Serum Monitoring and Phenotype Identification of Stage I Non-Small Cell Lung Cancer Patients.

A stage I non-small cell lung cancer (NSCLC) serum profiling platform is presented which is highly efficient and accurate. Test sensitivity (0.95) for stage I NSCLC is the highest reported so far. Test metrics are reported for discriminating stage I adenocarcinoma vs squamous cell carcinoma subtypes. Blinded analysis identified 23 out of 24 stage I NSCLC and control serum samples. Group-discriminating mass peaks were targeted for tandem mass spectrometry peptide/protein identification, and yielded a lung cancer phenotype. Bioinformatic analysis revealed a novel lymphocyte adhesion pathway involved with early-stage lung cancer.

Distinguishing patients with stage I lung cancer versus control individuals using serum mass profiling.

Serum mass profiling can discern physiological changes associated with specific disease states and their progression. Sera (86 total) from control individuals and patients with stage I nonsmall cell lung cancer or benign small pulmonary nodules were discriminated retrospectively by serum changes discerned by mass profiling. Control individuals were distinguished from patients with Stage I lung cancer or benign nodules with test sensitivities of 89% and 83%. Lung cancer patients versus those with benign nodules were distinguished with 80% sensitivity. This study exhibits progress toward a minimally-invasive aid in early detection of lung cancer and monitoring small pulmonary nodules for malignancy.

Physical Compatibility of Cefiderocol with Selected Intravenous Drugs During Simulated Y-site Administration.

The physical compatibility of cefiderocol for injection (prepared as a diluted 2% cefiderocol solution) with potential co-administration drug products is presented. The compatibility of cefiderocol with a selection of 91 intravenous drugs was tested at clinically relevant concentrations using the admixed volume ratio 1:1. Compatibility of the mixtures was determined by visual observations, turbidity, and particulate-matter measurements. The mixtures were examined immediately after mixing, and then at 1 hour and 4 hours thereafter at room temperature. When using 0.9% sodium chloride or 5% dextrose injection for diluents, solutions of dobutamine hydrochloride, esomeprazole sodium, methylprednisolone acetate, propofol, rocuronium bromide, amiodarone hydrochloride, famotidine, labetalol hydrochloride, mycophenolate mofetil, acyclovir sodium, amphotericin B, caspofungin acetate, doxycycline, posaconazole, diphenhydramine hydrochloride, and phenytoin sodium were found to cause visible cloudiness upon mixing with 2% cefiderocol in both diluents. Solutions of lorazepam, tobramycin sulfate, and vancomycin hydrochloride were determined incompatible by examining the mixtures with the aid of a Tyndall light. These 19 drugs were clearly incompatible with cefiderocol for injection by visual examination. In addition, solutions of iron sucrose and albumin were incompatible with 2% cefiderocol based on sub-visual tests for turbidity and/or particulate matter. Based on sub-visual data, the 0.9% sodium chloride admixture of aminophylline and 2% cefiderocol was incompatible, while inconclusive results were obtained for the 0.9% sodium chloride admixtures of 2% cefiderocol with amikacin sulfate. Similarly, the 5% dextrose admixtures of either ciprofloxacin or polymyxin B sulfate with 2% cefiderocol were incompatible, whereas data for phenylephrine hydrochloride morphine sulfate, or undiluted sodium bicarbonate were inconclusive. Overall, the 2% cefiderocol solution was physically compatible with 63 of 91 drugs challenged at 1:1 volume ratio in both 0.9% sodium chloride and 5% dextrose diluents for at least 4 hours at the concentrations tested in this study.

COVID-19 antibody seroprevalence in Santa Clara County, California.

