Increase in migraine diagnoses and guideline-concordant treatment in veterans, 2004-2012.

Background and aim Health administrators, policy makers, and educators have attempted to increase guideline adherence of migraine medications while reducing inappropriate use of opioid- and barbiturate-containing medications. We evaluated the burden of migraine and proportion of guideline-concordant care in a large, national health care system over time. Methods We conducted a time-series study using data from the Veterans Health Administration (VHA) electronic health record. Veterans with migraines were identified by ICD-9 code (346.X). Prescriptions and comorbid conditions were evaluated before and after migraine diagnosis. Chi-square tests and logistic regression were performed. Results A total of 57,064 veterans were diagnosed with migraine headache (5.3%), with women significantly more likely diagnosed (11.6% vs. 4.4%, p < 0.0001). The number of veterans diagnosed with migraine has significantly increased over the years. By 2012, triptans were prescribed to 43% of people with migraine, with no difference by gender. However, triptan prescriptions increased from 2004 to 2012 in men, but not women, veterans. Preventive medicines showed a significant increase with the year of migraine diagnosis, after controlling for age, sex, race, and for comorbidities treated with medications used for migraine prevention. Conclusions The burden of migraines is increasing within the VHA, with a corresponding increase in the delivery of guideline-concordant acute and prophylactic migraine-specific medication.

Prevalence and risk of fracture diagnoses in women across the adult life span: a national cross-sectional study.

In a national sample of women veterans, the rate of lower limb fracture diagnosis was the highest across ages 18-74 years; rates of fracture diagnosis of other skeletal sites peaked in women aged 75+. Women with two or more primary care visits or mental healthcare visits had elevated odds of fracture diagnosis. INTRODUCTION: We assessed the prevalence and healthcare utilization characteristics associated with a diagnosis of any fracture in women of all adult ages within the Veterans Health Administration. METHODS: In 344,488 women during fiscal year 2012, logistic regression models for fracture diagnosis included age, race/ethnicity, residence, number of primary care visits, number of mental healthcare visits, and degree of service-connected disability. RESULTS: Lower limb fracture diagnosis was most prevalent across ages 18-74 years and peaked in women aged 55-64 years. In women aged 75+, the prevalence rates of fracture diagnosis at the hip (102, 95 % CI = 88-115 per 10,000 women), upper limb (100, 95 % CI = 87-114 per 10,000 women), and lower limb (84, 95 % CI = 72-97 per 10,000 women) were the highest. Fractures at other skeletal sites peaked in those aged 75+ years. Black women had the lowest odds of a fracture diagnosis, followed by Asian/Pacific Islander and Hispanic women compared to non-Hispanic White (by 25-51 %, P < 0.05). Having two or more primary care visits or any mental health visit was each associated with an increased risk. Women with five or more primary care visits had a 3.36-fold (95 % CI = 3.02-3.75) greater odds than those with no such visit, and separately, women with five or more mental health visits had a 1.51-fold (95 % CI = 1.43-1.60) greater odds. Women with a fracture diagnosis had higher overall healthcare costs than those without (P < 0.001). CONCLUSIONS: Prevalence of fracture diagnosis differed by age, race/ethnicity, and skeletal site of fracture. Fracture diagnosis may identify women veterans with greater overall healthcare needs.

Early medical abortion with methotrexate and misoprostol.

OBJECTIVE: To evaluate the introduction of an early medical abortion program with methotrexate and misoprostol, using a standardized protocol. METHODS: A total of 1973 women at 34 Planned Parenthood sites participated in a case series of early medical abortion. Ultrasound was used to confirm gestational age of less than 49 days from the first day of the last menstrual period. Women were given intramuscular methotrexate 50 mg/m(2) of body surface area on day 1, and then they inserted misoprostol 800 microg vaginally at home on day 5, 6, or 7. Women were advised to have a suction curettage if the pregnancy appeared viable 2 weeks after methotrexate or if any gestational sac persisted 4 weeks after methotrexate. Outcomes were complete medical abortion and suction curettage. RESULTS: Sixteen hundred fifty-nine women (84.1%) had a complete medical abortion, and 257 (13.0%) had suction curettage. The most common reason for curettage was patient option (8.9%). At 2 weeks after methotrexate use, 1.4% of women had curettage because of a viable pregnancy; at 4 weeks, 1.6% of women had curettage because of a persistent but nonviable pregnancy. One percent of women had curettage because of physician recommendation, most commonly for bleeding. Suction curettage rates decreased with site experience (P <.006) and were lower at early gestational ages (P <.004) and in nulliparous women (P <.004). CONCLUSION: Medical abortion with methotrexate and misoprostol is safe and effective and can be offered in a community setting.

