Brand vs generic adverse event reporting patterns: An authorized generic-controlled evaluation of cardiovascular medications.

WHAT IS KNOWN AND OBJECTIVE: Some public scepticism exists about generics in terms of whether brand and generic drugs produce identical outcomes. This study explores whether adverse event (AE) reporting patterns are similar between brand and generic drugs, using authorized generics (AGs) as a control for possible generic drug perception biases. METHODS: Events reported to the FDA Adverse Event Reporting System from the years 2004-2015 were analysed. Drugs were classified as brand, AG or generic based on drug and manufacturer names. Reports were included if amlodipine, losartan, metoprolol extended release (ER) or simvastatin were listed as primary or secondary suspect drugs. Disproportionality analyses using the reporting odds ratio (ROR) assessed the relative rate of reporting labelled AEs compared to reporting these AEs with all other drugs. The Breslow-Day test compared RORs across brand, AG and generic. Interrupted time series analysis evaluated the impact of generic entry on reporting trends. RESULTS AND DISCUSSION: Generics accounted for significant percentages of total U.S. reports, but AGs accounted for smaller percentages of reports, including for amlodipine (14.26%), losartan (1.48%), metoprolol ER (0.35%) and simvastatin (0.70%). Whereas the RORs were significantly different for multiple brand vs generic comparisons, the AG vs generic comparisons yielded fewer statistically significant findings. Namely, only the ROR for AG differed from generic for amlodipine with peripheral oedema (P < .01). WHAT IS NEW AND CONCLUSION: Inconsistent reporting patterns were observed more between brand and generic compared with AG and generic. Use of AGs as a control for perception biases against generics is useful, but this approach can be limited by small AG report numbers. Requiring the manufacturer name to be printed on the prescription bottle or packaging could improve the accuracy of assignment for products being reported.

Concordance of the SHEA-IDSA severity classification for Clostridium difficile infection and the ATLAS bedside scoring system in hospitalized adult patients.

PURPOSE: The Society for Healthcare Epidemiology of America and Infectious Diseases Society of America (SHEA-IDSA) guidelines for the treatment of Clostridium difficile infection (CDI) recommend initial treatment of CDI based on disease severity. This severity definition has not been validated or evaluated based on clinical outcomes. The ATLAS scoring system is a validated tool useful in predicting treatment response and mortality in CDI. The main purpose of this study is to evaluate the concordance of the ATLAS scoring system and the SHEA-IDSA staging for CDI severity. METHODS: This was a retrospective study which included hospitalized patients with confirmed CDI. Bivariate analyses compared baseline demographics and clinical information between patients with nonsevere and severe CDI based on the SHEA-IDSA criteria for CDI severity. Kappa scores were calculated to compare the concordance of the two scoring systems in defining CDI severity. Sensitivity and specificity of the ATLAS scoring system to determine CDI severity were calculated using the SHEA-IDSA criteria as the reference standard. RESULTS: Sixty-four patients met inclusion criteria. Of those, 62.5% were classified as mild to moderate CDI, 25% were severe, uncomplicated, and 12.5% were severe, complicated based on SHEA-IDSA criteria. In the bivariate analyses, ATLAS score breakpoints of ≥ 4, ≥ 5, and ≥ 6 revealed moderate agreement with the SHEA-IDSA classification for severity. The sensitivities and specificities for ATLAS scores in predicting CDI severity ranged from 58.3 to 87.5, and 67.5-87.5%, respectively. CONCLUSION: The ATLAS score may be useful in evaluating CDI severity and determining drug therapy selection.

Comparison of Outcomes Following a Switch From a Brand to an Authorized Versus Independent Generic Drug.

Authorized generics are identical in formulation to brand drugs, manufactured by the brand company but marketed as a generic. Generics, marketed by generic manufacturers, are required to demonstrate pharmaceutical and bioequivalence to the brand drug, but repetition of clinical trials is not required. This retrospective cohort study compared outcomes for generics and authorized generics, which serves as a generic vs. brand proxy that minimizes bias against generics. For the seven drugs studied between 1999 and 2014, 5,234 unique patients were on brand drugs prior to generic entry and 4,900 (93.6%) switched to a generic. During the 12 months following the brand-to-generic switch, patients using generics vs. authorized generics were similar in terms of outpatient visits, urgent care visits, hospitalizations, and medication discontinuation. The likelihood of emergency department (ED) visits was slightly higher for authorized generics compared with generics. These data suggest that generics were clinically no worse than their proxy brand comparators.

