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Patient safety, improved patient outcomes, drug efficacy, system efficiency, costs, profits, convenience and other factors are among the driving forces behind the constant change in medication use. This paper gives an overview of selected elements of the medication use system, describes recent changes and trends in the system, and provides some thoughts about the impact of some of the elements on medication errors. [ABSTRACT FROM AUTHOR]

Background: The optimal regimen for prevention and treatment of venous thromboembolism in bariatric surgical patients remains controversial. Direct oral anticoagulants are potentially advantageous over other agents, but inadequate evidence exists regarding their effects in bariatric surgical patients., Objectives: To investigate single-dose pharmacokinetic (PK) and pharmacodynamic (PD) parameters of apixaban when administered to patients undergoing vertical sleeve gastrectomy (VSG) or Roux-en-Y gastric bypass (RYGB) and to determine whether the PK and PD parameters are affected by type of bariatric surgery and weight loss in the immediate and postoperative period up to 12 months., Setting: University Hospital and A Bariatric Center of Excellence, Baltimore, Maryland., Methods: Adults with a body mass index ≥35 kg/m 2 approved for bariatric surgery were enrolled in a single-center, open-label, nonrandomized, single-dose clinical study (NCT No. 02406885; www., Clinicaltrials: gov). Apixaban PK and PD parameters were measured after a single 5 mg dose of the drug was given preoperatively and at 1, 6, and 12 months postoperatively in patients undergoing VSG and RYGB. Change in PK parameters was assessed as maximum concentration, time to maximum concentration, elimination half-life, and area under the concentration-time curve from 0-72 hours and change in PD parameters were assessed by chromogenic factor X activity., Results: Of 33 patients enrolled, 28 (14 VSG, 14 RYGB) completed all visits and were analyzed. Most patients (89%) were female, with a mean age of 43.8 years and a body mass index of 48.7 kg/m 2 . Area under the concentration-time curve from 0-72 hours increased from baseline to 1 month (1009.1 to 1232.9 ng/mL/hr, P = .002), returned to baseline at 6 months (1000.9 ng/mL/hr, P = .88), and decreased significantly at 12 months (841.8 ng/mL/hr, P = .001). Maximum concentration did not change significantly. Predose factor X activity dropped significantly from 113% preoperatively to 89.8 % at 12 months postoperatively (P < .0001). Three-hour postdose factor X activity was significantly lower at 1, 6, and 12 months postoperatively versus preoperatively. However, the magnitude of the decrease from predose to 3-hour postdose was not significantly altered by surgery., Conclusion: The effect of either VSG or RYGB on apixaban PK and PD parameters is minimal. Factor X activity after 5 mg apixaban was lower in postoperative versus preoperative bariatric patients, but this effect appears to be primarily the result of a decrease in factor X activity from bariatric surgery itself and not a postoperative change in apixaban PK and PD parameters. Future studies should investigate the safety, efficacy, and clinical outcomes of apixaban and other direct oral anticoagulants perioperatively and beyond 12 months following bariatric surgery., (Copyright © 2021 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: There is currently no single treatment that mitigates all harms caused by severe acute respiratory syndrome coronavirus 2 infection. Tocilizumab, an interleukin-6 antagonist, may have a role as an adjunctive immune-modulating therapy., Methods: This was an observational retrospective study of hospitalized adult patients with confirmed coronavirus disease 2019 (COVID-19). The intervention group comprised patients who received tocilizumab; the comparator arm was drawn from patients who did not receive tocilizumab. The primary outcome was all-cause mortality censored at 28 days; secondary outcomes were all-cause mortality at discharge, time to clinical improvement, and rates of secondary infections. Marginal structural Cox models via inverse probability treatment weights were applied to estimate the effect of tocilizumab. A time-dependent propensity score-matching method was used to generate a 1:1 match for tocilizumab recipients; infectious diseases experts then manually reviewed these matched charts to identify secondary infections., Results: This analysis included 90 tocilizumab recipients and 1669 controls. Under the marginal structural Cox model, tocilizumab was associated with a 62% reduced hazard of death (adjusted hazard ratio [aHR], 0.38; 95% CI, 0.21 to 0.70) and no change in time to clinical improvement (aHR, 1.13; 95% CI, 0.68 to 1.87). The 1:1 matched data set also showed a lower mortality rate (27.8% vs 34.4%) and reduced hazards of death (aHR, 0.47; 95% CI, 0.25 to 0.88). Elevated inflammatory markers were associated with reduced hazards of death among tocilizumab recipients compared with controls. Secondary infection rates were similar between the 2 groups., Conclusions: Tocilizumab may provide benefit in a subgroup of patients hospitalized with COVID-19 who have elevated biomarkers of hyperinflammation, without increasing the risk of secondary infection., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Payers, providers, and patients increasingly recognize the importance of quality and safety in health care. Academic Departments of Medicine can advance quality and safety given the large populations they serve and the broad spectrum of diseases they treat. However, there are only few detailed examples of how quality and safety can be organized. This article describes a practical model at The Johns Hopkins Hospital Department of Medicine and details its structure and operation within a large academic health system. It is based on a fractal model that integrates multiple smaller units similar in structure (composition of faculty/staff), process (use of similar tools), and approach (using a common framework to address issues). This organization stresses local, multidisciplinary leadership, facilitates horizontal connections for peer learning, and maintains vertical connections for broader accountability.