Instituting medical abortion services: changes in outcome and acceptability related to provider experience.

A prospective case series carried out at 34 Planned Parenthood sites studied the safety, efficacy, and acceptability of medical abortion with methotrexate and misoprostol in 1973 women. Women with pregnancies of 26 to 49 gestational days were given methotrexate followed by vaginal misoprostol. Eighty-one percent of women had documented complete medical abortions; abortion was not confirmed by examination in 6%, and 13% had documented suction curettage. The rate of suction curettage decreased with site experience, from 17% during the first 20 procedures to 10% at sites that had performed more than 50. Sites that had previous experience with either methotrexate or mifepristone medical abortion had a rate of 9% after they had performed at least 50 procedures. Exit interviews with 755 of the 902 women having abortions in the first year inquired about the level of comfort with the abortion and its overall acceptability. Women's satisfaction with the side effects did not directly correlate with site experience. Overall satisfaction with the abortion experience was related to whether the women had complete medical abortions or suction curettage.

The determinants of arithmetic skills in young children: some observations.

The cause or causes of arithmetic difficulties in young children are manifold. The condition has its origins in a set of complex disorders and may be due to genetic factors, developmental delays, experiential limitations, language problems, and perceptual, motor, memory and other cognitive weaknesses. Other factors which may cause the disorder are inappropriate and ineffectual instructional practices. Anxiety and unfavourable attitudes towards the subject may influence mastery of arithmetic attainment in young children.

Activities of trovafloxacin compared with those of other fluoroquinolones against purified topoisomerases and gyrA and grlA mutants of Staphylococcus aureus.

Frequencies of mutation to resistance with trovafloxacin and four other quinolones were determined with quinolone-susceptible Staphylococcus aureus RN4220 by a direct plating method. First-step mutants were selected less frequently with trovafloxacin (1.1 x 10(-10) at 2 to 4x the MIC) than with levofloxacin or ciprofloxacin (3.0 x 10(-7) to 3.0 x 10(-8) at 2 to 4x the MIC). Mutants with a change in GrlA (Ser80-->Phe or Tyr) were most commonly selected with trovafloxacin, ciprofloxacin, levofloxacin, or pefloxacin. First-step mutants were difficult to select with sparfloxacin; however, second-step mutants with mutations in gyrA were easily selected when a preexisting mutation in grlA was present. Against 29 S. aureus clinical isolates with known mutations in gyrA and/or grlA, trovafloxacin was the most active quinolone tested (MIC at which 50% of isolates are inhibited [MIC(50)] and MIC(90), 1 and 4 microg/ml, respectively); in comparison, MIC(50)s and MIC(90)s were 32 and 128, 16 and 32, 8 and 32, and 128 and 256 microg/ml for ciprofloxacin, sparfloxacin, levofloxacin, and pefloxacin, respectively. Strains with a mutation in grlA only were generally susceptible to all of the quinolones tested. For mutants with changes in both grlA and gyrA MICs were higher and were generally above the susceptibility breakpoint for ciprofloxacin, sparfloxacin, levofloxacin, and pefloxacin. Addition of reserpine (20 microg/ml) lowered the MICs only of ciprofloxacin fourfold or more for 18 of 29 clinical strains. Topoisomerase IV and DNA gyrase genes were cloned from S. aureus RN4220 and from two mutants with changes in GrlA (Ser80-->Phe and Glu84-->Lys). The enzymes were overexpressed in Escherichia coli GI724, purified, and used in DNA catalytic and cleavage assays that measured the relative potency of each quinolone. Trovafloxacin was at least five times more potent than ciprofloxacin, sparfloxacin, levofloxacin, or pefloxacin in stimulating topoisomerase IV-mediated DNA cleavage. While all of the quinolones were less potent in cleavage assays with the altered topoisomerase IV, trovafloxacin retained its greater potency relative to those of the other quinolones tested. The greater intrinsic potency of trovafloxacin against the lethal topoisomerase IV target in S. aureus contributes to its improved potency against clinical strains of S. aureus that are resistant to other quinolones.