Supermodes in multiple coupled photonic crystal waveguides.

We analyze the supermodes in multiple coupled photonic crystal waveguides for long-wavelengths. In the tight-binding limit we obtain analytic results that agree with fully numerical calculations. We find that when the field flips sign after a single photonic crystal period, and there is an odd number of periods between adjacent waveguides, the supermode order is reversed, compared to that in conventional coupled waveguides, generalizing earlier results obtained for two coupled waveguides.

Effects of conjugated linoleic acids and docosahexaenoic acid on rat liver and reproductive tissue fatty acids, prostaglandins and matrix metalloproteinase production.

Long chain n-6 and n-3 fatty acids play important roles in labor and delivery. These effects may be mediated by prostaglandin (PG) synthesis and by regulation of matrix metalloproteinases (MMPs), both of which play roles in uterine contraction, cervical ripening and rupture of fetal membranes. The effects of altering dietary n-6:n-3 long chain fatty acid ratios, and the addition of dietary conjugated linoleic acids (CLA) and docosahexaenoic acid (DHA) on fatty acid composition of reproductive tissues, PG synthesis in liver and reproductive tissue and serum MMP levels were examined in pregnant rats. Modified AIN-96G diets with n-6:n-3 ratios of 7:1 and 34:1 with and without added 1.1% (by weight) conjugated linoleic acid (CLA) and/or 0.3% (by weight) DHA were fed through day 20 of gestation. Reproductive tissues readily incorporated both DHA and CLA. CLA significantly (P<0.05) depressed PGF(2 alpha)synthesis in placenta, uterus and liver by 50% when the n-6:n-3 ratio was 7:1 and by 66% at 34:1 ratio. Significant differences (P<0.05) in PGE(2)synthesis in uterus and liver were seen only between groups fed the high ratio of n-6:n-3 without CLA, and the low ratio with CLA. Addition of CLA to DHA containing diets depressed PGF(2alpha) by one-third in uterus and liver (P<0.05). Serum MMP-9 and active MMP-2 were suppressed (P<0.05) by addition of either CLA or DHA.

Identification of matrix metalloproteinases in canine cutaneous mast cell tumors.

Presence of matrix metalloproteinases has been associated with tumor invasion and metastasis in human neoplasia. The presence of matrix metalloproteinase 2 and matrix metalloproteinase 9 was determined in canine mast cell tumor tissue and normal stromal tissue from 24 dogs with spontaneously occurring cutaneous mast cell tumors. Seventeen of the mast cell tumors were of histologic grade 2, and 7 were of histologic grade 3. Gelatin zymography and computer assisted densitometry image analysis were used to quantify matrix metalloproteinase concentration. Bands from canine tissues migrated in the same location as human proenzyme and active enzyme matrix metalloproteinase 2 and matrix metalloproteinase 9 standards. A semiquantitative value for each patient sample was obtained by comparing the optical assessment density of each unknown band to the optical density of the human standard. The presence of matrix metalloproteinase 2 and matrix metalloproteinase 9 in histologic grade 2 mast cell tumors and histologic grade 3 mast cell tumors was compared, as was presence of matrix metalloproteinases in tumor and stromal tissue. There was dramatically more proenzyme matrix metalloproteinase 9 activity in histologic grade 3 mast cell tumors when compared to grade 2 tumors (P = .03). There was also dramatically more active enzyme matrix metalloproteinase 2 and active enzyme matrix metalloproteinase 9 activity in tumor tissue compared to stromal tissue (P = .02, P < .0001). This study demonstrates that the proenzyme and active enzyme forms of matrix metalloproteinase 2 and matrix metalloproteinase 9 are present in canine mast cell tumors. This appears to be related to the degree of histologic malignancy, although histologic grade 1 tumors were not evaluated.

