Hyponutrition among newly diagnosed gastric cancer.

OBJECTIVES: This study aims to determine the malnutrition status among Vietnamese patients newly diagnosed with gastric cancer (GC). BACKGROUND: GC remains the top rank of common and deadly diseases. With limited clinical manifestation, most GC patients were diagnosed at late stages when tumor is not radically resected. Malnutrition was associated with poor prognosis of GC, such as prolonged hospitalization, limited treatment efficacy and low survival rate. METHODS: The cross-sectional descriptive study recruited 77 patients newly diagnosed with GC and 90 healthy individuals (HC). The data used for this study were approved by the local Ethical Committee. The data were analysed on STATA 14.0 and GraphPad Prism 8.0. RESULTS: We observed the male dominant distribution in GC cohort and over 65% of GC were firstly diagnosed at advanced stages (III and IV). Anemia was detected in about 50% of GC patients. Hyponutrition was prevalent in newly diagnosed GC. We found the decreased tendency of anemia related indexes from HC to early stages (I and II) and advanced stages (III and IV) of GC patients. CONCLUSION: Anemia and hypoproteinemia occurred frequently among Vietnamese newly diagnosed GC. The nutrition therapy would benefit GC patients (Tab. 4, Fig. 4, Ref. 20).

The diagnostic and prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio on gastric cancer patients.

Gastric cancer (GC) is the remaining concern of cancer-associated health burden. Valuable predictive and prognostic indicators support the early diagnosis and improve outcome. Immune escape and inflammation are important cancer hallmarks. The prognostic and diagnostic value of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) was reported in some cancers. But these cheap and convenient indexes are far from clinical use. Thus, investigation the alteration of those index on GC is needed to impose the use of those indexes in clinic. The study recruited seventy-seven hospitalized patients newly diagnosed with GC and 90 healthy individuals. The clinical and preclinical data of participants were collected from Hospital Information Management system. This study were approved by the Ethical Committee, Vietnam Military Medical University. The data were analyzed on STATA version 14.0 and GraphPad Prism 8.0. The alteration of immunological system was reported by significantly higher white blood cell count, neutrophils, platelets, PLR, and NLR as well as decreased lymphocytes on GC, compared to healthy individuals. Those indexes were elevated on advanced stage GC, compared to early stage GC. Our receiver operating characteristic curve analysis showed the significant specificity and sensitivity of PLR (cutoff 135.0) and NLR (cutoff 2.0) on GC diagnosis with respective area under receiver operating characteristic curve of 84.74% and 85.17%, P < .0001. Besides, our results reported the tendency of increased PLR and NLR and short time from clinical signs to being diagnosed. PLR and NLR have significant specificity and sensitivity in diagnosis and prognosis of GC.

Predicting Food Effects on Oral Extended-Release Drug Products: A Retrospective Evaluation.

Theoretically, the risk of food effects for extended-release (ER) products compared to IR products may be less because: (1) postprandial physiological changes are usually transient and last for 2-3 h only; and (2) the percentage of drug release from an ER product within the first 2-3 h post dose is usually small under both fasted and fed states. The major postprandial physiological changes that can affect oral absorption of ER drugs are delayed gastric emptying and prolonged intestinal transit. Oral absorption of ER drugs under fasted state mainly occurs in large intestine (colon and rectum) while the absorption of ER drugs under fed state occurs in both small and large intestines. We hypothesized that food effects for ER products are mainly caused by intestinal region-dependent absorption and food intake is more likely to increase rather than decrease the exposure of ER products due to a longer transit time and improved absorption in small intestine. For drugs with good absorption from large intestine, food effects on the area under the curve (AUC) of ER products are usually not expected. Our survey of oral drugs approved by the US FDA between 1998-2021 identified 136 oral ER drug products. Among the 136 ER drug products, 31, 6 and 99 products exhibited increased, decreased, and unchanged AUC under fed conditions, respectively. In general, when an ER product exhibits a fasted bioavailability (BA) relative to its corresponding immediate-release (IR) product between 80-125%, regardless the solubility or permeability of drug substances, substantial food effects on the AUC of ER product are generally not expected. If the fasted relative BA data are not available, a high in vitro permeability (i.e., Caco-2 or MDCK cell permeability comparable or higher than that of metoprolol) may inform no food effect on the AUC of an ER product of high-solubility (BCS class I and III) drug.