BACKGROUND: Measuring the seroprevalence of antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is central to understanding infection risk and fatality rates. We studied Coronavirus Disease 2019 (COVID-19)-antibody seroprevalence in a community sample drawn from Santa Clara County. METHODS: On 3 and 4 April 2020, we tested 3328 county residents for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to SARS-CoV-2 using a rapid lateral-flow assay (Premier Biotech). Participants were recruited using advertisements that were targeted to reach county residents that matched the county population by gender, race/ethnicity and zip code of residence. We estimate weights to match our sample to the county by zip, age, sex and race/ethnicity. We report the weighted and unweighted prevalence of antibodies to SARS-CoV-2. We adjust for test-performance characteristics by combining data from 18 independent test-kit assessments: 14 for specificity and 4 for sensitivity. RESULTS: The raw prevalence of antibodies in our sample was 1.5% [exact binomial 95% confidence interval (CI) 1.1-2.0%]. Test-performance specificity in our data was 99.5% (95% CI 99.2-99.7%) and sensitivity was 82.8% (95% CI 76.0-88.4%). The unweighted prevalence adjusted for test-performance characteristics was 1.2% (95% CI 0.7-1.8%). After weighting for population demographics, the prevalence was 2.8% (95% CI 1.3-4.2%), using bootstrap to estimate confidence bounds. These prevalence point estimates imply that 53 000 [95% CI 26 000 to 82 000 using weighted prevalence; 23 000 (95% CI 14 000-35 000) using unweighted prevalence] people were infected in Santa Clara County by late March-many more than the ∼1200 confirmed cases at the time. CONCLUSION: The estimated prevalence of SARS-CoV-2 antibodies in Santa Clara County implies that COVID-19 was likely more widespread than indicated by the number of cases in late March, 2020. At the time, low-burden contexts such as Santa Clara County were far from herd-immunity thresholds.

Physical and chemical stability of esomeprazole sodium solutions.

BACKGROUND: Esomeprazole sodium (Nexium IV, AstraZeneca) is the S-isomer of omeprazole and acts as a proton pump inhibitor gastric antisecretory agent indicated for the short-term treatment of gastroesophageal reflux disease in patients with a history of erosive esophagitis. Currently, there is no information on the long-term stability of esomeprazole sodium in infusion solutions beyond 12 hours. OBJECTIVE: To evaluate the stability of esomeprazole sodium in 5% dextrose, 0.9% sodium chloride, and lactated Ringer's injection, at 2 concentrations, at room temperature and when refrigerated. METHODS: Triplicate samples of esomeprazole 0.4 and 0.8 mg/mL as the sodium salt were prepared in the solutions required. Stability evaluations were performed initially, over 2 days stored at 23 degrees C, and over 5 days stored at 4 degrees C. Physical stability was assessed using turbidimetric and particulate measurement, as well as visual observation. Chemical stability was evaluated by stability-indicating high-performance liquid chromatography. RESULTS: The samples in all 3 infusion solutions were physically stable throughout the study. None of the samples had evidence of visible haze or particulates. Most samples developed a slight yellow discoloration within 24 hours, but this discoloration was not accompanied by an excessive loss of drug content. The esomeprazole sodium samples in all 3 infusion solutions exhibited less than 7% loss over 2 days at 23 degrees C and over 5 days at 4 degrees C. CONCLUSIONS: Esomeprazole 0.4 and 0.8 mg/mL as the sodium salt in the infusion solutions tested is chemically and physically stable for at least 2 days at room temperature and 5 days under refrigeration.

Physical and chemical stability of palonosetron hydrochloride with five opiate agonists during simulated Y-site administration.

PURPOSE: The physical and chemical compatibility of palonosetron hydrochloride with fentanyl citrate, hydromorphone hydrochloride, meperidine hydrochloride, morphine sulfate, and sufentanil citrate during simulated Y-site administration was studied. METHODS: Test samples were prepared in triplicate by mixing 7.5-mL samples of undiluted palonosetron 50 microg/mL (of palonosetron) with 7.5-mL samples of fentanyl citrate 50 microg/mL, morphine sulfate 15 mg/mL, hydromorphone hydrochloride 0.5 mg/mL, meperidine hydrochloride 10 mg/mL, and sufentanil citrate 12.5 microg/mL (of sufentanil) per milliliter individually in colorless 15-mL borosilicate glass screw-cap culture tubes with polypropylene caps. Physical stability of the admixtures was assessed by visual examination and by measuring turbidity and particle size and content. Chemical stability was assessed by stability-indicating high-performance liquid chromatography. Evaluations were performed immediately and one and four hours after mixing. RESULTS: All of the admixtures were initially clear and colorless in normal fluorescent room light and when viewed with a high-intensity monodirectional light (Tyndall beam) and were essentially without haze. Changes in turbidity were minor throughout the study. Particulates measuring 10 microm or larger were few in all samples throughout the observation period. The admixtures remained colorless throughout the study. No loss of palonosetron hydrochloride occurred with any of the opiate agonists tested over the four-hour period. Similarly, little or no loss of the opiate agonists occurred over the four-hour period. CONCLUSION: Palonosetron hydrochloride was physically and chemically stable with fentanyl citrate, hydromorphone hydrochloride, meperidine hydrochloride, morphine sulfate, and sufentanil citrate during simulated Y-site administration.

Pharmacogenomics for the forensic toxicologist.

