Oebalus pugnax (Hemiptera: Pentatomidae) resistance to lambda-cyhalothrin in Texas and efficacy of 2 alternative insecticides in grain sorghum.

Along the Coastal Bend of Texas, the rice stink bug, Oebalus pugnax (F.), is a major pest of grain sorghum and rice that is primarily managed by insecticide applications. Reports of rice stink bug resistance to pyrethroids in Texas first surfaced in 2015 and continued to spread. To determine the status of pyrethroid resistance, rice stink bug populations across Texas and Louisiana were evaluated from 2021 to 2023. Mortality was assessed through glass vial exposures to eight concentrations (0, 0.03, 0.1, 0.3, 1, 3, 10, and 30 µg/vial) of a pyrethroid, lambda-cyhalothrin. The concentration of lambda-cyhalothrin required to kill 50% (LC50) of each population was estimated by probit analysis. Furthermore, the efficacy of insecticides, including lambda-cyhalothrin, dimethoate, and dinotefuran, were evaluated in field experiments conducted in 2021. Our results indicated that 14 of the 21 rice stink bug populations sampled were resistant to lambda-cyhalothrin, with LC50 values ranging from 42 to 1,600 times higher than a susceptible population. In the field trial, lambda-cyhalothrin did not control rice stink bugs. Dinotefuran provided excellent control of nymphs, but dimethoate provided greater control of adult rice stink bugs. To our knowledge, this is the first study to thoroughly evaluate the extent or geographic range of pyrethroid resistance in Texas for rice stink bugs.

Longitudinal medication adherence group-based trajectories of aging adults in the US: A retrospective analysis using monthly proportion of days covered calculations.

BACKGROUND: It is thought that half of the patients with chronic conditions are not adherent to their medications, which contributes to significant health and economic burden. Many studies estimate medication non-adherence by implementing a threshold of ≥80% of Proportion of Days Covered (PDC), categorizing patients as either adherent or non-adherent. Healthcare quality metrics pertaining to medication use are based on this dichotomous approach of medication adherence, including the Medicare Part D Star Ratings. Among others, the Medicare Part D Star Ratings rewards part D plan sponsors with quality bonus payments based on this dichotomous categorization of beneficiaries' medication adherence. OBJECTIVES: Describe the longitudinal adherence trajectories of adults ≥65 years of age covered by Medicare for 3 classes of drugs in the Part D Star Ratings: diabetes medications, statins, and select antihypertensives. METHODS: This study used Medicare healthcare administrative claims data linked to participants from the Health Retirement Study between 2008 and 2016. Group-based trajectory models (GBTM) elicited the number and shape of adherence trajectories from a sample of N = 11,068 participants for the three pharmacotherapeutic classes considered in this study. Medication adherence was estimated using monthly PDC. RESULTS: GBTM were estimated for the sample population taking antihypertensives (n = 7,272), statins (n = 8,221), and diabetes medications (n = 3,214). The hypertension model found three trajectories: high to very high adherence (47.55%), slow decline (32.99%), and rapid decline (19.47%) trajectories. The statins model found 5 trajectories: high to very high adherence (35.49%), slow decline (17.12%), low then increasing adherence (23.58%), moderate decline (12.62%), and rapid decline (11.20%). The diabetes medications model displayed 6 trajectories: high to very high adherence (24.15%), slow decline (16.84%), high then increasing adherence (25.56%), low then increasing (13.58%), moderate decline (10.60%), and rapid decline (9.27%). CONCLUSIONS: This study showed the fluid nature of long-term medication adherence to the medications considered in the Medicare Part D Star Ratings and how it varies by pharmacotherapeutic class. These challenge previous assumptions about which patients were considered adherent to chronic medications. Policy and methodological implications about medication adherence are discussed.

Development of a quantitative PCR-based method for studying temporal DNA degradation in waterlogged bone.