Combined Oral Contraceptives As Victims of Drug Interactions.

Combined oral contraceptives (COCs) are widely used in women of reproductive age in the United States. Metabolism plays an important role in the elimination of estrogens and progestins contained in COCs. It is unavoidable that a woman using COCs may need to take another drug to treat a disease. If the concurrently used drug induces enzymes responsible for the metabolism of progestins and/or estrogens, unintended pregnancy or irregular bleeding may occur. If the concurrent drug inhibits the metabolism of these exogenous hormones, there may be an increased safety risk such as thrombosis. Therefore, for an investigational drug intended to be used in women with reproductive potential, evaluating its effects on the pharmacokinetics of COCs is important to determine if additional labeling is necessary for managing drug-drug interactions (DDIs) between the concomitant product and the COCs. It is challenging to determine when this clinical drug interaction study is needed, whether an observed exposure change of progestin/estrogen is clinically meaningful, and if the results of a clinical drug interaction study with one COC can predict exposure changes of unstudied COCs to inform labeling. In this review, we summarize the current understanding of metabolic pathways of estrogens and progestins contained in commonly used COCs and known interactions of these COCs as victim drugs and we discuss possible mechanisms of interactions for unexpected results. We also discuss recent advances, knowledge gaps, and future perspectives on this important topic. The review will enhance the understanding of DDIs with COCs and improve the safe and effective use of COCs. SIGNIFICANCE STATEMENT: This minireview provides an overview of the metabolic pathways of ethinyl estradiol and progestins contained in commonly used combined oral contraceptives (COCs) and significant drug interactions of these COCs as victims. It also discusses recent advances, knowledge gaps, future perspectives, and potential mechanisms for unexpected results of clinical drug interaction studies of COCs. This minireview will help the reader understand considerations when evaluating the drug interaction potential with COCs for drugs that are expected to be used concurrently.

Leveraging Clinical Pharmacology Data to Assess Biosimilarity and Interchangeability of Insulin Products.

There is over a hundred years of clinical experience with insulin for the treatment of diabetes. The US Food and Drug Administration (FDA) approved the first insulin biosimilar interchangeable product in 2021 for improving glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Several recombinant insulin products are available in the United States, including the recently approved biosimilar insulins. The approval of the biosimilar insulin products was based on comparative analytical characterizations and comparative pharmacokinetic (PK) and pharmacodynamic (PD) data. The primary objective of this review is to discuss the scientific considerations in the demonstration of biosimilarity of a proposed insulin biosimilar to a reference product and the role of clinical pharmacology studies in the determination of biosimilarity and interchangeability. Euglycemic clamp studies are considered a "gold standard" for insulin PK and PD characterization and have been widely used to determine the time-action profiles of rapid-acting, intermediate-acting, and long-acting insulin products. Clinical pharmacology aspects of study design, including selection of appropriate dose, study population, PK, and PD end points, are presented. Finally, the role of clinical pharmacology studies in the interchangeability assessment of insulin and the regulatory pathways used for insulin and the experience with follow-on insulins and the two recently approved biosimilar insulin products is discussed.

Developing an In Vitro to In Vivo Extrapolation (IVIVE) Model to Predict Human Milk-to-Plasma Drug Concentration Ratios.