The effect of estrogen replacement therapy on cognitive function in women: a critical review of the literature.

OBJECTIVE: To conduct a review of the available clinical trials to determine whether sufficient evidence exists to support the conclusion that estrogen replacement therapy has a beneficial effect on cognitive performance in post-menopausal women and in women with Alzheimer's disease. Studies were identified through a MEDLINE search of all English-language publications between 1970 and 1996 in which the words estrogen and cognition or estrogen and memory appeared. DATA EXTRACTION: Data were extracted for each study, including features of subjects and eligibility criteria, duration of follow-up, and treatment regimen. Baseline characteristics were evaluated, including age; menopausal status; follicle-stimulating hormone, luteinizing hormone, and estradiol levels; mood; and measures of cognitive function. Psychological tests were evaluated for construct validity. RESULTS: Nineteen studies were reviewed, including 10 randomized trials of estrogen replacement therapy versus placebo. Extreme heterogeneity among subjects and variability in the use of cognitive measures across the studies precluded performing a quantitative summary. Of the 10 randomized trials, eight claimed therapeutic benefits for estrogen therapy, three of which reported significant improvements in memory and two of which showed improvements in attention. These studies did not control for potential confounds such as depression and vasomotor symptoms. Of the nine observational studies, five found a significant association between estrogen use and cognitive function. CONCLUSION: Although several observational studies provide encouraging evidence for the beneficial effect of estrogen on cognitive function, there is currently inadequate evidence available from randomized, controlled trials to support the conclusion that estrogen replacement therapy improves cognitive function in post-menopausal women or women with Alzheimer's dementia.

Clinical epidemiology of nocturnal leg cramps in male veterans.

This article describes patients with nocturnal leg cramps concerning their age, medical problems, and medications, and reviews any medical evaluation performed for the complaint of nocturnal leg cramps. Provided is a retrospective chart review of 50 patients who took quinine sulfate for nocturnal leg cramps. These patients were identified through computerized pharmacy records. A control group was chosen from age-matched patients who took medications other than quinine during the study period. In a university-affiliated Veterans Administration hospital, patients with nocturnal leg cramps had a significantly higher median number of medical problems than controls. Cardiovascular diseases and neurological diseases were significantly more common in patients with nocturnal leg cramps (cases) than in those without (controls) (82% versus 64% and 36% versus 18%, respectively). The most striking differences between patients with cramps and controls were peripheral vascular disease (34% versus 12%, P = 0.09) and peripheral neurological deficit (12% versus 0%, P = 0.012). Patients with nocturnal leg cramps were prescribed significantly more medications than were controls, but no specific medication or type of medication was prescribed more frequently to patients with cramps (other than quinine). Results suggested that men with nocturnal leg cramps have greater medical comorbidity and are prescribed more medications than age-matched control patients. Unlike in previous studies, no evidence was found that specific medications, such as diuretics, betaagonists, or calcium-channel antagonists are associated with nighttime cramps. The significantly increased frequency of peripheral vascular disease and peripheral neurologic deficits in patients with nocturnal leg cramps raised the possibility that these problems contribute to the occurrence of cramps. Although the size of the study and its methodologic limitations preclude definitive conclusions, areas for research to clarify the clinical epidemiology of nocturnal leg cramps are suggested.

Activity of the new fluoroquinolone trovafloxacin (CP-99,219) against DNA gyrase and topoisomerase IV mutants of Streptococcus pneumoniae selected in vitro.