While several studies have examined temporal DNA degradation in bones collected from terrestrial environments, studies on temporal DNA degradation in bones collected from aquatic environments are limited and mostly based on case studies. The objective of this study was to assess the impact of long-term submersion, aquatic environment, bone type and DNA extraction method on DNA quality and quantity. Bone samples (scapulae and ribs), collected every ~1000 ADD from a freshwater lake and river, underwent DNA extraction via ChargeSwitch® gDNA Plant Kit and organic phenol-chloroform methods, and DNA quantitation using both TaqMan and SYBR Green-based quantitative PCR (qPCR) methods. Results suggest that in both bone types, quality of recovered DNA (i.e., degradation index) declined significantly with increase in submersion time. Among two bone types, quality of recovered DNA from scapulae declined faster than rib samples. There was no significant difference in recovered DNA quantity between bone types, DNA extraction methods, or locations but various interactions between these variables showed significant difference. Overall, it can be concluded that DNA can be extracted from waterlogged bone in sufficient quantity to generate an STR profile up to 4000 ADD.

Economic burden of renal cell carcinoma among older adults in the targeted therapy era.

OBJECTIVE: This study examined the economic burden of renal cell carcinoma (RCC) among older adults. The study also examined healthcare costs by types of resources used and stage at which RCC was diagnosed. METHODS: The study analyzed the Surveillance Epidemiology and End Result-Medicare linked data. We included a prevalent cohort of RCC patients from 2013, diagnosed and continuously enrolled in Medicare from 2005 to 2013. RCC patients were matched to controls selected from a 5% sample of noncancer beneficiaries using propensity score matching to calculate incremental costs. Total healthcare costs (THC) were calculated using a phase-based approach, which classified patients into early, continuing, and late phases of care. Costs were also examined by types of resources used and stage at which RCC was diagnosed. Generalized linear models estimated annual incremental costs per patient. The number of older RCC patients was calculated using SEER-Stat and ProjPrev software. The average incremental THC was multiplied by the estimated number of RCC patients to calculate the total economic burden of RCC among older adults. RESULTS: The study included 10,392 each of RCC and control patients. The average annual THC associated with RCC was $7,419 for all phases, $22,752 for the initial phase, $4,860 for the continuing phase, and $13,232 for the late phase of care. The average THC was $4,584 for patients diagnosed at stage I, $4,727 for stage II, $9,331 for stage III, and $31,637 for stage IV. For patients diagnosed at stages I to III, hospital cost (approximately $1,500-$3,400) was the largest component of THC. For stage IV patients, prescription drug cost ($11,747) was the largest component of THC. The projected number of older RCC patients in 2015 was 204,256. The annual economic burden of RCC after weighting for proportion of patients diagnosed at various stages was estimated to be $2.1 billion. CONCLUSIONS: RCC was associated with a significant economic burden on Medicare. Healthcare costs associated with RCC varied substantially between early stage and metastatic patients. This research provided a baseline that can be used to assess the economic value of emerging therapies among older RCC patients.

Effect of Renin-Angiotensin system inhibition on cardiovascular events in older hypertensive patients with metabolic syndrome.

OBJECTIVE: Metabolic syndrome (MetS) is associated with cardiovascular disease (CVD). Insulin resistance has been hypothesized as the underlying feature of MetS. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are widely used antihypertensives that may improve insulin sensitivity. The aim of the study is to evaluate the effect of ACEI/ARB on incident CVD events in older hypertensive patients with MetS. MATERIALS/METHODS: We used the Cardiovascular Health Study, a prospective cohort study of individuals>65years of age to evaluate ACEI/ARB use and time to CVD events (including coronary and cerebrovascular events). The study included 777 subjects who had hypertension and ATP III-defined MetS, but free of CVD and diabetes at baseline. Cox regression models were used to evaluate the effect of ACEI/ARB as compared to other antihypertensives on the time to the first CVD events. RESULTS: ACEI/ARB use was associated with a decreased risk of CVD events (adjusted HR=0.658, 95 % C.I. [0.436-0.993]) compared to other antihypertensives. When CVD endpoints were evaluated separately, use of ACEI/ARB was associated with lower rates of angioplasty and coronary events (HR of 0.129 and 0.530 respectively, with 95 % CI [0.017-0.952] and [0.321-0.875]). CONCLUSIONS: ACEI/ARB use was associated with a lower risk of CVD events in older hypertensive patients with MetS, primarily due to a reduction in coronary events. The potential protective effect of ACEI/ARB on CVD events in older individuals with MetS will need further confirmation from prospective studies.