Determining the amount of drug transferred into human milk is critical for benefit-risk analysis of taking medication while breastfeeding. In this study, we developed an in vitro and in vivo extrapolation (IVIVE) model to predict human milk/plasma (M/P) drug concentration ratios. Drug unionized fractions at pH 7.0 (Fni,7.0) and 7.4 (Fni,7.4), drug fractions unbound in human plasma (fup) and milk (fum), and in vitro cell permeability in both directions (efflux ratio, ER) were incorporated into the IVIVE model. A multiple regression Emax model was chosen to predict fum from fup and polar surface area (PSA). A total of 97 drugs with experimental ER from Caco-2 cells were used to test the IVIVE model. The M/P ratios predicted by the IVIVE model had a 1.93-fold geometric mean fold error (GMFE) and 72% of predictions were within two-fold error (Pw2FE), which were superior to the performance of previously reported five models. The IVIVE model showed a reasonable prediction accuracy for passive diffusion drugs (GMFE = 1.71-fold, Pw2FE = 82%, N = 50), BCRP substrates (BCRP: GMFE = 1.91-fold, Pw2FE = 60%, N = 5), and substrates of P-gp and BCRP (GMFE = 1.74-fold, Pw2FE = 75%, N = 8) and a lower prediction performance for P-gp substrates (GMFE = 2.51-fold, Pw2FE = 55%, N = 22). By fitting the observed M/P ratios of 39 P-gp substrates, an optimized ER (1.61) was generated to predict the M/P ratio of P-gp substrates using the developed IVIVE model. Compared with currently available in vitro models, the developed IVIVE model provides a more accurate prediction of the drug M/P ratio, especially for passive diffusion drugs. The model performance is expected to be further improved when more experimental fum and ER data are available.

EXOGENOUS Sex Hormones and Sex Hormone Receptor Modulators in COVID-19: Rationale and Clinical Pharmacology Considerations.

Male patients with coronavirus disease 2019 (COVID-19) fare much worse than female patients in COVID-19 severity and mortality according to data from several studies. Because of this sex disparity, researchers hypothesize that the use of exogenous sex hormone therapy and sex hormone receptor modulators might provide therapeutic potential for patients with COVID-19. Repurposing approved drugs or drug candidates at late-stage clinical development could expedite COVID-19 therapy development because their clinical formulation, routes of administration, dosing regimen, clinical pharmacology, and potential adverse events have already been established or characterized in humans. A number of exogenous sex hormones and sex hormone receptor modulators are currently or will be under clinical investigation for COVID-19 therapy. In this review, we discuss the rationale for exogenous sex hormones and sex hormone receptor modulators in COVID-19 treatment, summarize ongoing and planned clinical trials, and discuss some of the clinical pharmacology considerations on clinical study design. To inform clinical study design and facilitate the clinical development of exogenous sex hormones and sex hormone receptor modulators for COVID-19 therapy, clinical investigators should pay attention to clinical pharmacology factors, such as dosing regimen, special populations (i.e., geriatrics, pregnancy, lactation, and renal/hepatic impairment), and drug interactions.

Advancing Estimation of Hepatobiliary Clearances in Physiologically Based Pharmacokinetic Models of Rosuvastatin Using Human Hepatic Concentrations.

PURPOSE: To estimate hepatobiliary clearances of rosuvastatin via simultaneously fitting to reported human positron emission tomography (PET) data in the liver and gallbladder. METHODS: A hepatobiliary model incorporating five intrinsic hepatobiliary clearances (active uptake clearance at the sinusoidal membrane, efflux clearance by passive diffusion through the sinusoidal membrane, influx clearance by passive diffusion through sinusoidal membrane, clearance of biliary excretion at the canalicular membrane, and intercompartment clearance from the intrahepatic bile duct to the gallbladder) and three compartments (liver, intrahepatic bile duct, and gallbladder) was developed to simultaneously fit rosuvastatin liver and gallbladder data from a representative subject reported by Billington et al. (1). Two liver blood supply input functions, arterial input function and dual input function (using peripheral venous as an alternative to portal vein), were assessed. Additionally, the predictive performance between the established model and four reported models trained with only systemic exposure data, was evaluated by comparing simulated liver and gallbladder profiles with observations. RESULTS: The established hepatobiliary model well captured the kinetic profiles of rosuvastatin in the liver and gallbladder during the PET scans. Application of dual input function led to a marked underestimation of liver concentrations at the initial stage after i.v. dosing which cannot be offset by altering model parameter values. The simulated hepatobiliary profiles from three of the reported models demonstrated substantial deviation from the observed data. CONCLUSIONS: The present study highlights the necessity of using hepatobiliary data to verify and improve the predictive performance of hepatic disposition of rosuvastatin.

Impact of injection sites on clinical pharmacokinetics of subcutaneously administered peptides and proteins.

