (CCM), a culinary spice, is widely consumed for its health benefits for managing oxidative and inflammatory conditions, metabolic syndrome, arthritis, and hyperlipidemia. However, due to its extensive metabolism, the oral bioavailability of CCM is very low. In this study, we developed a rapid, sensitive, and selective assay to examine the hypothesis that piperine improves CCM bioavailability after piperine co-ingestion. We developed a selective, sensitive, and robust LC-MS/MS method to quantify CCM in human urine. The method was linear over a concentration range 0.625-40 ng/mL with LLOQ and LLOD of 0.625 ng/mL and 0.312 ng/mL, respectively. Healthy volunteers have consumed test meals of CCM as turmeric powder with and without black pepper with 1 week wash out. Urine samples were collected for 24 hours and analyzed for CCM excretion. Black pepper increased CCM half-life from 2.2 ± 0.79 h (CCM alone) to 4.5 ± 0.80 h (CCM + pepper). The CCM 24-h urinary excreted amount was higher in individuals consuming CCM + pepper (218.14 ± 94.98 µg) than those who received CCM only (49.45 ± 12.94 µg). This preliminary study indicates that piperine significantly increased CCM oral absorption, reduced systemic clearance, and improved bioavailability.

Renin-Angiotensin System Components and Arachidonic Acid Metabolites as Biomarkers of COVID-19.

Through the ACE2, a main enzyme of the renin-angiotensin system (RAS), SARS-CoV-2 gains access into the cell, resulting in different complications which may extend beyond the RAS and impact the Arachidonic Acid (ArA) pathway. The contribution of the RAS through ArA pathways metabolites in the pathogenesis of COVID-19 is unknown. We investigated whether RAS components and ArA metabolites can be considered biomarkers of COVID-19. We measured the plasma levels of RAS and ArA metabolites using an LC-MS/MS. Results indicate that Ang 1-7 levels were significantly lower, whereas Ang II levels were higher in the COVID-19 patients than in healthy control individuals. The ratio of Ang 1-7/Ang II as an indicator of the RAS classical and protective arms balance was dramatically lower in COVID-19 patients. There was no significant increase in inflammatory 19-HETE and 20-HETE levels. The concentration of EETs was significantly increased in COVID-19 patients, whereas the DHETs concentration was repressed. Their plasma levels were correlated with Ang II concentration in COVID-19 patients. In conclusion, evaluating the RAS and ArA pathway biomarkers could provide helpful information for the early detection of high-risk groups, avoid delayed medical attention, facilitate resource allocation, and improve patient clinical outcomes to prevent long COVID incidence.

Circadian Modulation of the Antioxidant Effect of Grape Consumption: A Randomized Controlled Trial.

Grape consumption acts on the immune system to produce antioxidant and anti-inflammatory effects. Since immune activity demonstrates circadian rhythmicity, with peak activity occurring during waking hours, the timing of grape intake may influence the magnitude of its antioxidant effect. This study followed a 2 × 2 factorial randomized, controlled design wherein healthy men and women (n = 32) consumed either a grape or placebo drink with a high-fat meal in the morning or evening. Urine was collected for measurements of biomarkers of oxidative stress and grape metabolites at baseline and post-meal at hour 1 and hours 1-6. F-2 isoprostane levels showed main effects of time period (baseline < hour 1 < hours 1-6, p < 0.0001), time (a.m. > p.m., p = 0.008) and treatment (placebo > grape, p = 0.05). Total F2-isoprostane excretion expressed as % baseline was higher in the a.m. vs. p.m. (p = 0.004) and in the a.m. placebo vs. all other groups (p < 0.05). Tartaric acid and resveratrol excretion levels were higher in the grape vs. placebo group (p < 0.05) but were not correlated with F-2 isoprostane levels. The findings support a protective effect of grape consumption against morning sensitivity to oxidative stress.

Anti-Inflammatory Effects of Ang-(1-7) Bone-Targeting Conjugate in an Adjuvant-Induced Arthritis Rat Model.