Early inflammatory processes in the skin.

Skin is considered as the border defining the limits of the body from the external world and functions as a barrier between the two. In this capacity, it has evolved to be an integral part of the innate and adaptive immune system. Although many reviews have described skin inflammation and processes that lead to its clinical manifestations, we are not aware of any reviews that have focused on immunologic activity occurring in the absence of any visual inflammatory cues. In this review, we discuss the importance of subclinical inflammation in human skin and its relevance to innate immune surveillance under physiologic conditions. Reactive oxygen species generated by metabolic processes, ultraviolet radiation or oxidizers may damage cells, initiating proinflammatory cascades. In addition to serving as structural skin components, keratinocytes have significant immunologic activity: they secrete proinflammatory cytokines and mediators, including interleukin (IL)-1α, IL-6, IL-10, tumor necrosis factor-α and granulocyte-macrophage colony-stimulating factor. Infant skin is particularly susceptible to irritation, inflammation and infection, since skin barrier function is not fully developed after birth and continues to mature throughout the first few years of life. Non-invasive methods such as fluorescence spectroscopy, spectral imaging and diffuse reflectance spectroscopy, as well as minimally invasive tape stripping, can be used to assess subclinical inflammatory markers in vivo, including erythema, epidermal cell proliferation rate and cytokine concentrations. Appropriately formulated skin care products may help maintain skin barrier integrity and enhance its capacity. In the future, assessment of subclinical inflammation may help clinicians prevent acute or chronic inflammatory conditions of the skin.

Novel p63 target genes involved in paracrine signaling and keratinocyte differentiation.

The transcription factor p63 is required for proper epidermal barrier formation and maintenance. Herein, we used chromatin immunoprecipitation coupled with DNA sequencing to identify novel p63 target genes involved in normal human epidermal keratinocyte (NHEKs) growth and differentiation. We identified over 2000 genomic sites bound by p63, of which 82 were also transcriptionally regulated by p63 in NHEKs. Through the discovery of interleukin-1-α as a p63 target gene, we identified that p63 is a regulator of epithelial-mesenchymal crosstalk. Further, three-dimensional organotypic co-cultures revealed TCF7L1, another novel p63 target gene, as a regulator of epidermal proliferation and differentiation, providing a mechanism by which p63 maintains the proliferative potential of basal epidermal cells. The discovery of new target genes links p63 to diverse signaling pathways required for epidermal development, including regulation of paracrine signaling to proliferative potential. Further mechanistic insight into p63 regulation of epidermal cell growth and differentiation is provided by the identification of a number of novel p63 target genes in this study.

p63 consensus DNA-binding site: identification, analysis and application into a p63MH algorithm.

p53 and p63 belong to a family of sequence-specific transcription factors regulating key cellular processes. Differential composition of the p53 and p63 DNA-binding sites may contribute to distinct functions of these protein homologues. We used SELEX (systematic evolution of ligands by exponential enrichment) methodology to identify nucleic acid ligands for p63. We found that p63 bound preferentially to DNA fragments conforming to the 20 bp sequence 5'-RRRC(A/G)(A/T)GYYYRRRC(A/T)(C/T)GYYY-3'. Relative to the p53 consensus, the p63 consensus DNA-binding site (DBS) was more degenerate, particularly at positions 10 and 11, and was enriched for A/G at position 5 and C/T at position 16 of the consensus. The differences in DNA-binding site preferences between p63 and p53 influenced their ability to activate transcription from select response elements (REs) in cells. A computer algorithm, p63MH, was developed to find candidate p63-binding motifs on input sequences. We identified genes responsive to p63 regulation that contain functional p63 REs. Our results suggest that the sequence composition of REs could be one contributing factor to target gene discrimination between p63 and p53.