The MICs of trovafloxacin, ciprofloxacin, ofloxacin, and sparfloxacin at which 90% of isolates are inhibited for 55 isolates of pneumococci were 0.125, 1, 4, and 0.5 microgram/ml, respectively. Resistant mutants of two susceptible isolates were selected in a stepwise fashion on agar containing ciprofloxacin at 2 to 10 times the MIC. While no mutants were obtained at the highest concentration tested, mutants were obtained at four times the MIC of ciprofloxacin (4 micrograms/ml) at a frequency of 1.0 x 10(-9). Ciprofloxacin MICs for these first-step mutants ranged from 4 to 8 micrograms/ml, whereas trovafloxacin MICs were 0.25 to 0.5 microgram/ml. Amplification of the quinolone resistance-determining region of the grlA (parC; topoisomerase IV) and gyrA (DNA gyrase) genes of the parents and mutants revealed that changes of the serine at position 80 (Ser80) to Phe or Tyr (Staphylococcus aureus coordinates) in GrlA were associated with resistance to ciprofloxacin. Second-step mutants of these isolates were selected by plating the isolates on medium containing ciprofloxacin at 32 micrograms/ml. Mutants for which ciprofloxacin MICs were 32 to 256 micrograms/ml and trovafloxacin MICs were 4 to 16 micrograms/ml were obtained at a frequency of 1.0 x 10(-9). Second-step mutants also had a change in GyrA corresponding to a substitution in Ser84 to Tyr or Phe or in Glu88 to Lys. Trovafloxacin protected from infection mice whose lungs were inoculated with lethal doses of either the parent strain or the first-step mutant. These results indicate that resistance to fluoroquinolones in S. pneumoniae occurs in vitro at a low frequency, involving sequential mutations in topoisomerase IV and DNA gyrase. Trovafloxacin MICs for wild-type and first-step mutants are within clinically achievable levels in the blood and lungs of humans.

In vitro activity of CP-99,219, a novel 7-(3-azabicyclo[3.1.0]hexyl) naphthyridone antimicrobial.

The in vitro activity of CP-99,219 was compared with that of ciprofloxacin and sparfloxacin against 814 clinical bacterial isolates using a microdilution method with brain-heart infusion broth. CP-99,219 was the most potent agent tested against methicillin-resistant, ciprofloxacin-susceptible staphylocci (minimum inhibitory concentration [MIC]90 < or = 0.25 microgram/ml). CP-99,219 was 32-fold and fourfold more potent than ciprofloxacin and sparfloxacin, respectively, against Streptococcus pneumoniae, including strains resistant to penicillin G and erythromycin (MIC90 < or = 0.25 microgram/ml). CP-99,219 was also the most potent agent tested against S. pyogenes and Enterococcus faecalis (MIC90 < or = 0.5 microgram/ml). The activity of CP-99,219 against Enterobacteriaceae was comparable to that of sparfloxacin, with 90% of Escherichia coli, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Citrobacter freundii, C. diversus, Helicobacter pylori, and K. oxytoca being inhibited by < or = 0.5 microgram/ml. Serratia marcescens, Morganella morganii, and Pseudomonas aeruginosa were less susceptible, with MIC90 values to CP-99,219 of 4, 2, and 2 micrograms/ml, respectively. The MIC90 for Bacteroides fragilis was 0.39 microgram/ml for CP-99,219 compared with 12.5 micrograms/ml for ciprofloxacin. CP-99,219 was highly bactericidal at 1 x to 4 x MIC against both Gram-positive and Gram-negative organisms; its activity was similar in nutrient, trypticase soy, and cation-supplemented Mueller-Hinton broths. The spectrum and potency observed with CP-99,219 warrant further testing with this novel quinolone.

Bisulfite or sulfite inhibits growth of Helicobacter pylori.

Bisulfite or sulfite was found to be inhibitory to Helicobacter pylori growth. A modified version of Brucella broth (BB), bisulfite-less BB (BLBB), supported rapid, robust, and consistent growth of H. pylori. We suggest that BLBB simply be called "Pylori broth" for distinction from Brucella broth.

Placement of alkyl substituents on the C-7 piperazine ring of fluoroquinolones: dramatic differential effects on mammalian topoisomerase II and DNA gyrase.