Pharmacogenomics is the study of the linkage between an individual's genotype and the disposition of drugs in the body. The first association between adverse drug reactions and inherited variations was recognized in the 1950s, and since then, pharmacogenomics has come a long way. The importance of pharmacogenomics is accentuated by the incidence of adverse drug reactions, which may account for hospital expenditures of up to 5.6 billion dollars annually. Interindividual variations in drug metabolism are often the result of genetic variants or genetic polymorphisms, and polymorphisms have been known to alter the relationship between dose and plasma drug concentration. Drug disposition can be affected by polymorphisms in drug metabolizing enzymes, drug transport proteins, and drug targets. The cytochrome P450 (CYP) enzymes are responsible for the metabolism of a large number of drugs. Polymorphisms of the CYP enzymes have been well documented, and CYP2D6 is the most polymorphic CYP enzyme. However, there is a relative dearth of research on the role of transport proteins and drug targets. This review attempts to provide a brief synopsis of the pharmacogenomics of some common drug-metabolizing enzymes, transport proteins, and targets. The examples of tramadol, methadone, and oxycodone are used to illustrate the potential role of pharmacogenomics in forensic toxicology. Pharmacogenomics may present a practicable hypothesis in cases of incongruence between dose and plasma drug concentration, and the possibility of genotype-mediated drug plasma levels needs to be considered.

Topical Metered-dosing Dispenser Performance Evaluation.

Topical metered-dosing dispensers are designed for dosing accuracy and ease-of-use by the patients while protecting the packaged products from environmental exposure and contamination. The objective of this study was to evaluate the accuracy, precision, and residual of available topical metered-dosing dispensers with different types of topical cream for practical application. Triplicate samples of five different dispensers were tested. This test was completed using three types of commercial topical cream-bases of dissimilar Total Active Pharmaceutical Ingredient Load Percentages, Transdermal Penetration Percentages, and Specific Gravities. The dispensers were evaluated according to specified dose-uniformity criteria for a total dispensing capacity of 30 mL at 0.5 mL per dose for 60 doses. The study shows Topi-CLICK performed with the best precision and accuracy of dosing in comparison to the airless-pump type dispensers. While the dispensing was highly variable with airless pumps and may require calibration for each packaged product, remarkably the performance of Topi-CLICK was not affected by different types of cream-bases and does not require additional metering calibration.

Fatal seizures due to potential herb-drug interactions with Ginkgo biloba.

Alternative therapy including herbal drugs and complementary medicine is becoming increasingly popular. However, the rise in the incidence of herb-drug interactions is causing concern, especially in the absence of warning labels addressing potential adverse effects. We present the case of a 55-year-old male who suffered a fatal breakthrough seizure, with no evidence of non-compliance with his anticonvulsant medications. The autopsy report revealed subtherapeutic serum levels for both anticonvulsants Depakote and Dilantin. Concomitant with his prescribed medications, the decedent was also self-medicating with a cornucopia of herbal supplements and nutraceuticals, prominent among which was Ginkgo biloba. Ginkgo, an herbal extract from the leaves of the Ginkgo biloba tree, has been used medicinally for centuries and has been touted as a cure for a variety of medical conditions. The induction of Cytochrome P450 enzymes by components of herbal drugs has been known to affect the metabolism of various drugs. Dilantin is primarily metabolized by CYP2C9, and secondarily metabolized by CYP2C19. Valproate metabolism is also modulated in part by CYP2C9 and CYP2C19. A recent study revealed significant inductive effect of ginkgo on CYP2C19 activity. CYP2C19 induction by ginkgo could be a plausible explanation for the subtherapeutic levels of Dilantin and Depakote. Additionally, ginkgo nuts contain a potent neurotoxin, which is known to induce seizure activity. Evidence of other herbal drugs diminishing the efficacy of anticonvulsant medication does exist; however, there has been only one other documented instance of ginkgo potentiating seizure activity in the presence of anticonvulsant therapy. Highlighting the potential adverse effects and drug interactions of ginkgo on the packaging of the drug may help prevent inadvertent use in vulnerable individuals.

Stability of admixture containing morphine sulfate, bupivacaine hydrochloride, and clonidine hydrochloride in an implantable infusion system.