Effects of postural changes and vestibular lesions on genioglossal muscle activity in conscious cats.

Previous studies in humans showed that genioglossal muscle activity is higher when individuals are supine than when they are upright, and prior experiments in anesthetized or decerebrate animals suggested that vestibular inputs might participate in triggering these alterations in muscle firing. The present study determined the effects of whole body tilts in the pitch (nose-up) plane on genioglossal activity in a conscious feline model and compared these responses with those generated by roll (ear-down) tilts. We also ascertained the effects of a bilateral vestibular neurectomy on the alterations in genioglossal activity elicited by changes in body position. Both pitch and roll body tilts produced modifications in muscle firing that were dependent on the amplitude of the rotation; however, the relative effects of ear-down and nose-up tilts on genioglossal activity were variable from animal to animal. The response variability observed might reflect the fact that genioglossus has a complex organization and participates in a variety of tongue movements; in each animal, electromyographic recordings presumably sampled the firing of different proportions of fibers in the various compartments and subcompartments of the muscle. Furthermore, removal of labyrinthine inputs resulted in alterations in genioglossal responses to postural changes that persisted until recordings were discontinued approximately 1 mo later, demonstrating that the vestibular system participates in regulating the muscle's activity. Peripheral vestibular lesions were subsequently demonstrated to be complete through the postmortem inspection of temporal bone sections or by observing that vestibular nucleus neurons did not respond to rotations in vertical planes.

CYP2C19 pharmacogenetics in the clinical use of proton-pump inhibitors for gastro-oesophageal reflux disease: variant alleles predict gastric acid suppression, but not oesophageal acid exposure or reflux symptoms.

BACKGROUND: The rate of metabolic inactivation of proton-pump inhibitors is determined by polymorphisms of CYP2C19. It is not known if CYP2C19 variant alleles affect responses to proton-pump inhibitor therapy in gastro-oesophageal reflux disease (GERD). AIM: To determine if the CYP2C19 genotype is associated with clinical effectiveness of proton-pump inhibitors during GERD therapy. METHODS: GERD patients undergoing ambulatory gastric and oesophageal pH monitoring were genotyped for CYP2C19 polymorphisms. RESULTS: Sixty subjects were enrolled. Forty-four subjects had two wild-type alleles, 15 had one variant, and one had two variant CYP2C19 alleles. The presence of a variant allele was significantly associated with a lower odds of gastric acid breakthrough during proton-pump inhibitor therapy [odds ratio 5.14, 95% confidence interval (CI) 1.17-22.61]. The presence of a variant allele was not associated with a lower odds of significant oesophageal acid exposure (odds ratio 2.50, 95% CI 0.60-10.52), or the occurrence of symptoms (incidence rate ratio 1.06, 95% CI 0.54-2.06). CONCLUSIONS: These results indicate that factors other than gastric acid secretion are important determinants of reflux in GERD patients. This suggests that CYP2C19 genotype testing will not be useful in proton-pump inhibitor therapy of GERD, except perhaps in identifying patients at risk for hypochlorhydria and consequent hypergastrinemia.

Changes in soil quality and below-ground carbon storage with conversion of traditional agricultural crop lands to bioenergy crop production.