Serum alhpa 1-acid glycoprotein concentrations in healthy and tumor-bearing cats.

The purpose of this study was to evaluate alpha 1-acid glycoprotein (AGP) concentrations in tumor-bearing and healthy cats. The hypothesis of the present study was that AGP concentrations would be significantly increased in tumor-bearing cats. Serum from 51 healthy and 97 tumor-bearing, client-owned cats was harvested at the time of presentation and stored at -80 degrees C until assayed. Cats with measurable, histologically confirmed malignancies, and healthy cats of similar ages were included. Serum was assayed for AGP concentration by using a radial immunodiffusion method. AGP concentrations were significantly (P = .0051) higher in tumor-bearing (763 +/- 595 microg/mL; mean +/- SD) when compared to healthy cats (501 +/- 377 microg/mL; mean +/- SD). Of the tumor-bearing cats, 35 had carcinomas, 33 had sarcomas, and 26 had discrete, round cell tumors. AGP concentrations were 645 +/- 62 microg/mL, 660 +/- 540 microg/mL, and 967 +/- 860 microg/mL, respectively, and there were no significant differences among the groups.

Serum zinc, chromium, and iron concentrations in dogs with lymphoma and osteosarcoma.

We compared serum concentrations of zinc, chromium, and iron in dogs with cancer to those of normal dogs. Dogs with lymphoma (n = 50) and osteosarcoma (n = 52) were evaluated. Dogs with lymphoma had significantly lower (P = .0028) mean serum zinc concentrations (mean +/- SD; 1.0 +/- 0.3 mg/L) when compared to normal dogs (1.2 +/- 0.4 mg/L). Dogs with osteosarcoma also had lower mean serum zinc concentrations (1.1 +/- 0.4 mg/L), but this difference was not significant (P = .075). Serum chromium concentrations were significantly lower in dogs with lymphoma (2.6 +/- 2.6 microg/L, P = .0007) and osteosarcoma (2.4 +/- 3.1 microg/L, P = .0001) compared to normal dogs (4.7 +/- 2.8 microg/L). Serum iron concentrations and total iron-binding capacity were significantly lower in dogs with lymphoma (110.8 +/- 56.7 microg/dL, P < .0001, and 236.6 +/- 45.6 microg/dL, P < .0001, respectively) and osteosarcoma (99.6 +/- 49.3 microg/dL, P < .0001, and 245.0 +/- 43.8 microg/dL, P = .0011, respectively) when compared to normal dogs (175.1 +/- 56.7 microg/dL and 277.1 +/- 47.4 microg/dL). Mean ferritin concentration was significantly higher in dogs with lymphoma (1291.7 +/- 63.0 microg/L) than in normal dogs (805.8 +/- 291.1 microg/L, P < .0001) and dogs with osteosarcoma (826.5 +/- 309.2 microg/L, P < .0001). Further investigation is needed to explore the clinical significance of these mineral abnormalities in dogs with cancer.

Identification of matrix metalloproteinases in canine neoplastic tissue.

OBJECTIVE: To identify matrix metalloproteinases (MMP) 2 and 9 in canine tumor tissue and to compare the amount of activity to that in unaffected stromal tissue. ANIMALS: 30 dogs with spontaneously developing, high-grade osteosarcoma. PROCEDURE: Tumor and nearby stromal tissue (muscle) were obtained at the time of surgery. Specimens were homogenized, and supernatants were assayed, using gelatin zymography. Human derived standards were run concurrently. Densitometry was done to obtain a semiquantitative arbitrary unit value for each specimen. The amount of activity in tumor tissue was compared with the amount in stromal tissue. RESULTS: Gelatinolytic bands were observed from the analysis of all tumor tissues and in most stromal tissues. These bands migrated in the same molecular weight area as the human MMP 2 and 9 standards. Gelatinolytic activity could be quenched by the addition of 50 mM EDTA and 1 microg of synthetic tissue inhibitor of metalloproteinase (TIMP) 2 per 100 ml. There was significantly more gelatinolytic activity in tumor tissue than in stromal tissue. CONCLUSIONS AND CLINICAL RELEVANCE: MMP 2 and 9 are detectable in canine neoplastic tissue. Matrix metalloproteinases activity in tumor tissue is higher than in unaffected stromal tissue, indicating that canine MMP may be involved in the pathogenesis of tumor growth and metastasis.