As quality improvement and patient safety come to play a larger role in health care, academic medical centers and health systems are poised to take a leadership role in addressing these issues. Academic medical centers can leverage their large integrated footprint and have the ability to innovate in this field. However, a robust quality management infrastructure is needed to support these efforts. In this context, quality and safety are often described at the executive level and at the unit level. Yet, the role of individual departments, which are often the dominant functional unit within a hospital, in realizing health system quality and safety goals has not been addressed. Developing a departmental quality management infrastructure is challenging because departments are diverse in composition, size, resources, and needs.In this article, the authors describe the model of departmental quality management infrastructure that has been implemented at the Johns Hopkins Hospital. This model leverages the fractal approach, linking departments horizontally to support peer and organizational learning and connecting departments vertically to support accountability to the hospital, health system, and board of trustees. This model also provides both structure and flexibility to meet individual departmental needs, recognizing that independence and interdependence are needed for large academic medical centers. The authors describe the structure, function, and support system for this model as well as the practical and essential steps for its implementation. They also provide examples of its early success.

General Internal Medicine research evolves in response to the needs of the patients to whom we provide care. Currently, many studies exclude older adults who deeply affect the clinical care of this population. With the number of older adults increasing, creating research protocols that include older adults with multiple chronic comorbidities is imperative. Through funding from the Association of Specialty Physicians, a working group of aging-responsive researchers from the Society of General Internal Medicine was convened to tackle this issue. The goal of this article is threefold: 1) to shed light on the current exclusion of older adults in research; 2) to identify and propose research protocol solutions for overcoming barriers to including older adults in research; and 3) to provide suggestions for research funding. The extent to which these recommendations can create change depends greatly on our researcher colleagues. By embracing these challenges, we hope that the care provided to older adults with multiple chronic conditions will no longer be extrapolated, but become evidence-based.

This manuscript summarizes current thinking on the value and promise of evolving circulating tumor cell (CTC) technologies for cancer patient diagnosis, prognosis, and response to therapy, as well as accelerating oncologic drug development. Moving forward requires the application of the classic steps in biomarker development-analytical and clinical validation and clinical qualification for specific contexts of use. To that end, this review describes methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the US Food & Drug Administration (FDA) and the US National Cancer Institute (NCI).

The centuries-old antimalarial drug, quinine, continues to play a critical role in the treatment of severe falciparum malaria and uncomplicated malaria in pregnant women. It shares cytochrome P450 (CYP )-mediated metabolic pathways with several commonly used antiretroviral drugs, raising the potential for clinically important drug–drug interactions. A phase I pharmacokinetic study was conducted to assess the impact of long-term use of ritonavir-boosted lopinavir (LPV/r) on quinine pharmacokinetics in healthy volunteers. LP V/r significantly decreased the exposure of quinine and its major active metabolite, 3-hydroxyquinine, in both total and free (unbound) forms. These findings highlight the complex nature of the influence exerted by LPV/r on several of the drug-metabolizing enzymes involved in quinine disposition,including CYP 3A4, UDP-glucuronosyltransferase (UG T), and P-glycoprotein (P-gp). A decline in quinine exposure may compromise clinical efficacy. Further studies are warranted to assess changes in quinine pharmacokinetics and treatment outcomes in patients with acute malaria receiving antiretroviral therapy that includes LPV/r.

Objective: To estimate the risks and benefits associated with continuation of anticoagulants or antiplatelet medication use before cataract surgery., Design: Prospective cohort study., Participants: Patients 50 and older scheduled for 19,283 cataract surgeries at nine centers in the United States and Canada between June 1995 and June 1997., Intervention: None., Main Outcome Measures: Intraoperative and postoperative (within 7 days) retrobulbar hemorrhage, vitreous or choroidal hemorrhage, hyphema, transient ischemic attack (TIA), stroke, deep vein thrombosis, myocardial ischemia, and myocardial infarction., Results: Before cataract surgery 24.2% and 4.0% of patients routinely used aspirin and warfarin, respectively. Among routine users, 22.5% of aspirin users and 28.3% of warfarin users discontinued these medications before surgery. The rates of stroke, TIA, or deep vein thrombosis were 1.5/1000 among those who did not use aspirin or warfarin and 3.8/1000 surgeries among routine users of aspirin and warfarin who continued their medication before surgery. The rate was 1 event per 1000 surgeries among those who discontinued aspirin use (relative risk = 0.7, 95% confidence interval = 0.1-5.9). There were no events among warfarin users who discontinued use. The rates of myocardial infarction or ischemia were 5.1/1000 surgeries (aspirin) and 7.6/1000 surgeries (warfarin) among routine continuous users and no different from those of routine users who discontinued use., Conclusions: The risks of medical and ophthalmic events surrounding cataract surgery were so low that absolute differences in risk associated with changes in routine anticoagulant or antiplatelet use were minimal.