Several substituted analogs of 7-(cis-3,5-dimethylpiperazinyl)-6,8-difluoro-5-amino-1-cyclopropyl quinolone were prepared and tested in a DNA cleavage assay with calf thymus topoisomerase II. Positioning of the methyl groups on the C-7 piperazine ring influenced potency against the mammalian enzyme; the cis-3,5-dimethyl configuration did not stimulate cleavage at drug concentrations less than or equal to 2,000 microM, while the trans configuration was active at drug levels as low as 36 microM. Removal of the cis-methyl groups produced a compound that was only sixfold less potent than the antitumor agent etoposide in stimulating enzyme-mediated DNA cleavage. The cis- and trans-methyl substitutions on the piperazine that conferred potency against the mammalian type II enzyme had little effect on bacterial DNA gyrase cleavage activity, suggesting that an asymmetric barrier exists with the mammalian enzyme which influences productive quinolone interaction, favoring the less bulky trans-3,5-dimethylpiperazine substituent at C-7.

Synthesis and structure-activity relationships of 7-diazabicycloalkylquinolones, including danofloxacin, a new quinolone antibacterial agent for veterinary medicine.

A series of novel 6-fluoro-7-diazabicycloalkylquinolonecarboxylic acids substituted with various C8 (H, F, Cl, N) and N1 (ethyl, cyclopropyl, vinyl, 2-fluoroethyl, 4-fluorophenyl, 2,4-difluorophenyl) substituents, as well as, 9-fluoro-10-diazabicycloalkylpyridobenzoxazinecarboxylic acids, were prepared and evaluated for antibacterial activity against a range of important veterinary pathogenic bacteria. The diazabicycloalkyl side chains investigated at the 7-position (benzoxazine 10-position) include (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (2), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane (3), (1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (4), 8-methyl-3,8-diazabicyclo[3.2.1]octane (5), 9-methyl-3,9-diazabicyclo[4.2.1]nonane (6), 1,4-diazabicyclo[3.2.2]nonane (7), 1,4-diazabicyclo[3.3.1]nonane (8), and 9-methyl-3,9-diazabicyclo[3.3.1]nonane (9). Among these side chains, in vitro potency was not highly variable; other properties therefore proved more critical to the selection of possible development candidates. However, the relative potencies observed for several of these compounds in mouse, swine, and cattle infection models correlated well with those seen in vitro. A combination of the N1 cyclopropyl group and the C7 (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl appendage conferred the best overall antibacterial, physiochemical, and pharmacodynamic properties. Hence, danofloxacin (Advocin, 2c) (originally CP-76,136, 1-cyclopropyl-6-fluoro-7-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1] hept-2-yl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid) was selected as a candidate for development as a therapeutic antibacterial agent for veterinary medicine.

Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution.

Azithromycin (CP-62,993), a new acid-stable 15-membered-ring macrolide, was well absorbed following oral administration in mice, rats, dogs, and cynomolgus monkeys. This compound exhibited a uniformly long elimination half-life and was distributed exceptionally well into all tissues. This extravascular penetration of azithromycin was demonstrated by tissue/plasma area-under-the-curve ratios ranging from 13.6 to 137 compared with ratios for erythromycin of 3.1 to 11.6. The significance of these pharmacokinetic advantages of azithromycin over erythromycin was shown through efficacy in a series of animal infection models. Azithromycin was orally effective in treating middle ear infections induced in gerbils by transbulla challenges with amoxicillin-resistant Haemophilus influenzae or susceptible Streptococcus pneumoniae; erythromycin failed and cefaclor was only marginally active against the H. influenzae challenge. Azithromycin was equivalent to cefaclor and erythromycin against Streptococcus pneumoniae. In mouse models, the new macrolide was 10-fold more potent than erythromycin and four other antibiotics against an anaerobic infection produced by Fusobacterium necrophorum. Similarly, azithromycin was effective against established tissue infections induced by Salmonella enteritidis (liver and spleen) and Staphylococcus aureus (thigh muscle); erythromycin failed against both infections. The oral and subcutaneous activities of azithromycin, erythromycin, and cefaclor were similar against acute systemic infections produced by Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, or S. aureus, whereas azithromycin was more potent than erythromycin and cefaclor against the intracellular pathogen Listeria monocytogenes. The pharmacokinetic advantage of azithromycin over erythromycin in half-life was clearly demonstrated in prophylactic treatment of an acute mouse model of S. aureus infection. These properties of azithromycin strongly support the further evaluation of this new macrolide for use in community-acquired infections of skin or soft tissue and respiratory diseases.