Rheumatoid arthritis (RA) is a chronic inflammatory condition of synovial joints that causes disability and systemic complications. Ang-(1-7), one of the main peptides in the renin-angiotensin (Ang) system (RAS), imposes its protective effects through Mas receptor (MasR) signaling. It has a short half-life, limiting its feasibility as a therapeutic agent. In this study, we evaluated the anti-inflammatory effects of Ang-(1-7)'s novel and stable conjugate (Ang. Conj.) by utilizing its affinity for bone through bisphosphonate (BP) moiety in an adjuvant-induced arthritis (AIA) rat model. The rats received subcutaneous injections of vehicle, plain Ang-(1-7), or an equivalent dose of Ang. Conj. The rats' body weights, paws, and joints' diameters were measured thrice weekly. After 14 days, the rats were euthanized, and the blood and tissue samples were harvested for further analysis of nitric oxide (NO) and RAS components' gene and protein expression. The administration of Ang. Conj. reduced body weight loss, joint edema, and serum NO. Moreover, the Ang. Conj. treatment significantly reduced the classical arm components at peptide, enzyme, and receptor levels while augmenting them for the protective arm. The results of this study introduce a novel class of bone-targeting natural peptides for RA caused by an inflammation-induced imbalance in the activated RAS. Our results indicate that extending the half-life of Ang-(1-7) augments the RAS protective arm and exerts enhanced therapeutic effects in the AIA model in rats.

Recovery of virus-free Almond (Prunus dulcis) cultivars by somatic embryogenesis from meristem undergone thermotherapy.

One of the world's main horticulture problems is the contamination of fruit trees with a variety of plant diseases, especially viral and pseudo-viral diseases. Due to the non-sexual propagation of the trees, these diseases have been transmitted to different parts of the world. The main aim of this study was to obtain a new effective method for virus elimination from almond cultivars, which was performed in two phases. In the first phase, we tested various almond cultivars with ELISA and RT-PCR. The results showed the infection of mother plantlets. So, three types of in vitro thermotherapy treatments were performed on infected plants to make them virus-free. The plantlets obtained from 0.5 mm meristem treated with the first type of thermotherapy (TH1: 8 h at 27 °C and 16 h at 38 °C for 18 days) showed the highest percentage of elimination of ApM, ACLS and TRS viruses. In the second phase, meristems were cultured on MS medium containing 0, 0.5, 1 and 2 mg/L 2,4-D with 1 mg/L TDZ and after two weeks, thermotherapy treatments were performed. The results showed, combining three methods of thermotherapy (TH1), meristem culture and somatic embryogenesis induction from meristem on MS medium supplemented with 0.5 mg/L 2,4-D and 1 mg/L TDZ is the most effective and safe technique for virus eradication without meristem size challenges. The samples that were diagnosed as virus-free were proliferated in temporary immersion bioreactor systems, and rooted to be used for later propagation and establishment of mother healthy orchards.

Bone-Targeted Delivery of Novokinin as an Alternative Treatment Option for Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune inflammatory bone destructive disorder that is orchestrated by multiple systems in the body, including Renin-Angiotensin System (RAS) and arachidonic acid (ArA) pathway. Current therapeutic options are not highly effective and are associated with severe side effects, including cardiovascular complications. Therefore, new safe and effective disease modulators are seriously needed. In this study, we investigate the anti-inflammatory effects of a synthetic peptide, novokinin, through Angiotensin Type (II) receptor (AT2R). Peptide drugs like novokinin suffer from plasma instability and short half-life. Thus, we developed a novel bone targeting novokinin conjugate (Novo Conj). It uses the bone as a reservoir for sustained release and protection from systemic degradation, improving stability and enhancing pharmacological efficacy. We tested Novo Conj's anti-inflammatory effects in adjuvant-induced arthritis (AIA) rat model to prove our hypothesis by measuring various RAS and ArA pathway components. We observed that inflammation causes a significant imbalance in cardioprotective RAS components like ACE2, AT2R, and Ang 1-7 and increases the ArA inflammatory metabolites like hydroxyeicosatetraenoic acids (HETEs). Treatment with novokinin or Novo Conj restores balance in the RAS and favors the production of different epoxyeicosatrienoic acids (EETs), which are anti-inflammatory mediators. This study demonstrated that the bone-targeted delivery improved the stability and enhanced the anti-inflammatory effects of the parent peptide novokinin in AIA. These observations offer an efficacious alternative therapy for managing RA.