Duration of effects of dietary fish oil supplementation on serum eicosapentaenoic acid and docosahexaenoic acid concentrations in dogs.

OBJECTIVE: To determine how long serum concentrations of omega-3 fatty acids remain elevated after cessation of dietary fish oil supplementation. ANIMALS: 12 healthy Beagles. PROCEDURE: Baseline serum concentrations of linoleic acid, linolenic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) were measured. Dogs were then fed a diet supplemented with soybean oil or fish oil for 8 weeks, and serum fatty acid concentrations were measured while dogs were fed the experimental diets and for 18 weeks after they were switched to a maintenance diet. RESULTS: For dogs fed the fish oil diet, serum EPA and DHA concentrations were significantly increased by week 1 and remained increased for 7 (DHA concentration) or 3 (EPA concentration) weeks after dietary fish oil supplementation was discontinued. CONCLUSIONS: In dogs, supplementation of the diet with fish oil may have effects for several weeks after dietary supplementation is discontinued. CLINICAL RELEVANCE: Studies of the effects of fish oil supplementation that use a crossover design should allow for an appropriate washout period.

The ethics of caring for patients with HIV or AIDS.

Health care professionals encounter many ethical issues in the care of persons who are HIV positive or who have been diagnosed as having AIDS. Such issues include the allocation of scarce resources for research and health care; the use of various methods of disease control, including mandatory testing, forced isolation, informing of sexual partners, and education; and the determination of the responsibility to treat infected patients. These issues are presented as a stimulus to readers to examine their own attitudes regarding HIV and AIDS. The usefulness and limitations of occupational therapy's professional code in resolving ethical dilemmas are discussed, followed by the description of a process that can be used to analyze and solve these dilemmas.

Influence of occupational therapy curricula on students' attitudes toward persons with disabilities.

The influence of occupational therapy curricula on students' attitudes toward persons with disabilities was studied. Twenty-six female students in either their first or fourth (i.e, final) semester of the occupational therapy curriculum were assessed with the Attitudes Toward Disabled Persons Scale (ATDP) (Yukor, Block, & Younng, 1966). A comparison group, 26 female students in either their first or fourth semester of the medical technology program, was also assessed with this scale. As hypothesized, the fourth-semester occupational therapy students showed significantly higher scores than did the other three groups of subjects. Also as predicted, this same group showed significantly higher scores than their first-semester counterparts and the fourth-semester medical technology students. No significant difference was found between first-semester and fourth-semester medical technology students. The occupational therapy curriculum appears to positively influence students' attitudes toward persons with disabilities.

Medication error reporting in nursing homes: identifying targets for patient safety improvement.

BACKGROUND: Legislation enacted in the US State of North Carolina in 2003 requires all licenced nursing homes to report all medication errors. In 2007, nursing homes were encouraged to voluntarily convert from aggregate reporting to a new online system where they reported each individual error. METHODS: A new optional web-based reporting tool was made available to all 393 North Carolina nursing homes to submit error reports for each distinct medication error as they occurred during the year. RESULTS: A total of 5823 medication error reports were submitted by 203 sites (52%) using the new system during the reporting year, a median of 18 error reports per site. Of the 5823 error reports, 612 (10.5%) were categorised as serious. Serious errors were more likely to be caused by drugs given to the wrong patient (RR 4.39, CI 3.7 to 5.2), lab-work error (RR 2.40, CI 1.4 to 4.0), wrong product given (RR 2.22, CI 1.8 to 2.8) and medication overdoses (RR 1.49, 1.2 to 1.8). Serious errors were more likely to occur on second shift (RR 1.32, 1.1 to 1.5). Common medications that are involved in the most serious errors include warfarin (RR 2.58, CI 2.09 to 3.18) and insulin (RR 2.35, CI 1.86 to 2.97), and oxycodone combinations (RR 1.48, CI 1.07 to 2.06). CONCLUSIONS: Data collected from a nursing home medication error system can provide helpful information on serious errors that can be used to focus patient safety efforts to reduce harm. This improved information will be useful in nursing homes for continuous quality improvement efforts.