Purpose: To determine the utility and limitations of D-dimer testing for the evaluation of venous thromboembolism in hospitalized patients., Methods: We performed D-dimer testing by four different methods in unselected inpatients undergoing radiologic evaluation for possible venous thromboembolism. We included patients with a history of malignancy, recent surgery, thrombosis, and anticoagulation treatment. C-reactive protein levels were assayed as a measure of inflammation., Results: Of 45 patients with radiographically proven proximal deep venous thrombosis or pulmonary embolism, 43 had elevated D-dimer levels by enzyme-linked immunosorbent assay (ELISA) (sensitivity, 96%); the specificity of the test was 23% (36/157). The qualitative non-ELISA tests had higher specificities, but their sensitivities were <70%. Nineteen patients (42%) with thrombosis had false-negative D-dimer tests by at least one assay. The specificity of the tests decreased with increasing duration of hospitalization, increasing age, and increasing C-reactive protein levels. D-dimer testing had little or no utility in distinguishing patients with thrombosis from those without in patients who had been hospitalized for more than 3 days, were older than 60 years, or had C-reactive protein levels in the highest quartile., Conclusion: In unselected inpatients, D-dimer testing has limited clinical utility because of its poor specificity. This is particularly true for older patients, those who have undergone prolonged hospitalization, and those with markedly elevated C-reactive protein levels. In some patient subsets, a negative non-ELISA D-dimer test cannot discriminate between inpatients with and without thrombosis.

One of the consultant's roles is to make recommendations regarding the use of medications in the perioperative period. Unfortunately, the data in this area are often insufficient to provide evidence-based recommendations. In this article, we have provided advice considering the pharmacokinetics of the drug, the effect on the primary disease of stopping medications, and the effect of the medication on perioperative risk, including potential drug interactions with anesthetic agents.

Background: With the expiration of the patent on albuterol metered-dose inhalers (MDIs) in 1989, methods to assess in vivo bioequivalence of generic formulations required investigation., Objective: In an effort to develop a sensitive method to document bioequivalence, bronchoprovocation with methacholine chloride was used to assess the dose-response relationship of albuterol as delivered by MDI. Sensitivity was assessed in terms of magnitudes of ED(50), the estimated albuterol dose required to achieve 50 % of the fitted maximal value of the pharmacodynamic effect above baseline, and change in response as a function of dose, with emphasis on 1 and 2 actuations., Methods: On separate study days, 15 nonsmokers with mild asthma received randomized nominal albuterol doses of 0 to 576 microg by using specially manufactured MDI canisters. FEV(1) was measured 15 minutes after MDI dosing. Serially increasing doses of methacholine were administered, and FEV(1) was measured after each methacholine dose until a 20 % decrease in FEV(1) (PD(20)) was achieved., Results: Mean PD(20) values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD(20) values (P <.05). Mean responses and most individual subject responses to 1 and 2 actuations (90 and 180 microg) of albuterol MDI were within the sensitive region of the dose- response curve. The mean estimated ED(50) value on the basis of nonlinear mixed effect modeling was 119.2 microg (range, 33.3-337.1 microg), with an intersubject percentage coefficient of variation of 69.0 %., Conclusions: The methacholine bronchoprovocation model is safe and useful in the study of albuterol MDI dose-response in asthmatic subjects. Bronchoprovocation studies may be used for determination of bioequivalence of multisource albuterol MDI products.

Objective: To compare adverse medical events by different anesthesia strategies for cataract surgery., Design: Prospective cohort study., Participants: Patients 50 years of age and older undergoing 19,250 cataract surgeries at nine centers in the United States and Canada between June 1995 and June 1997., Intervention: Local anesthesia applied topically or by injection, with or without oral and intravenous sedatives, opioid analgesia, hypnotics, and diphenhydramine (Benadryl)., Main Outcome Measures: Intraoperative and postoperative adverse medical events., Results: Twenty-six percent of surgeries were performed with topical anesthesia and the remainder with injection anesthesia. There was no increase in deaths and hospitalizations associated with any specific anesthesia strategy. No statistically significant difference was observed in the prevalence of intraoperative events between topical and injection anesthesia without intravenous sedatives (0.13% and 0.78%, respectively). The use of intravenous sedatives was associated with a significant increase in adverse events for topical (1.20%) and injection anesthesia (1.18%), relative to topical anesthesia without intravenous sedation. The use of short-acting hypnotic agents with injection anesthesia was also associated with a significant increase in adverse events when used alone (1.40%) or in combination with opiates (1.75%), sedatives (2.65%), and with the combination of opiates and sedatives (4.04%). These differences remained after adjusting for age, gender, duration of surgery, and American Society of Anesthesiologists risk class., Conclusions: Adjuvant intravenous anesthetic agents used to decrease pain and alleviate anxiety are associated with increases in medical events. However, cataract surgery is a safe procedure with a low absolute risk of medical complications with either topical or injection anesthesia. Clinicians should weigh the risks and benefits of their use for individual patients.