Structure-activity relationships of 6-(heterocyclyl)-methylene penam sulfones; a new class of beta-lactamase inhibitors.

6-(Heterocyclyl)methylene penam sulfones (1) are effective beta-lactamase inhibitors and potent ampicillin and cefazolin potentiators against both Gram-positive and Gram-negative beta-lactamase producing bacteria. Several of these analogs having a pi-deficient 2-heteroaryl substituent attached to the C6-methylene position showed better inhibitory activity than clavulanic acid, Ro 15-1903, 6 beta-bromopenicillanic acid, and sulbactam against a variety of beta-lactamases. The compounds were devoid of any antibacterial activity, but in combination with ampicillin or cefazolin, exhibited synergistic activity at least equal to clavulanic acid, Ro 15-1903, 6 beta-bromopenicillanic acid or sulbactam against beta-lactamase producing strains. Structure-activity relationships for a number of compounds are described. The structure-activity relationships can be rationalized by an enzyme inhibition mechanism which we have previously proposed on the basis of methanolysis of 6-(2-pyridyl)methylene penam sulfone (1a). Two synthetic routes to prepare compounds of structural type 1 via either a Wittig reaction or an aldol condensation are reported. beta-Lactamase inhibition and MIC data are presented.

Pharmacokinetics of sultamicillin in mice, rats, and dogs.

The irreversible beta-lactamase inhibitor sulbactam has been combined chemically via ester linkages with ampicillin to form sultamicillin . Upon oral absorption, sultamicillin is completely hydrolyzed to equimolar proportions of sulbactam and ampicillin, thereby acting as an efficient mutual prodrug. In rats, sultamicillin delivered 2 to 2.5 times greater total bioavailability for ampicillin and sulbactam than when each was used individually. Actual plasma or serum concentrations (measured in micrograms per milliliter) of ampicillin and sulbactam produced by sultamicillin were generally equivalent in rats, mice, and beagle dogs. Further studies also indicated that the components of sultamicillin were widely distributed in the various tissues of rats. These findings suggest that sultamicillin might be an effective agent against a variety of infections produced by both beta-lactamase-resistant and beta-lactamase-susceptible microorganisms.

Use of a cDNA library for the study of mRNA changes during muscle differentiation.

A cDNA library was used to measure changes in many individual mRNAs during muscle differentiation in culture. A library of 1000 clones was constructed from total myofiber poly(A) RNA. About 23% of these clones gave a detectable colony hybridization signal using end-labeled myofiber mRNA, the remainder containing muscle sequences too rare to be detected with this assay. The 230 positive clones were grouped into four classes based on relative visual intensity. Reconstruction experiments using pure globin mRNA enable us to determine the approximate percentage of total RNA made up by each mRNA hybridizing to a cDNA clone. Those clones containing sequences complementary to developmentally regulated mRNAs were identified by a differential hybridization procedure. The cDNA library was screened with end-labeled mRNA from both undifferentiated myoblasts and differentiated myofibers. Although the bulk of the clones hybridized essentially the same with both RNA populations, several dozen were found which hybridized differentially. Some clones contained sequences which were not present at all in myoblasts and present in very high quantities in myofibers. Others contained sequences found in both myoblasts and myofibers but in increased quantities in the differentiated cells. Still others contained sequences which decreased in quantity during muscle differentiation. The clones in the first group were chosen for immediate analysis since they likely contain contractile protein mRNA sequences. However, all the characterized cDNA clones can now be used as probes to study the chromosomal organization and developmental expression of genes active during muscle differentiation.