Formulation, Characterization, and In Vitro/In Vivo Efficacy Studies of a Novel Liposomal Drug Delivery System of Amphiphilic Jaspine B for Treatment of Synovial Sarcoma.

Sphingomyelin is a cell membrane sphingolipid that is upregulated in synovial sarcoma (SS). Jaspine B has been shown to inhibit sphingomyelin synthase, which synthesizes sphingomyelin from ceramide, a critical signal transducer; however, jaspine B's low bioavailability limits its application as a promising treatment option. To address this shortcoming, we used microfluidics to develop a liposomal delivery system with increased anticancer efficacy. The nano-liposome size was determined by transmission electron microscopy. The jaspine B liposome was tested for its tumor inhibitory efficacy compared to plain jaspine B in in vitro and in vivo studies. The human SS cell line was tested for cell viability using varying jaspine B concentrations. In a mouse model of SS, tumor growth suppression was evaluated during four weeks of treatment (3 times/week). The results show that jaspine B was successfully formulated in the liposomes with a size ranging from 127.5 ± 61.2 nm. The MTT assay and animal study results indicate that jaspine B liposomes dose-dependently lowers cell viability in the SS cell line and effectively suppresses tumor cell growth in the SS animal model. The novel liposome drug delivery system addresses jaspine B's low bioavailability issues and improves its therapeutic efficacy.

Plasma angiotensin peptides as biomarkers of rheumatoid arthritis are correlated with anti-ACE2 auto-antibodies level and disease intensity.

BACKGROUND: This study aimed to explore a correlation between plasma angiotensin II/(1-7) (Ang II/Ang-(1-7)) ratio, anti-ACE2 autoantibodies level and disease activity in rheumatoid arthritis (RA) patients. METHODS: In a pilot study, the plasma level of Ang II, Ang-(1-7), and anti-ACE2 autoantibodies of twelve RA patients (five in active stage and seven in remission) were measured using an LC-MS/MS method and an ELISA kit, respectively. RESULTS: The Ang-(1-7) level was significantly higher in the remission group than in the active RA patients (7.63 ± 2.61 vs. 1.29 ± 0.81 ng/mL). On the contrary, the Ang II level was higher in those with active RA compared to the remission group (5.43 ± 1.82 vs. 0.87 ± 0.16 ng/mL). The mean ELISA score of anti-ACE2 autoantibodies in patients with active RA was significantly higher than patients in remission (1.41 ± 0.11 vs. 1.81 ± 0.11, p < 0.05). CONCLUSION: This study result suggests that the angiotensin peptides concentration and anti-ACE2 autoantibodies levels can be used as biomarkers of RA. This will help clinicians evaluate better treatment success rates and disease prognosis to prevent long-term complications of RA.

Tissue Engineering Through 3D Bioprinting to Recreate and Study Bone Disease.

The applications of 3D bioprinting are becoming more commonplace. Since the advent of tissue engineering, bone has received much attention for the ability to engineer normal bone for tissue engraftment or replacement. While there are still debates on what materials comprise the most durable and natural replacement of normal tissue, little attention is given to recreating diseased states within the bone. With a better understanding of the cellular pathophysiology associated with the more common bone diseases, these diseases can be scaled down to a more throughput way to test therapies that can reverse the cellular pathophysiology. In this review, we will discuss the potential of 3D bioprinting of bone tissue in the following disease states: osteoporosis, Paget's disease, heterotopic ossification, osteosarcoma, osteogenesis imperfecta, and rickets disease. The development of these 3D bioprinted models will allow for the advancement of novel therapy testing resulting in possible relief to these chronic diseases.

Improved pharmacokinetics and bone tissue accumulation of Angiotensin-(1-7) peptide through bisphosphonate conjugation.