The effects of age and gender on the pharmacokinetics of tenidap sodium in patients with rheumatoid arthritis and osteoarthritis.

1. This open-label study was conducted to evaluate the effects of age and gender on the pharmacokinetics of tenidap sodium in patients with either rheumatoid arthritis (RA) or osteoarthritis (OA). 2. A total of 145 male and female patients, 80 with RA (aged 22-91 years) and 65 with OA (aged 45-83 years) each received a single dose of 120 mg tenidap sodium. Pharmacokinetic parameters were estimated from individual tenidap plasma concentration-time curves determined up to 120 h post-dose. Tenidap plasma protein binding was determined in the youngest and oldest age groups for both RA and OA patients. 3. In RA patients, age and gender did not significantly affect the disposition of tenidap or the percentage of unbound tenidap in plasma. Only for tmax were statistically significant effects in the analysis of covariance observed and these were attributed to very high tmax values in two female patients. Likewise, in patients with OA, age and gender did not significantly affect the pharmacokinetics of tenidap, although patients with larger body weights had lower Cmax values. 4. Pharmacokinetic parameters were not significantly different between RA and OA patients, except for t1/2, where two outlier RA patients had low values that caused the mean value to be significantly lower in RA (24 h) than in OA (26 h) patients. Pharmacokinetic parameters for pooled values from RA and OA patients were as follows: t1/2 = 25 h, AUC = 538.4 micrograms ml-1 h, Cmax = 21.9 micrograms ml-1, tmax = 3.2 h.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of ziprasidone in healthy volunteers treated with cimetidine or antacid.

AIMS: To evaluate the effects of cimetidine and Maalox(R) (aluminium hydroxide 1.35 g and magnesium hydroxide 1.2 g) on the pharmacokinetics of ziprasidone. METHODS: Eleven healthy young subjects aged 18-45 years were given single oral doses of ziprasidone 40 mg on three occasions at least 7 days apart. On one occasion ziprasidone was administered alone, on another occasion ziprasidone was co-administered with oral cimetidine 800 mg and on a third occasion ziprasidone was co-administered with oral Maalox(R). RESULTS: The administration of cimetidine increased the ziprasidone AUC(0,infinity) by 6% but there were no statistically significant differences in Cmax, tmax or lambda(z) between the ziprasidone+cimetidine group and the ziprasidone group. The administration of Maalox did not produce any statistically significant differences in AUC(0,infinity), Cmax, tmax or lambda(z) between the ziprasidone+Maalox group and the ziprasidone group. CONCLUSIONS: The pharmacokinetics of ziprasidone are not affected by concurrent administration of cimetidine or Maalox. This suggests that other nonspecific inhibitors of cytochrome P450 and antacids are unlikely to alter the pharmacokinetics of ziprasidone.

The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone in healthy volunteers.

AIMS: To evaluate the effect of steady-state carbamazepine administration on the steady-state pharmacokinetics of ziprasidone in healthy young adults, in an open, randomised, parallel-group study. METHODS: Twenty-five subjects were randomized to one of two treatment groups. Group 1 received 20 mg ziprasidone twice daily on days 1 and 2, and a single dose on day 3. A single 100 mg dose of carbamazepine was given once daily on days 5 and 6 and twice daily on days 7 and 8, followed by 200 mg twice daily until day 28 and on the morning only on day 29. Ziprasidone 20 mg was also administered twice daily on days 26 and 27 and in the morning only on day 28. Group 2 received the same treatment regimen with carbamazepine replaced by placebo. Pharmacokinetic data were obtained on days 3 and 28. RESULTS: Nine subjects in group 1 and 10 in group 2 completed all three treatment periods (ziprasidone, carbamazepine or placebo; and ziprasidone plus carbamazepine or placebo). Carbamazepine administration to group 1 was associated with modest reductions in ziprasidone exposure, with mean decreases in ziprasidone AUC(0,12 h) and Cmax values of 36% and 27%, respectively, on day 28 compared with day 3 (P<0.03). The mean differences between day 28 and day 3 ziprasidone AUC(0,12 h) and Cmax values were also statistically significantly greater in the carbamazepine group than in the placebo group. The mean half-life of ziprasidone decreased by 1 h from day 3 to day 28 in the subjects receiving carbamazepine, compared with virtually no change in the placebo group. All adverse events were mild or moderate in severity and there were no serious adverse events, or clinically significant changes in ECGs and vital signs throughout the study. CONCLUSIONS: Induction of CYP3A4 with carbamazepine led to a modest reduction (<36%) in steady-state exposure to ziprasidone that is believed to be clinically insignificant.