For most approved subcutaneously (SC) administered drug products in the US, the recommended injection sites (i.e., abdomen, thigh, and upper arm) are usually based on experience from phase 3 trials. Relative bioavailability data directly comparing the pharmacokinetics (PK) of different SC injection sites are often not available and the underlying mechanisms that may affect SC absorption have not been systematically investigated. In this study, we surveyed clinical PK data (AUC, Cmax, and Tmax) for SC administered drug products including therapeutic proteins and peptides based on literature and FDA database. The PK data after abdominal injection was used as a reference to determine the relative bioavailability of SC injections to the arm and thigh. The survey retrieved 19 immunoglobulin G (IgGs), 18 peptides/small proteins (molecular weight < 16 kDa), and 8 non-IgG proteins that had available clinical PK data from multiple SC injection sites. Among these, 5 (26%) IgGs, 9 (50%) peptides/small proteins, and 3 (38%) non-IgG proteins, exhibited injection site-dependent PK (i.e. PK differed by injection sites). Correlation analyses revealed that the PK of peptides/small proteins undergoing rapid SC absorption (Tmax ≤ 2 h), elimination (CL/F ≥ 39 L/h) or low plasma protein binding were more sensitive to injection sites. Similarly, non-IgG proteins (molecular weight ≥ 16 kDa) with high CL/F and low Tmax are associated with high risk of injection site-dependent SC absorption. IgGs with T1/2 < 15 days or Tmax < 5 days are more likely to show injection site-dependent SC absorption. Positive charge of the drug molecule (isoelectric point ≥8) may reduce SC absorption from all three injection sites but is not associated with high risk of injection site-dependent SC absorption. In summary, the results suggested that regional differences in pre-systemic catabolism and local SC blood flow potentially contribute injection site-dependent SC absorption of peptides/small proteins while local lymphatic flow and FcRn binding likely contribute to site-dependent SC absorption of IgGs.

Use of Model-Informed Drug Development to Streamline Development of Long-Acting Products: Can These Successes Be Translated to Long-Acting Hormonal Contraceptives?

Long-acting contraceptives are the most effective reversible contraceptive methods. Increasing patients' access to these contraceptives may translate into fewer unintended pregnancies and lead to substantial individual and public health benefits. However, development of long-acting products can be complex and challenging. This review provides (a) an overview of representative development programs for long-acting antipsychotics as cases for conceptual translation to long-acting contraceptives, (b) several case examples on how modeling and simulation have been used to streamline the development of long-acting products, and (c) examples of challenges andopportunities in developing long-acting contraceptives and information on how exposure-response relationships of commonly used progestins may enable regulators and developers to rely on prior findings of effectiveness and safety from an approved contraceptive to streamline the development of long-acting contraceptives. The US Food and Drug Administration is seeking assistance from stakeholders to provide data from studies in which pharmacokinetic and pharmacodynamic or clinical outcomes of hormonal contraceptives were evaluated and not previously submitted.

Biliary Excretion-Mediated Food Effects and Prediction.

Many orally administered drugs with negative food effects (i.e., lower exposure under fed conditions) are often primarily or partially eliminated by biliary excretion. The aim of this study is to assess the potential correlation between a negative food effect and biliary excretion. Correlation analysis was conducted using a training dataset containing 27 drugs which met the following criteria: (1) immediate-release formulations, (2) shows a negative food effect, (3) > 10% biliary clearance, and (4) does not undergo extensive metabolism. A correlation between fed-state biliary clearance (CLb,fed) and fasted-state biliary clearance (CLb,fast) (y = 1.81*x, R2 = 0.68) was observed. The 1.8-fold increase in biliary clearance was then used as a correction factor to improve physiologically based pharmacokinetic (PBPK) prediction of food effects for 12 test drugs. The mean deviations of predicted fed/fasting AUC ratio and Cmax ratio from clinically observed values were reduced from 32.4 to 17.2% and from 63.3 to 54.3%, respectively. In contrast to the positive food effects on most biopharmaceutics classification system (BCS) class II drugs for which food-stimulated bile flow increases drug solubility and absorption, our results suggest that the elimination of biliary excreted drugs is increased by food-stimulated bile flow, resulting in negative food effects.

Navigating sticky areas in transdermal product development.