Berm-isolated (0.5 ha) plots have been used since 1995 to quantify changes in soil and water quality with conversion from agricultural to bioenergy crops. Soil quality improvements, including increases in soil carbon storage, have occurred on sites planted to woody or herbaceous species, and no-till corn compared with tilled corn or cotton. Initial increases in soil carbon occurred within the upper 10 cm of the soil profile. Soil carbon on plantings of switchgrass, no-till corn, and sweetgum with a cover crop between the rows increased over the first 3 years. Soil carbon decreased by 6% on the sweetgum plantings without a cover crop and remained lower through the fifth growing season. Overall, the greatest increases in below ground carbon storage have occurred primarily within the upper 40 cm. Former land use, growth characteristics, management practices, and soil characteristics appear to be the primary factors determining the timing, depth. and extent of changes in soil carbon storage for bioenergy and no-till crops.

Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide.

AIM: We evaluated the effect of coadministration of sulphasalazine, mesalamine, and balsalazide on the pharmacokinetics and pharmacodynamics of azathioprine and 6-mercaptopurine. METHODS: Thirty four patients with Crohn's disease receiving azathioprine or 6-mercaptopurine were enrolled in an eight week non-randomised parallel group drug interaction study and treated with mesalamine 4 g/day, sulphasalazine 4 g/day, or balsalazide 6.75 g/day. The primary outcome measure was the occurrence of clinically important leucopenia during the study, defined separately as total leucocyte counts < 3.0 x 10(9)/l and < or = 3.5 x 10(9)/l. Whole blood 6-thioguanine nucleotide concentrations were determined. RESULTS: Three patients could not be evaluated for the primary outcome measure. In the remaining 31 patients, the frequency of total leucocyte counts < 3.0 and < or = 3.5 were: 1/10 and 5/10 in the mesalamine group; 1/11 and 6/11 in the sulphasalazine group; and 0/10 and 2/10 in the balsalazide group. There were significant increases in mean whole blood 6-thioguanine nucleotide concentrations from baseline at most time points in the mesalamine and sulphasalazine groups but not in the balsalazide group. CONCLUSIONS: In patients with Crohn's disease receiving azathioprine or 6-mercaptopurine, coadministration of mesalamine, sulphasalazine, and possibly balsalazide results in an increase in whole blood 6-thioguanine nucleotide concentrations and a high frequency of leucopenia.

Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease.

BACKGROUND: Measurement of 6-thioguanine nucleotide concentrations may be useful for optimising treatment with azathioprine and 6-mercaptopurine. METHODS: We conducted a study of 170 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between 6-thioguanine nucleotide concentrations and both disease activity, as measured by the inflammatory bowel disease questionnaire (active disease < 170, remission > or = 170) and leucopenia. Blood was submitted for whole blood 6-thioguanine nucleotide concentration and leucocyte count. RESULTS: Mean (SD) inflammatory bowel disease questionnaire score was 176 (32). There was no correlation between inflammatory bowel disease questionnaire scores and 6-thioguanine nucleotide concentrations (r(s) = -0.09, p = 0.24). Median 6-thioguanine nucleotide concentrations in 56 patients with active disease and 114 patients in remission were similar (139 v 131 pmol/8 x 10(8) red blood cells; p = 0.26). There was no correlation between 6-thioguanine nucleotide concentrations and leucocyte counts. CONCLUSIONS: In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, 6-thioguanine nucleotide concentrations did not correlate with disease activity, as measured by the inflammatory bowel disease questionnaire, or leucocyte count. These findings are discrepant with most previous studies, possibly due to selection of responding patients who tolerated the medications. A prospective, randomised, dose optimisation trial using 6-thioguanine nucleotide concentrations is warranted.

Improved methods for determining the concentration of 6-thioguanine nucleotides and 6-methylmercaptopurine nucleotides in blood.