The renin-angiotensin system (RAS) has a central role in renal and cardiovascular homeostasis. Angiotensin-(1-7) (Ang1-7), one of the RAS active peptides, exerts beneficial effects through different mechanisms. These biological actions suggest that Ang1-7 is an effective therapeutic agent for treating various diseases associated with activated RAS. However, its short half-life and poor pharmacokinetics restrict its therapeutic utility. Our laboratory has successfully synthesized and characterized an Ang1-7 conjugate (Ang Conj.) with a prolonged half-life and improved pharmacokinetics profile. The Ang Conj. has been prepared by PEGylation of Ang1-7 and conjugation with a bisphosphonate using solid-phase peptide synthesis and characterized by HPLC and mass spectrometer. The compound's stability has been tested in different storage conditions. The bone binding capacity was evaluated using a hydroxyapatite assay. Pharmacokinetic and tissue distribution studies were performed using iodinated peptides in rats. Ang Conj. was synthesized with > 90% purity. Bone mineral affinity testing showed Ang Conj. exhibited significantly higher bone mineral affinity than Ang1-7. The Ang Conj. remained stable for more than a month using all tested storage conditions. The Ang Conj. demonstrated higher affinity to bone, a longer half-life, and better bioavailability when compared with the native peptide. These results support that conjugation of Ang1-7 with bisphosphonate enables it to utilize bone as a reservoir for the sustained delivery of Ang1-7 to maintain therapeutic plasma levels. High chemical stability and about five to tenfold prolongation of Ang Conj. plasma half-life after administrations into rats proves the effectiveness of our approach.

Update on Angiotensin II Subtype 2 Receptor: Focus on Peptide and Nonpeptide Agonists.

Angiotensin II (Ang II) is the most dominant effector component of the renin-angiotensin system (RAS) that generally acts through binding to two main classes of G protein-coupled receptors, namely Ang II subtype 1 receptor (AT1R) and angiotensin II subtype 2 receptor (AT2R). Despite some controversial reports, the activation of AT2R generally antagonizes the effects of Ang II binding on AT1R. Studying AT2R signaling, function, and its specific ligands in cell culture or animal studies has confirmed its beneficial effects throughout the body. These characteristics classify AT2R as part of the protective arm of the RAS that, along with functions of Ang (1-7) through Mas receptor signaling, modulates the harmful effects of Ang II on AT1R in the activated classic arm of the RAS. Although Ang II is the primary ligand for AT2R, we have summarized other natural or synthetic peptide and nonpeptide agonists with critical evaluation of their structure, mechanism of action, and biologic activity. SIGNIFICANCE STATEMENT: AT2R is one of the main components of the RAS and has a significant prospective for mediating the beneficial action of the RAS through its protective arm on the body's homeostasis. Targeting AT2R offers substantial clinical application possibilities for modulating various pathological conditions. This review provided concise information regarding the AT2R peptide and nonpeptide agonists and their potential clinical applications for various diseases.

Targeting the Protective Arm of the Renin-Angiotensin System: Focused on Angiotensin-(1-7).

The in vivo application and efficacy of many therapeutic peptides is limited because of their instability and proteolytic degradation. Novel strategies for developing therapeutic peptides with higher stability toward proteolytic degradation would be extremely valuable. Such approaches could improve systemic bioavailability and enhance therapeutic effects. The renin-angiotensin system (RAS) is a hormonal system within the body essential for the regulation of blood pressure and fluid balance. The RAS is composed of two opposing classic and protective arms. The balance between these two arms is critical for the homeostasis of the body's physiologic function. Activation of the RAS results in the suppression of its protective arm, which has been reported in inflammatory and pathologic conditions such as arthritis, cardiovascular diseases, diabetes, and cancer. Clinical application of angiotensin-(1-7) [Ang-(1-7)], a RAS critical regulatory peptide, augments the protective arm and restores balance hampered by its enzymatic and chemical instability. Several attempts to increase the half-life and efficacy of this heptapeptide using more stable analogs and different drug delivery approaches have been made. This review article provides an overview of efforts targeting the RAS protective arm. It provides a critical analysis of Ang-(1-7) or its homologs' novel drug delivery systems using different administration routes, their pharmacological characterization, and therapeutic potential in various clinical settings. SIGNIFICANCE STATEMENT: Ang-(1-7) is a unique peptide component of the renin-angiotensin system with vast potential for clinical applications that modulate various inflammatory diseases. Novel Ang-(1-7) peptide drug delivery could compensate its lack of stability for effective clinical application.