Objective: To compare patient reports of intraoperative pain and postoperative side effects by different anesthesia strategies for cataract surgery., Design: Prospective cohort study., Participants: Men and women 50 years of age and older undergoing 19,250 cataract surgeries at nine centers in the United States and Canada from June 1995 through June 1997., Intervention: Topical anesthesia or anesthesia with injection, with or without sedatives, opioid analgesia, hypnotics, and diphenhydramine (Benadryl)., Main Outcome Measures: Patient ratings of intraoperative pain, satisfaction with pain management, and early postoperative side effects (drowsiness, nausea, vomiting, or a combination thereof)., Results: Twenty-six percent of surgeries were performed using topical anesthesia alone, and the remainder were performed with peribulbar, retrobulbar, or facial nerve block, or a combination thereof. Local anesthesia by injection with sedatives and diphenhydramine resulted in the lowest reporting of any intraoperative pain (1.3%), with postoperative drowsiness (9.6%) and nausea, vomiting, or both (1.5%) comparable with those administered topical anesthesia alone. Among those receiving topical anesthesia, use of sedatives and opioids reduced reports of any pain during surgery by 56% (95% confidence interval [CI], 34%, 70%), but increased nausea and vomiting (odds ratio, 2.27; 95% CI, 1.26, 4.09) compared with those administered topical anesthesia alone, after adjusting for age, gender, race, American Society of Anesthesiologists risk class, self-reported health status, and duration of surgery. Among those receiving local injections, use of opioids reduced reports of any pain among those receiving sedatives by 37% (95% CI, 15%, 54%), but did not increase postoperative side effects. The use of diphenhydramine among those receiving sedatives decreased reports of any pain by 59% (95% CI, 33%, 75%) and also reduced drowsiness and nausea and vomiting by 57% (95% CI, 48%, 65%) and by 60% (95% CI, 36%, 75%), respectively. Use of hypnotics with sedatives was associated with increased reports of any pain during surgery and increased nausea and vomiting after surgery., Conclusions: Patient reports of any pain during cataract surgery (5%) and postoperative side effects (16% drowsiness and 4% nausea and vomiting) were low, but varied by anesthesia strategy. Patient perceptions of pain and side effects can be helpful in guiding the appropriate choice of anesthesia strategy.

This phase I, double-blind, randomized, placebo-controlled study evaluated the safety of single and multiple (daily for 7 days) subcutaneous administrations of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy human volunteers at seven doses, ranging from 3 to 500 microg/kg/day. No serious or life-threatening adverse events occurred. The most frequently recorded adverse effects were mild injection-site pain, diarrhea, and elevation of liver function tests. No change in neurologic function was noted with these dosing regimens. We conclude that r-metHuNT3 is safe and well tolerated in the dosages used in this study., (Copyright 2000 John Wiley & Sons, Inc.)

Background: Routine preoperative medical testing is commonly performed in patients scheduled to undergo cataract surgery, although the value of such testing is uncertain. We performed a study to determine whether routine testing helps reduce the incidence of intraoperative and postoperative medical complications., Methods: We randomly assigned 19,557 elective cataract operations in 18,189 patients at nine centers to be preceded or not preceded by a standard battery of medical tests (electrocardiography, complete blood count, and measurement of serum levels of electrolytes, urea nitrogen, creatinine, and glucose), in addition to a history taking and physical examination. Adverse medical events and interventions on the day of surgery and during the seven days after surgery were recorded., Results: Medical outcomes were assessed in 9408 patients who underwent 9626 cataract operations that were not preceded by routine testing and in 9411 patients who underwent 9624 operations that were preceded by routine testing. The most frequent medical events in both groups were treatment for hypertension and arrhythmia (principally bradycardia). The overall rate of complications (intraoperative and postoperative events combined) was the same in the two groups (31.3 events per 1000 operations). There were also no significant differences between the no-testing group and the testing group in the rates of intraoperative events (19.2 and 19.7, respectively, per 1000 operations) and postoperative events (12.6 and 12.1 per 1000 operations). Analyses stratified according to age, sex, race, physical status (according to the American Society of Anesthesiologists classification), and medical history revealed no benefit of routine testing., Conclusions: Routine medical testing before cataract surgery does not measurably increase the safety of the surgery.

WR 6026 is an 8-aminoquinoline with activity against Pneumocystis carinii in vitro and in an animal model of P. carinii pneumonia that has predicted the clinical utility of related compounds. This study was conducted to assess the safety and tolerance of WR 6026 given once daily for 21 days to HIV-infected subjects with CD4 counts <500 cells/microl. This double-blind, placebo-controlled study employed WR 6026 doses starting at 30 mg once daily and increasing to 60, 90, 120, or 150 mg once daily. Weekly visits for clinical and laboratory monitoring were conducted. Forty-nine study subjects, including 25 subjects with CD4 counts <200 cells/microl and 12 subjects with CD4 counts <100 cells/microl, entered the study. The maximum tolerated dose was 120 mg/day. Dose-limiting methemoglobinemia (>20%) was seen in 3 of 6 study subjects who received 150 mg/day for > or =19 days. Methemoglobin level was correlated with peak plasma WR 6026 concentrations. Three other study subjects developed skin rashes that may have been drug-related, and two developed asymptomatic serum triglyceride levels >1000 mg/dl. We conclude that WR 6026 is well tolerated at doses up to 120 mg/day for 21 days in HIV-infected volunteers including those with CD4 counts <200 cells/microl. Methemoglobinemia appears to be the primary dose-limiting toxicity.