The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al. (2004) [1]; Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits. While different technical aspects of transdermal system development have been discussed at various industry meetings and scientific workshops, uncertainties have persisted regarding the pharmaceutical industry's conventionally accepted approach for the development and manufacturing of transdermal systems. This review provides an overview of the challenges frequently faced and the industry's best practices for assuring the quality and performance of transdermal delivery systems and topical patches (collectively, TDS). The topics discussed are broadly divided into the evaluation of product quality and the evaluation of product performance; with the overall goal of the discussion to improve, advance and accelerate commercial development in the area of this complex controlled release dosage form.

Maximal Usage Trial: An Overview of the Design of Systemic Bioavailability Trial for Topical Dermatological Products.

Dermatologic diseases can present in varying forms and severity, ranging from the individual lesion and up to almost total skin involvement. Pharmacokinetic assessment of topical drug products has previously been plagued by bioanalytical assay limitations and the lack of a standardized study design. Since the mid-1990's the US Food and Drug Administration has developed and implemented a pharmacokinetic maximal usage trial (MUsT) design to help address these issues. The MUsT design takes into account the following elements: the enrollment of patients rather than normal volunteers, the frequency of dosing, duration of dosing, use of highest proposed strength, total involved surface area to be treated at one time, amount applied per square centimeter, application method and site preparation, product formulation, and use of a sensitive bioanalytical method that has been properly validated. This paper provides a perspective of pre-MUsT study designs and a discussion of the individual elements that make up a MUsT.

Effect of Isomorphous Substitution on the Thermal Decomposition Mechanism of Hydrotalcites.

Hydrotalcites have many important applications in catalysis, wastewater treatment, gene delivery and polymer stabilization, all depending on preparation history and treatment scenarios. In catalysis and polymer stabilization, thermal decomposition is of great importance. Hydrotalcites form easily with atmospheric carbon dioxide and often interfere with the study of other anion containing systems, particularly if formed at room temperature. The dehydroxylation and decomposition of carbonate occurs simultaneously, making it difficult to distinguish the dehydroxylation mechanisms directly. To date, the majority of work on understanding the decomposition mechanism has utilized hydrotalcite precipitated at room temperature. In this study, evolved gas analysis combined with thermal analysis has been used to show that CO2 contamination is problematic in materials being formed at RT that are poorly crystalline. This has led to some dispute as to the nature of the dehydroxylation mechanism. In this paper, data for the thermal decomposition of the chloride form of hydrotalcite are reported. In addition, carbonate-free hydrotalcites have been synthesized with different charge densities and at different growth temperatures. This combination of parameters has allowed a better understanding of the mechanism of dehydroxylation and the role that isomorphous substitution plays in these mechanisms to be delineated. In addition, the effect of anion type on thermal stability is also reported. A stepwise dehydroxylation model is proposed that is mediated by the level of aluminum substitution.

Pharmacokinetics of 1,4-butanediol in rats: bioactivation to gamma-hydroxybutyric acid, interaction with ethanol, and oral bioavailability.

1,4-Butanediol (BD), a substance of abuse, is bioactivated to gamma-hydroxybutyrate (GHB), but its fundamental pharmacokinetics (PK) have not been characterized. Because this bioactivation is partly mediated by alcohol dehydrogenase, we hypothesized that there may also be a metabolic interaction between ethanol (ETOH) and BD. We therefore studied, in rats, the plasma PK of GHB, BD and ETOH each at two intravenous (IV) doses, when each substance was given alone, and when GHB or BD was co-administered with ETOH. Results showed that bioconversion of intravenously administered BD to GHB was complete, and that both GHB and BD exhibited nonlinear PK. Various population PK models were analyzed using NONMEM VI, and the best disposition model was found to include two PK compartments each for BD, an (unmeasured) putative semialdehyde intermediate (ALD), GHB and ETOH, the presence of nonlinear (Michaelis-Menten) elimination for each compound, and several mutual inhibition processes. The most prominent mutual metabolic inhibition was found between ETOH and BD, while that between GHB and ETOH was not significant. In vitro studies using liver homogenates confirmed mutual metabolic inhibitions between GHB and BD. Oral absorption of BD was best described by a first-order process with lag-time and pre-systemic metabolism from BD to ALD. Oral absorption of BD (as BD plus ALD) was rapid and complete. The fraction of the absorbed dose entering the central compartment as BD was 30% for the 1.58 mmol/kg dose and 55% for the 6.34 mmol/kg dose. At 6.34 mmol/kg IV, the onset of loss of righting reflex (LRR) for BD was significantly delayed vs. that produced by GHB (72.0 +/- 9.1 min vs. 6.7 +/- 0.6 min, respectively, p < 0.001), and the total duration of LRR was prolonged for BD vs. GHB (192 +/- 28 min vs. 117 +/- 2 min, respectively, p < 0.05). Relative to IV dosing, oral BD produced similar but more variable LRR effects. These results may provide a quantitative PK framework for the understanding of the toxicokinetics and toxicodynamics of both BD and GHB.

