Effect of Dose on Serum Pharmacokinetics of Intravenous Ciprofloxacin with Identification and Characterization of Extravascular Compartments Using Noncompartmental and Compartmental Pharmacokinetic Models

The effect of dose on the pharmacokinetics of ciprofloxacin in serum and urine following single intravenous doses of 100, 150, and 200 mg was studied in nine healthy volunteers. Mean peak levels in serum were 1.4, 2.0, and 3.2 mg/liter for the 100-, 150-, and 200-mg doses, respectively. The data on concentrations in serum were best described by a three-compartment pharmacokinetic model. The terminal half-life (from noncompartmental analysis) averaged between 4.2 and 4.6 h. Average urinary recovery ranged between 45.8 and 48.1%. The average renal clearance of ciprofloxacin was 2.9- to 3.4-fold greater than the measured creatinine clearance. Total serum and renal clearances decreased with increasing dose; however, this was not statistically significant (P \u3e 0.05; repeated-measures analysis of variance). Ciprofloxacin was well tolerated by all subjects. In this dose range, ciprofloxacin pharmacokinetics are independent of dose

Significance of Extravascular Protein Binding for Antimicrobial Pharmacodynamics in an In Vitro Capillary Model of Infection

The effect of protein binding in an extravascular space on antimicrobial pharmacodynamics was studied in an in vitro capillary model of infection. Simulated 500-mg oral doses of dicloxacillin (~ 96% bound) or cephalexin (\u3c 5% bound) were administered every 6 h for four doses. A 10-fold-higher dose of dicloxacillin was also studied to determine the effect of drug concentration on the reduction of bacterial killing in the presence of protein. Staphylococcus aureus ATCC 25923 was inoculated into peripheral chambers filled with either Mueller-Hinton broth or Mueller-Hinton broth plus 25% human serum. Serial samples for bacterial counts were collected over 24 h. The presence of serum in the chambers significantly reduced bacterial killing by dicloxacillin but not by cephalexin during the first 6 h (two-way analysis of variance, F = 6.04, P \u3c 0.05) but not at 24 h. Reduction of dicloxacillin activity in serum-containing chambers persisted with the higher dose. These data suggest that despite attaining higher total drug concentrations in protein-containing extravascular spaces with highly bound drugs, protein binding reduces bactericidal activity during the early stages of treatment in this model

In Vitro Postantibiotic Effect Following Repeated Exposure to Imipenem, Temafloxacin, and Tobramycin

The postantibiotic effect (PAE) following three consecutive 2-h exposures to imipenem, temafloxacin, and tobramycin was determined in Pseudomonas aeruginosa. A PAE and a bactericidal effect were consistently observed for imipenem following each cycle of drug exposure and regrowth. In contrast, the PAE increased with repeated exposure with temafloxacin (1.8 to \u3e 5 h), but disappeared with tobramycin by the third exposure (0.9 to 0 h). These data show that the in vitro PAE may change within a strain following multiple cycles of drug exposure and bacterial regrowth

Combination Therapy with Ciprofloxacin plus Azlocillin against Pseudomonas aeruginosa: Effect of Simultaneous versus Staggered Administration in an In Vitro Model of Infection

The effect of dose scheduling on the pharmacodynamics of simulated human doses of ciprofloxacin (200 mg intravenously [iv] every 12 h) and azlocillin (4 g iv every 12 h) alone or in combination against Pseudomonas aeruginosa was studied in a two-compartment in vitro kinetic model of infection. Studies with the two drugs in combination were compared using simultaneous or staggered (first doses of each drug were administered 6 h apart) dosing schedules. Bacterial regrowth and resistance were prevented by all combination dosing schedules; however, the simultaneous regimen consistently provided the greatest extent of killing for all strains, particularly in those initially resistant to ciprofloxacin. These enhanced effects of the combination were corroborated by an increase in the peak and duration of bactericidal activity in the analogous "serum” compartment of the model. These data show the potential usefulness of simultaneous dosing of an antipseudomonal µ-lactam with ciprofloxacin against P. aeruginos

Effect of 2\u27,3\u27-Didehydro-3\u27-Deoxythymidine in an In Vitro Hollow-Fiber Pharmacodynamic Model System Correlates with Results of Dose-Ranging Clinical Studies

We sought to validate an in vitro system which could predict the minimal effect dose of antiretroviral agents. Mixtures of uninfected CEM cells and CEM cells chronically infected with human immunodeficiency virus (HIV) type 1 MN were exposed to 2\u27,3\u27-didehydro-3\u27-deoxythymidine (D4T) in vitro in a hollow-fiber model which simulates the plasma concentration-time profile of D4T in patients. Drug concentration was adjusted to simulate continuous intravenous infusion, or an intravenous bolus administered twice daily. The effect of the dosing regimen was measured with viral infectivity, p24 antigen, and reverse transcriptase or PCR for unintegrated HIV DNA. Dose deescalation studies on a twice-daily dosing schedule predicted a minimum effect dose of 0.5 mg/kg of body weight per day which correlated with the results of a clinical trial. Antiviral effect was demonstrated to be independent of schedule for every 12-h dosing versus continuous infusion. Finally, at or near the minimal effect dose, efficacy appeared to depend on the viral load. The ability of this in vitro pharmacodynamic model to assess the response of HIV-infected cells to different doses and schedules of antiviral agents may be useful in the design of optimal dosing regimens for clinical trials but requires validation with other types of antiretroviral agents