The pharmacokinetics and bioavailability of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosi ne (cyclic HPMPC) were examined at four doses in 22 patients with human immunodeficiency virus infection. Two groups of six patients received a single dose of cyclic HPMPC at 1.5 or 3.0 mg/kg of body weight by each of the oral and intravenous routes in a random order with a 2-week washout period between administrations. Additional patients received single intravenous doses of cyclic HPMPC at 5.0 mg/kg (n = 6) or 7.5 mg/kg (n = 4). Serial serum and urine samples were collected at intervals over 24 h after dosing. The concentrations of cyclic HPMPC and cidofovir in serum and urine samples were determined by validated reverse-phase ion-pairing high-performance liquid chromatography methods with derivatization and fluorescence detection. After intravenous administration of cyclic HPMPC, concentrations of cyclic HPMPC declined in a biexponential manner, with a mean +/- standard deviation half-life of 1.09 +/- 0.12 h (n = 22). The pharmacokinetics of cyclic HPMPC were independent of dose over the dose range of 1.5 to 7.5 mg/kg. The total clearance of cyclic HPMPC from serum and the volume of distribution of intravenous cyclic HPMPC were 198 +/- 39.6 ml/h/kg and 338 +/- 65.1 ml/kg, respectively (n = 22). The renal clearance of cyclic HPMPC (132 +/- 27.3 ml/h/kg; n = 22) exceeded the creatinine clearance (86.2 +/- 16.3 ml/h/kg), indicating active tubular secretion. The cyclic HPMPC excreted in urine in 24 h accounted for 71.3% +/- 16.0% of the administered dose. Cidofovir was formed from cyclic HPMPC in vivo with a time to the maximum concentration in serum of 1.64 +/- 0.23 h (n = 22). Cidofovir levels declined in an apparent monoexponential manner, with a mean terminal half-life of 3.98 +/- 1.26 h (n = 22). The cidofovir excreted in urine in 24 h accounted for 9.40% +/- 2.33% of the administered cyclic HPMPC dose. Exposure to cidofovir after intravenous administration of cyclic HPMPC was dose proportional and was 14.9% of that from an equivalent dose of cidofovir. The present study suggests that intravenous cyclic HPMPC also has a lower potential for nephrotoxicity in humans compared to that of intravenous cidofovir. The oral bioavailabilities of cyclic HPMPC were 1.76% +/- 1.48% and 3.10% +/- 1.16% with the administration of doses of 1.5 and 3.0 mg/kg, respectively (n = 6 per dose). The maximum concentrations of cyclic HPMPC in serum were 0.036 +/- 0.021 and 0.082 +/- 0.038 microgram/ml after the oral administration of doses of 1.5 and 3.0 mg/kg, respectively. Cidofovir reached quantifiable levels in the serum of only one patient for each of the 1.5- and 3.0-mg/kg oral cyclic HPMPC doses.

For systemic use, the anti-cytomegalovirus (CMV) agent foscarnet must be given intravenously because oral administration results in unmeasurable or barely measurable plasma levels. At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oral bioavailability might be due to decomposition of foscarnet in gastric acid. We evaluated whether increasing gastric pH with ranitidine would enhance the absorption of oral foscarnet in six asymptomatic HIV-infected individuals. Each volunteer received two oral 4000-mg (60 mg/kg) doses of foscarnet, preceded intravenously by a 20-min infusion of either ranitidine 50 mg in D5W or D5W alone in a randomized, double-blind, cross-over study. Intragastric pH monitoring revealed that subjects had evidence of gastric acid production (pH < 2.0) prior to administration of ranitidine and increased gastric pH (pH > 6.0) following ranitidine administration. Most foscarnet plasma levels were below the assay limit of detection (33 microM) with only 4/30 levels detectable after D5W and 8/30 after ranitidine. Urinary recovery of foscarnet increased after ranitidine pretreatment. A mean recovery of 9.9% of the drug was realized in the urine in 24 h following ranitidine pretreatment compared to 6.2% of the dose after D5W pretreatment (P < 0.03). We estimate that 9.9% recovery in the urine in 24 h is equivalent to absorption of 17.1% of the oral dose. In spite of the enhanced bioavailability associated with ranitidine pretreatment, the degree of absorption is still insufficient to achieve effective plasma concentrations for the treatment of CMV or acyclovir-resistant herpes viruses. We conclude that gastric acidity is a determinant of foscarnet absorption, albeit not a major one. Oral foscarnet is unlikely to be clinically useful even if administered in the setting of increased gastric pH.

This open-label study enrolled five subjects with biopsy-proven cirrhosis and moderate to severe hepatic impairment (Child-Pugh classification grade B or C) and five age- and gender-matched controls. All subjects received a single 40-mg oral dose of stavudine (d4T). Stavudine pharmacokinetics in subjects with hepatic impairment were similar to those in age- and gender-matched control subjects and were not substantially different from those previously observed in human immunodeficiency virus-infected patients. Based on these findings, stavudine use does not require modification of the dose or dosing interval for patients with liver disease.

The statistical and practical implications of including second eye surgeries were examined in a clinical trial designed to evaluate the impact of routine preoperative testing prior to cataract surgery on major medical events occurring within seven days following surgery. In order to detect a 0.8% difference in the rates of rare major medical events between the tested and untested groups, 20,000 surgeries must be randomized. About 30% of cataract operations were estimated to be done on second eyes of patients already included in the cohort. Different options for dealing with second eye surgeries were: (1) exclusion of all second eye surgeries, (2) inclusion of second eye surgeries only if the first eye is not enrolled, (3) inclusion of first and second eyes but randomization of patients rather than eyes, and (4) inclusion of first and second eyes but randomization of surgeries rather than patients. The final decision was to exclude second eye surgeries done within 28 days of first eye surgeries, but to rerandomize all other second eye surgeries. Differences in event rates between treatment groups can be estimated using Generalized Estimating Equations, and the association between outcomes of first and second eye operations estimated with pairwise odds ratios. An anticipated small positive correlation is likely to have minimal impact on statistical power and effective sample size.