Effects of repeated in vivo inhalant nitrite exposure on gene expression in mouse liver and lungs.

Exposure to inhalant organic nitrites (drugs of abuse commonly known as "poppers") has been reported to enhance tumor growth in mice, but the mechanism is not fully defined. This study examined the effect of repeated in vivo nitrite exposures on gene expression in the mouse liver and lungs using a gene array panel of 94 cancer- and angiogenesis-related genes. Using 2-fold change as a threshold criterion, repeated nitrite exposure was found to alter the expression of 65 and 23 genes in the liver and lungs, respectively. Six genes were significantly upregulated (p

Effects of inhalant nitrites on VEGF expression: a feasible link to Kaposi's sarcoma?

Because inhalant nitrites (commonly known as "poppers") were thought to be rapidly cleared from the body, the lay literature has somewhat downplayed their toxicity. However, scientific reports have documented their immunosuppressive effects in animals, and epidemiological studies have implicated their use with the development of Kaposi's sarcoma (KS) in humans. Because inhalant nitrites are exogenous nitric oxide donors, we hypothesized that these substances of abuse might exert part of their toxicological effects through this biochemical product, which has been shown to alter gene regulation and angiogenesis. In a series of studies, we showed that acute and chronic in vivo exposure to isobutyl nitrite (a representative inhalant nitrite) produced significant tissue-dependent alterations in the expression of a number of cancer- and angiogenesis-related genes in mice. In particular, hepatic mRNA and protein expression of vascular endothelial growth factor (VEGF) was significantly stimulated. The in vivo growth rate of a subcutaneous VEGF-responsive tumor was also shown to be accelerated by inhalant nitrite exposure. Because the development of KS is extensively linked to VEGF and its receptors, the purported link between inhalant nitrites and KS may be explained mechanistically, at least in part, through the stimulation of VEGF expression by these inhalants.

Determination of nitric oxide-donor effects on tissue gene expression in vivo using low-density gene arrays.

Gene array technology has been used to examine gene expression changes following drug treatments, including administration of nitric oxide (NO) donors. High-density arrays represent a powerful and popular method to analyze a large number of genes simultaneously. On the other hand, low-density arrays, available commercially at a lower cost, allow for the use of gene-specific primers, which reduces the risk of cross-hybridization among genes with similar sequence. For certain experiments in which the hypothesis is focused on a selected set of genes, use of low-density arrays might be more productive and cost-effective. Here, we describe our experience using low-density arrays to examine the effect of exposure to the NO-donor isobutyl nitrite on the expression of 23 cancer- and angiogenesis-related genes in mouse tissues. Detailed descriptions of data capture procedures, statistical tests, and confirmation studies using real-time quantitative (RTQ) reverse transcription polymerase chain reaction (RT-PCR) are presented. Three simple statistical methods, namely Student's t test, significant analysis of microarrays (SAM), and permutation adjusted t statistics (PATS), were applied on our gene array data, and their utilities were compared. All three methods yielded concordant results for the most significant genes, namely vascular endothelial growth factor (VEGF), VEGF receptor 3, Smad5, and Smad7. RT-PCR confirmed VEGF upregulation as observed via gene arrays. PATS appeared to be more robust than SAM in handling our small gene array data set. This statistical method, therefore, appears more suited for analyzing low-density gene array data. We conclude that low-density gene array is a useful screening method that can be performed with lower cost and less cumbersome data treatment.