Drug-Disease Interaction: Effect of Inflammation and Nonsteroidal Anti-Inflammatory Drugs on Cytochrome P450 Metabolites of Arachidonic Acid.

Inflammatory conditions increase cardiovascular (CV) risk. Some nonsteroidal anti-inflammatory drugs (NSAIDs) that are used to treat pain and inflammation are also associated with CV complications. Inflammation, but not NSAIDs, disrupts the balance of vasodilator and vasoconstrictor components of the renin-angiotensin system within the heart. Herein, we report the effect of both inflammation and NSAIDs (rofecoxib, celecoxib, and meloxicam) on the physiologically active cytochrome P450 metabolites of arachidonic acid (ArA) in the rat with adjuvant arthritis. After oral administration of 7 daily therapeutically equivalent doses of NSAIDs or vehicle, the anti-inflammatory response, as well as the ArA metabolites and drug concentrations in plasma, heart and kidneys were assessed. Inflammation in the form of adjuvant arthritis caused a significant tissue-dependent imbalance of ArA metabolites by elevating the ratio of cardiotoxic 20-hydroxyeicosatetraenoic acid over cardioprotective epoxyeicosatrienoic acids in the heart, and reducing the ratio in the kidney. The observed imbalance was augmented by cardiotoxic rofecoxib but not by other examined NSAIDs with known milder cardiotoxicity. The cardio-renal toxicity of NSAIDs with known severe CV side effects may be due to altered cytochrome P450-mediated ArA acid metabolism. The ArA metabolism profile may be a marker of NSAIDs safety and toxicity.

Bone-targeting parathyroid hormone conjugates outperform unmodified PTH in the anabolic treatment of osteoporosis in rats.

Synthetic parathyroid hormone (PTH) is clinically indicated for the treatment of osteoporosis, through its anabolic effects on parathyroid hormone receptors (PTHRs), located on osteoblast cells. However, the bioavailability of PTH for bone cells is restricted by the short half-life of PTH and the widespread distribution of PTHRs in non-skeletal tissues. To impart affinity for mineralized bone surfaces, bisphosphonate (BP)-mediated PTH analogues were synthesized, characterized, and evaluated in vitro and in vivo. The successful synthesis of PTH-PEG-BP was identified on MALDI-ToF mass spectra; bone-targeting potential was evaluated by hydroxyapatite binding test; and receptor bioactivity was assessed in UMR-106 (rat osteosarcoma) cells that constitutively express PTHRs. Therapeutic efficacy was evaluated using ovariectomized rats that remained untreated for 8 weeks to allow development of osteopenia. Those rats then received daily subcutaneous injections of PTH-PEG-BP, thiol-BP vehicle, or unmodified PTH, and compared to sham-operated healthy rats at 0, 4, 8, 12, and 16 weeks. In vivo micro-CT was conducted on the proximal tibial metaphysis to measure microstructural bone parameters, and new bone formation was detected using dynamic labeling. Bone strength was assessed using three-point bending mechanical testing. Our study determined that PTH-PEG-BP conjugates significantly enhanced PTH targeting to the bone matrix while retaining full PTH bioactivity. Moreover, PTH-PEG-BP conjugates significantly increased trabecular bone quality, anabolic bone formation, and improved bone strength over systemically administered PTH alone. We highlight the promise of a novel class of bone-targeting anabolic compound for the treatment of osteoporosis and related bone disorders.

Genetic Transformation of Date Palm Via Microprojectile Bombardment.

Efficient protocols for date palm embryogenic callus and somatic embryo transformation with uidA gene are described in this chapter. The embryogenic callus transformation procedure is 1.6 µm gold particle size coated with 2.5 µg DNA (pAct1-D plasmid), 1100 psi helium pressure, 9 cm target distance, 26 inHg vacuum pressure, 3 mm distance between the rupture disk and macrocarrier, and osmotic pretreatment with 0.4 M mannitol followed by 60 min air desiccation. The somatic embryo transformation procedure is 0.6 µm gold particle size coated with 2.5 µg DNA (pAct1-D plasmid), 1350 psi helium pressure, 6 cm target distance, 28 inHg vacuum pressure, 3 mm distance between the rupture disk and macrocarrier, and osmotic pretreatment with 0.4 M mannitol followed by 60 min air desiccation. Protocols for analysis of the transgenic plantlets have also been described.