Purpose: To compare the efficacy and safety of inpatient oral antibiotic treatment (oral) versus standard parenteral antibiotic treatment (intravenous) for right-sided staphylococcal endocarditis in injection drug users., Patients and Methods: In a prospective, randomized, non-blinded trial, febrile injection drug users were assigned to begin oral or intravenous (IV) treatment on admission, before blood culture results were available. Oral therapy consisted of ciprofloxacin and rifampin. Parenteral therapy was oxacillin or vancomycin, plus gentamicin for the first 5 days. Antibiotic dosing was adjusted for renal dysfunction. Administration of other antibacterial drugs was not permitted during the treatment or follow-up periods. Bacteremic subjects having right-sided staphylococcal endocarditis received 28 days of inpatient therapy with the assigned antibiotics. Test-of-cure blood cultures were obtained during inpatient observation 6 and 7 days after the completion of antibiotic therapy, and again at outpatient follow-up 1 month later. Criteria for treatment failure and for drug toxicity were prospectively defined., Results: Of 573 injection drug users who were hospitalized because of a febrile illness and suspected right-sided staphylococcal endocarditis, 93 subjects (16.2%) had two or more sets of blood cultures positive for staphylococci; 85 of these bacteremic subjects (14.8%) satisfied diagnostic criteria for at least possible right-sided staphylococcal endocarditis (no other source of bacteremia was apparent) and entered the trial. Forty-four (oral, 19; IV, 25) of these 85 subjects completed inpatient treatment and evaluation including test-of-cure blood cultures. There were four treatment failures (oral, 1 [5.2%]; IV, 3 [12.0%]; not significant, Fisher's exact test). Drug toxicity was significantly more common in the parenterally treated group (oral, 3%; IV, 62%; P < 0.0001), consisting largely of oxacillin-associated increases in liver enzymes., Conclusions: For selected patients with right-sided staphylococcal endocarditis, oral ciprofloxacin plus rifampin is effective and is associated with less drug toxicity than is intravenous therapy.

We conducted a single-center, double-blind, placebo-controlled phase I study in HIV-positive subjects to ascertain the safety, tolerance, bioavailability, pharmacokinetics, and maximum tolerated dose of HPMPC (cidofovir). Five subjects were randomized to receive drug and two to receive placebo at each of three dosage tier (1, 3, and 10 mg/kg) with a 2-week washout period doses. Subjects at 1 and 3 mg/kg received single doses of HPMPC by subcutaneous (s.c.) intravenous (i.v.), and oral (p.o.) routes, while subjects at 10 mg/kg received only i.v. and p.o. doses. For subjects already taking zidovudine, zidovudine AUC values are determined before and then with HPMPC administration for each route. The AUC values of HPMPC were dose-proportional. Subcutaneous bioavailability was essentially equivalent to that of the intravenous route, but the development of transient local fibrosis ad the volumes needed for subcutaneous dosing precluded higher subcutaneous dosing than 3 mg/kg. Oral bioavailability was poor, estimated to be less than 5%. Drug elimination was predominantly renal. Nephrotoxicity in one subject was the only serious adverse event observed. This subject had a significant lag period prior to oral absorption and also had the highest AUC values for both HPMPC and zidovudine. We found no consistent effect on zidovudine AUC concomitant HPMPC.

The magnitude and duration of the antiviral and clinical effect of alpha-interferon was measured in healthy volunteers. A single 3 million unit intramuscular dose of interferon was given either alone (controls) or after 72 h of concomitant medications. These medications included either aspirin (650 mg every 4 h), acetaminophen (650 mg every 4 h), or prednisone (40 mg per day). Peripheral blood mononuclear cells were assayed for resistance to vesicular stomatitis virus infection and induction of 2'-5'-oligoadenylate synthetase activity as evidence of interferon's antiviral effect. Co-administration of acetaminophen increased both antiviral parameters by more than 70% (P < 0.05) and reduced symptoms after interferon dosing, compared to controls. Aspirin and prednisone did not demonstrate any significant differences from controls in antiviral effect. As a group, acetaminophen, aspirin, and prednisone reduced the clinical symptoms by 47% compared to controls (P = 0.03) after interferon dosing, although individual drug comparisons failed to reach statistical significance. Independent of treatment group, the changes in antiviral markers after interferon dosing correlated closely with each other (r = 0.72, P < 0.001), but neither correlated with symptoms or fever (r < 0.30, P > 0.05). Acetaminophen enhances the antiviral effects of a single intramuscular dose of alpha-interferon, considering the parameters measured in these healthy volunteers.