The conversion of the cytotoxic and immunosuppressive 6-mercaptopurine (6MP) to the active 6-thioguanine nucleotides (6TGN) is necessary for clinical efficacy of 6MP and its prodrug azathioprine. Another metabolite, 6-methylmercaptopurine nucleotide (6MMPN), is formed via a competing pathway by thiopurine methyl transferase. The concentrations of 6TGN and 6MMPN are measured in washed erythrocytes as a surrogate to the intracellular levels of these metabolites in the target tissues. Analysis of 6TGN and 6MMPN in multi-center clinical studies is more complicated because of the requirement to wash erythrocytes. In this investigation, we found no differences in the concentrations of 6TGN and 6MMPN in blood versus washed erythrocytes in samples obtained from patients taking therapeutic doses of oral 6MP or azathioprine for inflammatory bowel disease. We concluded that whole blood could be used for the analysis of these analytes, thus saving sample preparation time. We also found that the erythrocyte 6TGN concentration in blood at ambient temperature declined 2-4% per day, a loss that can be avoided by shipping blood samples frozen. The loss of 6TGN in blood stored at approximately -80 degrees C was 1% after 1 week and 12% after 24 weeks, indicating the analyte was moderately stable. 6MMPN in blood did not significantly change after 24 weeks of storage at approximately -80 degrees C. In addition, the sensitivity of the 6TGN assay was improved by modifying the HPLC conditions, which made the method more suitable for quantifying low levels of 6TGN in human intestinal biopsy samples and blood.

Kinetics of p53 binding to promoter sites in vivo.

Downstream target genes of p53 are thought to mediate its tumor-suppressive activity, but it is unknown whether differential transactivation of these genes is regulated at the level of p53 binding to their promoters. To address this issue, p53 binding in vivo to consensus sites in the p21(Waf1), MDM2, and PIG3 promoters was investigated in cells exposed to adriamycin (ADR) or ionizing radiation as well as in an inducible p53 cell line. p53-DNA complexes were cross-linked in vivo by treating the cells with formaldehyde and processed by chromatin immunoprecipitation-PCR. This methodology allowed for the analysis of relevant p53-DNA complexes by preventing redistribution of cellular components upon collection of cell extracts. Increased p53 binding to the p21(Waf1), MDM2, and PIG3 promoters occurred within 2 h after p53 activation; however, significant increases in PIG3 transcription did not occur until 15 h after p53 binding. Gel shift analyses indicated that p53 had lower affinity for the consensus binding site in the PIG3 promoters compared to its consensus sites in the p21 and MDM2 genes, which suggests that additional factors may be required to stabilize the interaction of p53 with the PIG3 promoter. Further, acetylated p53 (Lys382) was found in chemically cross-linked complexes at all promoter sites examined after treatment of cells with ADR. In summary, the kinetics of p53 binding in vivo to target gene regulatory regions does not uniformly correlate with target gene mRNA expression for the p53 target genes examined. Our results suggest that target genes with low-affinity p53 binding sites may require additional events and will have delayed kinetics of induction compared to those with high-affinity binding sites.

Determination of in vivo adducts of disulfiram with mitochondrial aldehyde dehydrogenase.

Extensive use for disulfiram (DSF) has been found in the aversion therapy treatment of recovering alcoholics. Although it is known to irreversibly inhibit hepatic aldehyde dehydrogenase (ALDH), the specific mechanism of in vivo inhibition of the enzyme by the drug has not been determined yet. We have demonstrated in this report a novel, but simple and rapid method for structurally characterizing in vivo derived protein-drug adducts by linking on-line sample processing to HPLC-electrospray ionization mass spectrometry (HPLC-MS) and HPLC-tandem mass spectrometry (HPLC-MS/MS). Employing this approach, rats were administered DSF, and their liver mitochondria were isolated and solubilized. Both native and in vivo DSF-treated mitochondrial ALDH (mALDH) were purified in one step with an affinity cartridge. The in vivo DSF-treated mALDH showed 77% inhibition in enzyme activity as compared with that of the control. Subsequently, the control and DSF-inhibited mALDH were both subjected to HPLC-MS analyses. We were able to detect two adducts on DSF-inhibited mALDH, as indicated by the mass increases of approximately 71 and approximately 100 Da. To unequivocally determine the site and structure of these adducts, on-line pepsin digestion-HPLC-MS and HPLC-MS/MS were performed. We observed two new peptides at MH(+) = 973.7 and MH(+) = 1001.8 in the pepsin digestion of DSF-inhibited enzyme. These two peptides were subsequently subjected to HPLC-MS/MS for sequence determination. Both peptides possessed the sequence FNQGQC(301)C(302)C(303), derived from the enzyme active site region, and were modified at Cys(302) by N-ethylcarbamoyl (+71 Da) and N-diethylcarbamoyl (+99 Da) adducts. These findings indicated that N-dealkylation may be an important step in DSF metabolism, and that the inhibition of ALDH occurred by carbamoylation caused by one of the DSF metabolites, most likely S-methyl-N,N-diethylthiocarbamoyl sulfoxide (MeDTC-SO). Finally, there was no evidence of the presence of an intramolecule disulfide bridge modification on the peptide FNQGQCCC.