Cardiovascular effect of inflammation and nonsteroidal anti-inflammatory drugs on renin-angiotensin system in experimental arthritis.

A co-morbidity of inflammatory conditions is increased cardio-renal risks. Additionally, nonsteroidal anti-inflammatory drugs (NSAIDs) which are used to treat pain and inflammation are also associated with increase in such risks. We hypothesized that inflammation and NSAIDs impose the cardio-renal risk through the activation of the renin-angiotensin-system (RAS), a regulating pathway of the renal and cardiovascular homeostasis. We investigated the effect of adjuvant arthritis and NSAIDs on the RAS. Western blotting and ELISA were used to measure the RAS components. Inflammation caused significant imbalances in the cardiac and renal angiotensin converting enzymes, their biologically active angiotensin peptides (AngII and Ang1-7) and the target proteins involved in the peptide-receptor binding (AngII type 1 and type 2, and Ang1-7 receptor, Mas) toward cardio-renal toxicity. However, 7 days treatment of arthritic animals with NSAIDs (rofecoxib, meloxicam, celecoxib and flurbiprofen) restored the constitutive balances, perhaps due to their anti-inflammatory properties. Inflammation exerts its cardio-renal effects by causing imbalance in the RAS. NSAIDs through their anti-inflammatory effect restore this imbalance. Thus, mechanisms other than imbalances in the RAS may be involved in the NSAIDs cardiotoxicity.

Immune analysis of cry1Ab-genetically modified potato by in-silico analysis and animal model.

The safety of feeding transgenic potato (Solanum tuberosum), resistant to the potato tuber moth, to Wistar rats was examined from an immunological perspective. The genetically modified potato (GMP) was harbouring cry1Ab and nptII genes as target and selectable marker genes, respectively. In-silico analysis reconfirmed that Cry1Ab and NPTII protein sequences have no significant homology to known toxins or known allergens. The Wistar rats were fed a diet containing 20% GMP or its parental control, non-GMP (NGMP), for 90 days. The consumption of GMP food did not affect the growth rate, food intake, food efficiency, and general health status of the rats. There were no significant differences in the serum concentrations of immunoglobulin A (IgA), IgG, IgM, interleukin 6 (IL-6), and IFN-γ between GMP and NGMP-fed rats. Based on such data, it is concluded that the transgenic potato had no adverse effect on immunity functions of Wistar rats.

Disease specific modeling: Simulation of the pharmacokinetics of meloxicam and ibuprofen in disease state vs. healthy conditions.

PURPOSE: Studies have shown altered pharmacokinetic patterns (PK) in patient suffering from acute pain. Thus, we aimed to simulate pharmacokinetics of meloxicam and ibuprofen in pain and pain-free states using a physiological based software program to identify the underlining mechanistic changes for the observed differences. METHOD: Published in vivo data of meloxicam and ibuprofen were used for the simulations. Two drug formulations were studied: a fast dissolving (FD) and regular release (RR) tablet formulation. The oral bioavailability was compared between these formulations in vagally suppressed rats (gastric dysfunction) and a control group. For ibuprofen additional human data of a control and post dental surgery group were used. All simulations were performed using GastroPlus™. The in vivo drug release and PK of all formulations were estimated for both drugs using the software's immediate release (IR) or gastric release (GR) models. RESULT: For meloxicam, the IR model predicted the in vivo absorption in the control group after administration of the FD and RR formulations. When gastric dysfunction was induced, the IR model did not predict absorption while the GR model did for both formulations, FD and RR. For ibuprofen, the predictions were also very close for both formulations, using the IR model for the control group and the GR model for the vagally suppressed condition in rats and humans. CONCLUSIONS: Gastric control of the drug release in pain/disease state was identified as the major factor causing the observed differences in the pharmacokinetics. Computer simulations of disease states can be employed to optimize drug release from dosage forms to overcome the reported shortfalls in the drug absorption.