To assess variation in reported use of preoperative medical tests in patients undergoing cataract surgery and to identify factors that influence test use by different physician groups we performed a national survey of ophthalmologists, anesthesiologists, and internists. Participants included randomly selected members of American professional societies who provided care to one or more patients undergoing cataract surgery in 1991. Responses were obtained from 538 (82%) of 655 eligible ophthalmologists, 109 (76%) of 143 anesthesiologists, and 54 (44%) of 122 internists. Fifty percent of ophthalmologists, 40% of internists, and 33% of anesthesiologists frequently or always obtained a chest x-ray film, while 20% of ophthalmologists, 27% of internists, and 37% of anesthesiologists never obtained a chest x-ray film for patients being considered for cataract surgery who had no history of major medical problems (P < .01 for differences between ophthalmologists and the other groups). Similarly, 70% to 90% of ophthalmologists, 73% to 79% of internists, and 41% to 79% of anesthesiologists frequently or always obtained a complete blood cell count, electrolyte panel, and electrocardiogram, while 4% to 11% of ophthalmologists, 13% to 17% of internists, and 9% to 28% of anesthesiologists never obtained these tests for such patients. Many respondents (32% to 80%) believed tests were unnecessary but cited multiple reasons for obtaining tests (eg, medicolegal concerns and institutional requirements). Many physicians in each group viewed preoperative evaluations as screening opportunities or believed that one of the other two types of physicians "required" tests. We conclude that marked variation exists within and across physician specialties in the use and rationale for use of medical tests in patients undergoing cataract surgery.

The pharmacokinetics of cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.0 mg/kg of body weight and declined biexponentially with an overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 h (n = 25). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 24 h. The overall mean +/- standard deviation total clearance of the drug from serum (148 +/- 25 ml/h/kg; n = 25) approximated renal clearance (129 +/- 42 ml/h/kg; n = 25), which was significantly higher (P < 0.001) than the baseline creatinine clearance in the same patients (83 +/- 21 ml/h/kg; n = 12). These data indicate that active tubular secretion played a significant role in the clearance of cidofovir. The steady-state volume of distribution of cidofovir was approximately 500 ml/kg, suggesting that the drug was distributed in total body water. Repeated dosing with cidofovir at 3.0 and 10.0 mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant administration of intravenous cidofovir and oral probenecid to hydrated patients had no significant effect on the pharmacokinetics of cidofovir at a 3.0-mg/kg dose. At higher cidofovir doses, probenecid appeared to block tubular secretion of cidofovir and reduce its renal clearance to a level approaching glomerular filtration.

Two concentration-controlled trials (CCTs) defined the relationship between plasma concentrations of 3'-deoxy-3'-fluorothymidine (alovudine) and changes in surrogate markers of antiretroviral activity. In an initial open-label CCT involving 14 subjects infected with human immunodeficiency virus (HIV), unacceptable hematologic toxicity occurred when the area under the concentration-time curve during a 12-h dosing interval (AUC12) was > or = 300 ng*h/mL. Consequently, 46 subjects were assigned to AUC12s of 50, 100, or 200 ng*h/mL for up to 16 weeks in a prospective, randomized, double-blind CCT. Alovudine caused a concentration-dependent reduction in p24 antigen and peripheral blood mononuclear cell HIV titers within 4 weeks of start of treatment. The AUC12 producing a 50% reduction in p24 (108 ng*h/mL) had a trough concentration identical to the reported IC50 of alovudine in HIV-infected H9 cells. It may be possible to predict the antiretroviral activity of certain nucleoside analogues as a function of plasma drug concentration.

This phase I double-masked, randomized, placebo-controlled study evaluated the safety of single intravenous or subcutaneous doses of recombinant human nerve growth factor (rhNGF) in healthy human volunteers at doses ranging from 0.03 to 1 micrograms/kg. No life-threatening adverse events were seen at any dose. At doses above 0.1 microgram/kg, subjects reported mild to moderate muscle pain, primarily in the bulbar and truncal musculature. The duration and severity of these myalgias varied in a dose-dependent manner, and women appeared to be more susceptible than men. Intravenous rhNGF produced earlier and more pronounced systemic effects than did identical subcutaneous doses. Subjects receiving subcutaneous rhNGF noted hyperalgesia at the injection site, a local effect persisting up to 7 weeks, that also varied in a dose-dependent manner. Antibodies to NGF were not detected in any subject. These results indicate that systemically administered rhNGF exerts a characteristic and reproducible biological effect in healthy subjects at very low doses and in a dose-dependent manner.

Poly(I):poly(C12U) (mismatched double-stranded RNA; atvogen), an interferon inducer, is active against human immunodeficiency virus in vitro. To determine the extent and duration of the biologic effects of poly(I):poly(C12U), we administered a single dose of the drug to healthy volunteers in a randomized, double-blind, placebo-controlled 2-week crossover study. We analyzed blood for alpha and gamma interferons, neopterin, 2',5'-oligoadenylate synthetase, lymphocyte surface markers, lymphocyte proliferation after exposure to soluble antigens and mitogens, and natural killer cell activity. Minimal biologic effects were observed after administration of a single 200-mg dose to four volunteers; therefore, the dose was increased to 600 mg in 10 subjects. Only neopterin levels and symptoms were greater after administration of 600 mg of poly(I):poly(C12U) than after administration of placebo (Wilcoxon signed rank sum test, P = 0.06). A definite response in 2',5'-oligoadenylate synthetase activity, however, was seen in a few subjects. Neither alpha nor gamma interferon was detectable in serum after poly(I):poly(C12U) dosing. The neopterin changes after administration of poly(I):poly(C12U) were similar at both poly(I):poly(C12U) dose levels, with an early decrease at 6 h, a peak at 1 day, and a gradual decrease toward the baseline over the following 3 days. A mild flu-like syndrome occurred in one-half of the subjects following administration of poly(I):poly(C12U) and in only one subject following administration of placebo. This syndrome resolved within 16 h after poly(I):poly(C12U) dosing. We conclude that poly(I):poly(C12U) does not induce measurable levels of interferon and causes only minimal biologic or toxic effects among those parameters measured after administration of a single dose in the 200- to 600-mg dose range in health volunteers.