Intrathecal infusion is often performed using drug combinations. This study was conducted to evaluate the stability of the admixture of morphine sulfate, bupivacaine hydrochloride, and clonidine hydrochloride when used in an implantable pump under simulated clinical use conditions. SynchroMed implantable pumps were filled with an admixture and incubated at 37 degrees C for a period of 90 days. Drug admixture stored in glass vials at 4 degrees C and at 37 degrees C served as controls. Samples which included pump reservoir and catheter delivered aliquots were collected every 30 days and analyzed for drug concentrations using a stability-indicating HPLC method. All drugs contained in the admixture were stable and the original concentrations remained greater than 96%. Over 90 days, and with the pump at the simulated body temperature of 37 degrees C, there were no evident heat catalyzed or device catalyzed reactions.

A non-fatal case of sodium toxicity.

A non-fatal case of sodium toxicity in a six-year-old boy is presented. Hypernatremia is the clinical term for an excessive concentration of sodium relative to water in the body. The diagnosis of hypernatremia was made at serum sodium (Na(+)) concentrations exceeding 150 mEq/L, and few people have been reported to survive concentrations greater than 160 mEq/L. This case involves a six-year-old boy who was taken to the hospital following a seizure attack, and lab analyses revealed serum sodium (Na(+)) levels of 234 mEq/L and serum chloride (Cl(-)) levels of 205 mEq/L. Clinical tests ruled out diabetes insipidus, dehydration, renal pathology, and other primary causes of hypernatremia. The child's purported history of pica, and the lab results indicating corresponding increases in levels of serum sodium (Na(+)) and serum (Cl(-)), led to a diagnosis of acute sodium toxicity by ingestion of sodium chloride. A search of the boy's house led to the discovery of rock salt in the cabinet and a container of table salt. Extrapolating from the serum sodium (Na(+)) level, it was estimated that the child had ingested approximately four tablespoons of rock salt, leading to the acute toxicity. A literature search revealed that the serum sodium (Na(+)) concentration in the present report was the highest documented level of sodium in a living person.

The essentials of United States Pharmacopeia Chapter <51> antimicrobial effectiveness testing and its application in pharmaceutical compounding.

Antimicrobial preservatives are excipients added to multi-dose containers of both sterile and non-sterile drug products. Antimicrobial preservatives are used primarily to inhibit growth of microbial contamination occurring during the period of use. Demonstration of antimicrobial preservative effectiveness is required for these functional excipients. This article reviews key factors for consideration in the selection of preservatives, principles of the preservative-effectiveness test, and the significance of requirements for preservative-effectiveness testing in the compounding practice.

Quality Control: microbial limit tests for nonsterile pharmaceuticals, part 2.

Cases of contaminated nonsterile products have been reported in increasing numbers. Often, these contaminated products are associated with the presence of objectionable microorganisms. The major contaminants of nonsterile pharmaceutical products and ingredients are bacteria, yeasts, and molds. The combination of parts 1 and 2 of this series of articles provides a thorough examination of microbiological quality testing for nonsterile products.

Quality control analytical methods: microbial limit tests for nonsterile pharmaceuticals, Part 1.

Contamination of pharmaceuticals with microorganisms may lead to deleterious effects on the therapeutic properties of the drug, and may potentially cause injuries to intended recipients. Cases of contaminated nonsterile products have been reported in increasing numbers, and often associated with the presence of objectionable microorganisms. Methods for detection of these organisms are described in three major Pharmacopeias. Their functions and their limitations in the examination of microbiological quality for nonsterile products will be reviewed in this report.

A fatality due to an accidental methadone substitution in a dental cocktail.

A 6-year-old male child was scheduled for a dental procedure requiring conscious sedation. Prior to the procedure, the child was administered a dental cocktail containing chloral hydrate, hydroxyzine, and methadone. After returning from the dentist, the child appeared groggy and was allowed to sleep. A few hours later, he was found unresponsive, and following resuscitation attempts at a local medical center, he was pronounced dead. Toxicological analyses of femoral blood indicated the presence of hydroxyzine at less than 0.54 µg/mL, trichloroethanol (TCE) at 8.3 µg/mL, and methadone at 0.51 µg/mL. No meperidine was detected. The cause of death was reported to be due to the toxic effects of methadone. The toxicological analysis was corroborated by the analysis of the contents of the dental cocktail, which revealed the presence of hydroxyzine, chloral hydrate, and methadone. Residue from a control sample obtained from the same pharmacy, but administered to a different subject, was found to contain hydroxyzine, chloral hydrate, and meperidine. This report represents the first known fatality due to accidental substitution of methadone in a dental cocktail.

Compatibility of ceftaroline fosamil for injection with selected drugs during simulated Y-site administration.