Metabolism of a disulfiram metabolite, S-methyl N,N-diethyldithiocarbamate, by flavin monooxygenase in human renal microsomes.

S-Methyl N,N-diethyldithiocarbamate (MeDDC), a metabolite of the alcohol deterrent disulfiram, is converted to MeDDC sulfine and then S-methyl N,N-diethylthiocarbamate sulfoxide, the proposed active metabolite in vivo. Several isoforms of CYP450 and to a lesser extent flavin monooxygenase (FMO) metabolize MeDDC in the liver. The human kidney contains FMO1 and several isoforms of CYP450, including members of the CYP3A, CYP4A, CYP2B, and CYP4F subfamilies. In this study the metabolism of MeDDC by the human kidney was examined, and the enzymes responsible for this metabolism were determined. MeDDC was incubated with human renal microsomes from five donors or with insect microsomes containing human FMO1, CYP4A11, CYP3A4, CYP3A5, or CYP2B6. MeDDC sulfine was formed at 5 microM MeDDC by renal microsomes at a rate of 210 +/- 50 pmol/min/mg of microsomal protein (mean +/- S.D., n = 5) and by FMO1 at 7.6 +/- 0.2 nmol/min/nmol (n = 3). Oxidation of 5 microM MeDDC was negligible by all CYP450 tested (< or =0.03 nmol/min/nmol). Inhibition of FMO by methimazole or heat diminished MeDDC sulfine formation 75 to 89% in renal microsomes. Inhibition of CYP450 in renal microsomes by N-benzylimidazole or antibody to the CYP450 NADPH reductase had no effect on MeDDC sulfine production. Benzydamine N-oxidation, a probe for FMO activity, correlated with MeDDC sulfine formation in renal microsomes (r = 0.951, p = 0.013). The K(M) values for MeDDC sulfine formation by renal microsomes and recombinant human FMO1 were 11 and 15 microM, respectively. These results demonstrate a role for the kidney and FMO1 in the metabolism of MeDDC in humans.

Quality of pharmacotherapy consultations provided by drug information centers in the United States.

We evaluated the performance of 116 U.S. drug information centers in responding to specific questions about drugs. The primary measures were correctness of responses and extent of probing for patient data. Questions addressed the effect of ranitidine on blood alcohol concentrations, the potential interaction between didanosine and dapsone, prevention of nonsteroidal antiinflammatory drug (NSAID)-induced peptic ulcers, and use of erythromycin for diabetic gastroparesis. The percentages of centers providing correct overall responses were 70% for the ranitidine question, 90% for the didanosine-dapsone question, 8% for the NSAID question, and 20% for the erythromycin question. For the three patient-specific questions, the percentages of centers eliciting vital patient data were 27% for the didanosine-dapsone question, 86% for the NSAID question, and 5% for the erythromycin question. In providing pharmacotherapy consultations, drug information centers generally failed to obtain pertinent patient data, thereby risking incorrect responses and inappropriate recommendations.