Cardiovascular Magnetic Resonance and prognosis in cardiac amyloidosis

Background: Cardiac involvement is common in amyloidosis and associated with a variably adverse outcome. We have previously shown that cardiovascular magnetic resonance (CMR) can assess deposition of amyloid protein in the myocardial interstitium. In this study we assessed the prognostic value of late gadolinium enhancement (LGE) and gadolinium kinetics in cardiac amyloidosis in a prospective longitudinal study.Materials and methods: The pre-defined study end point was all-cause mortality. We prospectively followed a cohort of 29 patients with proven cardiac amyloidosis. All patients underwent biopsy, 2D-echocardiography and Doppler studies, I-123-SAP scintigraphy, serum NT pro BNP assay, and CMR with a T-1 mapping method and late gadolinium enhancement (LGE).Results: Patients with were followed for a median of 623 days (IQ range 221, 1436), during which 17 (58%) patients died. The presence of myocardial LGE by itself was not a significant predictor of mortality. However, death was predicted by gadolinium kinetics, with the 2 minute post-gadolinium intramyocardial T1 difference between subepicardium and subendocardium predicting mortality with 85% accuracy at a threshold value of 23 ms (the lower the difference the worse the prognosis). Intramyocardial T1 gradient was a better predictor of survival than FLC response to chemotherapy (Kaplan Meier analysis P = 0.049) or diastolic function (Kaplan-Meier analysis P = 0.205).Conclusion: In cardiac amyloidosis, CMR provides unique information relating to risk of mortality based on gadolinium kinetics which reflects the severity of the cardiac amyloid burden

Family Caregiver Identity: A Literature Review

Background: Despite the multitude of available resources, family caregivers of those with chronic disease continually underutilize support services to cope with the demands of caregiving. Several studies have linked self-identification as a caregiver to the increased likelihood of support service use. Purpose: The present study reviewed the literature related to the development of family caregiver identity. Methods: After a systematic process to locate literature was completed, content analysis was conducted to determine major themes related to the development of caregiving identity. Results: Findings suggest that there are multiple factors related to the development of family caregiver identity, including role engulfment and reversal, loss of shared identity, family obligation and gender norming, extension of the former role, and development of a master identity. Discussion: Considering the role of identity in human behavior, health professionals can address the underutilization of support services by family caregivers of those with chronic disease by understanding the influences on the development of caregiver identity. Translation to Health Education Practice: This literature review will assist health educators in addressing the underutilization of support services by family caregivers of those with chronic disease

Antimicrobial Drug Resistance, Regulation, and Research1

Research models and regulatory measures could aid in developing antimicrobial drugs to address bacterial resistance

Diffusion of medication drop-boxes in North Carolina from 2007 to 2016

Introduction: A permanent drug donation box (“drop-box”) is one strategy implemented in communities across the United States to reduce the availability of excess controlled medications, including prescription opioids, for diversion. The objective of this study was to examine correlates of the diffusion and implementation of drop-boxes in North Carolina.Methods: We assessed the number and location of drop-boxes implemented in North Carolina. Cox proportional hazards models were used to examine covariates associated with drop-box implementation in NC counties (n?=?100) between 2007 and 2016.Results: There were 311 drop-boxes implemented in 91 (out of 100) counties. Most drop-boxes were in law enforcement agencies (78.8%) and a growing number were in pharmacies (14.5%). Counties with a higher percentage of whites, more educated residents, a substance abuse prevention coalition, higher rates of controlled medications dispensed and prescription opioid overdose, and that were Appalachian were more likely to be early adopters. Rural counties were less likely to have a drop-box. In the multivariate model, only higher rate of controlled medicines dispensed was significant.Conclusions: A growing number of drop-boxes are being implemented in law enforcement offices and pharmacies. Given that communities with higher rates of controlled medication dispensing likely have the highest need for disposal opportunities, it is promising that they are early adopters of drop-boxes. Future research should assess the effectiveness of drop-boxes as they become more widespread in a variety of locations

Continuous Equilibrium in Affine and Information-Based Capital Asset Pricing Models

We consider a class of generalized capital asset pricing models in continuous time with a finite number of agents and tradable securities. The securities may not be sufficient to span all sources of uncertainty. If the agents have exponential utility functions and the individual endowments are spanned by the securities, an equilibrium exists and the agents' optimal trading strategies are constant. Affine processes, and the theory of information-based asset pricing are used to model the endogenous asset price dynamics and the terminal payoff. The derived semi-explicit pricing formulae are applied to numerically analyze the impact of the agents' risk aversion on the implied volatility of simultaneously-traded European-style options.Comment: 24 pages, 4 figure