PURPOSE: The physical compatibility of ceftaroline fosamil with commonly used medications and diluents (a total of 73 drugs in 219 admixtures) during simulated Y-site administration was evaluated. METHODS: Duplicate 5-mL samples of ceftaroline fosamil (2.22 mg/mL) in 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's injection were combined at a 1:1 ratio with samples of 73 drugs (diluted or undiluted). Visual examinations were performed with the unaided eye in fluorescent light and with the aid of a Tyndall beam; the turbidity and particulate content of each sample were also measured. The compatibility of ceftaroline fosamil with propofol was evaluated by visually inspecting for emulsion separation and particle formation after centrifugation. All evaluations were performed within 15 minutes of sample preparation and at one and four hours after preparation. RESULTS: Ceftaroline fosamil was physically compatible with 64 drugs in a combination of 196 admixtures for at least four hours, exhibiting color, clarity, turbidity, and microparticle content similar to those of control solutions. Signs of physical incompatibility, including visible precipitation, increased turbidity, and microparticle formation, were observed with 9 drugs in 23 admixtures during the four-hour observation period. CONCLUSION: Of the 73 drugs evaluated, 64 were compatible and 7 were incompatible with ceftaroline fosamil 2.22 mg/mL in 3 standard infusion solutions. Nine drugs in 23 admixtures were observed to exhibit signs of incompatibility with ceftaroline fosamil within four hours of mixing; those drugs should not be simultaneously administered via a Y-site with ceftaroline preparations.

Serum discrimination of early-stage lung cancer patients using electrospray-ionization mass spectrometry.

The goal of this study was to evaluate the usefulness of electrospray ionization-mass spectrometry (ESI-MS) technology to distinguish sera of early-stage lung cancer patients from control individuals. ESI-MS m/z (mass divided by charge) data were generated from sera of 43 non-small cell lung cancer patients (pathological stages I and II) and 21 control individuals. Identifications of m/z peak area significances between cancer and control ESI-MS sera spectra were performed using t-tests. A "leave one out" cross validation procedure, which mimics blinded sera analysis and corrects for "over-fitting" of data, yielded discriminatory cancer versus control distribution p value and ROC curve area value of <0.001 and 0.87, respectively. Analysis without the "leave one out" cross validation procedure yielded a ROC curve area of 0.99 for discrimination of sera from lung cancer patients versus control individuals. Predictive value measurements revealed overall test efficiency and sensitivity for distinguishing sera from lung cancer patients from controls (using "leave one out" cross validation) of 80% and 84%, respectively. ESI-MS serum analysis between control individuals and lung cancer patients who smoked or did not smoke had p values in ranges indicating that smoking effects are not pronounced in our analysis. These studies indicate that ESI-MS analyses of sera from early stage non-small cell lung cancer patients were helpful in distinguishing these patients from control individuals.

Quality-control analytical methods: compounding slow-release pharmaceuticals.

Slow-release dosage forms are designed to release active drugs at slower rates for prolonging drug effects. These unconventional dosage forms are complex drug delivery systems, which require specialized technical knowledge and skills in their formulation. Verification of the compounding process for slow-release oral dosage forms can be accomplished through quality-control testing of pilot batches to ensure acceptable preparation and patient safety.

Applications and sterility of autologous serum eye drops.

Severe dry eye syndrome can adversely affect a patient's quality of life. When preservative-free artificial tear solutions are not adequate to reduce symptons, the patient's own serum can be compounded into eye drops that improve the ocular surface. The aim of our study was to test the sterility of autologous serum eye drops in refrigerator conditions for up to 30 days and in freezer conditions for up to 180 days. It was determined that sterility was maintained throughout this period.

Compatibility and stability of palonosetron hydrochloride and propofol during simulated y-site administration.

Palonosetron hydrochloride is a longer-acting, selective 5-HT3 receptor antagonist that has been approved for prevention of chemotherapy-induced nausea and vomiting and is being evaluated for prevention of postoperative nause and vomiting. The objective of this study was to evaluate the physical and chemical stablity of palonosetron hydrochloride 50 mcg/mL when mixed with undiluted propofol 1% during simulated Y-site administation. Duplicate samples of this mixture were tested. Samples were stored and evaluated for up to 4 hours at room temperature. Physical stability was assessed by visual inspection. Chemical stability was assessed by high-performance liquid chromatographic analysis. All of the admixtures were opaque white when viewed in normal fluorescent room light and when viewed with a Tyndall beam. After centrifugation, no evidence of precipitation was found. The drug concentrations were essentially unchanged in all of the samples throughout the study. Palonosetron hydrochloride is physically and chemically stable when mixed with propofol as undiluted injections during simulated Y-site administration over 4 hours at ambient room temperature.