Pharmacokinetics of fluconazole in renal failure.

Fluconazole (FLU) is a widely used antifungal agent. The multiple-dose pharmacokinetics of FLU in renal impairment have not been previously investigated. The following groups were studied: volunteers with creatinine clearances (CLcr, > 50 mL/min) of 107 mL/min, given a loading dose of 400 mg and a daily dose of 200 mg/day for 9 days (Group 1); subjects with CLcr between 21 and 50 mL/min with a mean of 38 mL/min, given a loading dose of 200 mg and a maintenance dose of 100 mg/day for 9 days (Group 2); subjects with CLcr between 11 and 20 mL/min with a mean of 14.8 ml/min, given a loading dose of 100 mg and a maintenance dose of 50 mg/day for 9 days (Group 3); and subjects on hemodialysis (three times per week) receiving a loading dose of 200 mg and then 100 mg after each of four dialysis sessions (Group 4) (N = 10 per group). After the administration of the loading dose on Day 1, the mean area under the curve (AUC) (0-24) measurements were approximately proportional to the dose of FLU and independent of renal function. After 10 days of FLU dosing, the mean renal clearance of FLU decreased as CLcr decreased for Groups 1 to 3, and the Day 10 mean half-lives were inversely related to mean CLcr (36.7 h in Group 1, 84.5 h in Group 2, and 101.9 h in Group 3). The mean AUC (0-24) on Day 10 was similar for Group 1 compared with Group 2, despite a reduction in the maintenance dose by 50%. (ABSTRACT TRUNCATED AT 250 WORDS)

Single and multiple dose pharmacokinetics of tenidap sodium in healthy subjects.

1. The absorption, protein binding, clearance and absolute bioavailability of tenidap sodium were studied after single and multiple dosing. 2. Thirteen healthy male volunteers received a single 120 mg oral dose of tenidap sodium and a 20 mg intravenous infusion of deuterated tenidap ([D3]-tenidap) on day 1. This was followed by a 6-day washout period (days 2-7) and then further daily doses of oral tenidap sodium 120 mg for 21 consecutive days (days 8-28) with an additional 20 mg intravenous infusion of [D3]-tenidap on day 28. Twelve subjects were eligible for pharmacokinetic evaluation. 3. Following multiple oral doses, the half-life of tenidap is approximately 23 h. 4. Following single and multiple dose administration, the absolute bioavailability is 85%. 5. Systemic clearance of [D3]-tenidap was 29% greater on day 28 than on day 1 indicating a significant increase in intrinsic clearance (CLint) of tenidap since protein binding of tenidap in plasma did not change during the study. Consistent with the increase in systemic clearance, the half-life of [D3]-tenidap decreased and the ratio of AUC(0,24h) day 28/AUC day 1 following oral dosing was less than one. Tenidap is subject to extensive hepatic metabolism, so the increase in CLint may indicate that tenidap induces its own metabolism. 6. Steady-state was achieved by the eleventh day of dosing. Since numerous studies in patients with rheumatoid arthritis have shown that multiple dosing with tenidap is clinically efficacious, this suggests that the pharmacokinetic differences observed between the first and twenty-first day of multiple tenidap dosing do not influence the clinical response.