Polysulfated polysaccharides are attractive candidates for antiviral drug development because of their potent in vitro activities against human immunodeficiency virus (HIV), herpesviruses, and other enveloped viruses. To determine the potential anti-HIV activity of a prototypical polysulfated polysaccharide, we administered the maximally tolerated dose of dextran sulfate by continuous intravenous infusion to 10 subjects with symptomatic HIV infection for up to 14 days. Since parenteral dextran sulfate is an anticoagulant, the infusion was adjusted to produce the greatest acceptable increase in activated partial thromboplastin time. Drug concentrations in plasma achieved with this protocol were up to 200-fold greater than the 50% inhibitory concentration for free HIV infectivity in vitro. Despite this, circulating HIV antigen (p24) levels increased in all eight subjects who received the drug for more than 3 days (median proportional increase, 73.5%; range, 32 to 130%); this increase was highly significant when it was compared with that in a large cohort of untreated historical controls (Fisher's exact test, P less than 0.001). Frequent decreases in infusion rate were required in all subjects to maintain a constant activated partial thromboplastin time; plasma dextran sulfate levels did not fall as the infusion rate decreased, suggesting a decline in estimated drug clearance over time. Continuous intravenous dextran sulfate was toxic, producing profound but reversible thrombocytopenia in all eight subjects who received drug for more than 3 days and extensive but reversible alopecia in five of these subjects. Because of its toxicity and lack of beneficial effect on surrogate markers, dextran sulfate is unlikely to have a practical role in the treatment of symptomatic HIV infection.

Hypercupremia with central deposition of copper in Descemet's membrane and lens capsule has been reported previously in lymphoproliferative disorders in two cases. A 60-year-old white man presented with visual acuity loss and was found to have an iridescent brown corneal and lenticular discoloration. Laboratory investigation revealed hypercupremia secondary to a poorly differentiated adenocarcinoma of the lung. Presence of copper in the eye was confirmed by specific atomic absorption spectra and histochemical stains of ocular tissue. This appears to be the first report of a carcinoma with associated hypercupremia presenting initially with ocular copper deposition.

Ceftriaxone was compared with cefotaxime for the treatment of serious bacterial infections in a prospective, randomized, double-blind clinical trial. The dose of ceftriaxone was 2 g once a day, and the dose of cefotaxime was 2 g every 4 h. Metronidazole was added if anaerobic infection was suspected. Explicit criteria were used to define infections, clinical response, and adverse effects. Ceftriaxone was given to 88 patients and cefotaxime to 83. The two treatment groups did not differ in types of infection, infecting organisms, and severity of underlying disease. The response rate was 81% (71/88) for ceftriaxone and 80% (66/83) for cefotaxime. The power of the study to detect a 15% difference in response rate at P less than .1 was 90%. The frequency of diarrhea, thrombophlebitis, prothrombin time, prolongation, colonization, and superinfection did not differ between treatment groups. Ceftriaxone 2 g once a day was as safe and effective as cefotaxime 2 g every 4 h for suspected serious bacterial infections.

Hemophilus aphrophilus is an uncommon pathogen in man. It has rarely been reported as a cause of meningitis, exclusively in boys three years or younger. Osteomyelitis due to this organism is also rare. H. aphrophilus was responsible for meningitis, probable thoracic empyema, and ultimately vertebral osteomyelitis and suppurative psoas abscess formation in a woman following metrizamide myelography. The patient responded well to antibiotic treatment and surgical drainage. The organism was sensitive not only to chloramphenicol but also to newer cephalosporin antibiotics.

The effects of probenecid, a known inhibitor of glucuronidation, on the pharmacokinetics of zidovudine were assessed in eight subjects receiving zidovudine as treatment for human immunodeficiency virus infection. Zidovudine plasma concentrations were measured while subjects were receiving zidovudine alone, after 3 days of zidovudine plus 500 mg probenecid every 8 h, and after 3 days of zidovudine plus 500 mg probenecid plus 260 mg quinine sulphate every 8 h. A median increase of 80% in the area under the zidovudine plasma concentration/time curve occurred with the addition of probenecid. Quinine sulphate prevented the probenecid effect but had no effect on zidovudine kinetics when taken without probenecid by four other subjects. All of the effects were secondary to changes in zidovudine metabolism, since neither probenecid nor quinine changed the renal elimination of zidovudine. Probenecid could be used in combination with zidovudine to extend the interval between doses and reduce the daily requirement for zidovudine, thus enhancing convenience and reducing costs.

We studied promotions at Johns Hopkins University School of Medicine to determine whether clinician-teachers are less likely to be promoted or are promoted later in life than researchers and whether those who are promoted have more articles published than those who are not promoted. Over a five-year period, 93 percent of candidates for the rank of associate professor and 79 percent of the candidates for the rank of professor were promoted. There were no significant differences between clinical and research faculty members in terms of the probability that they would be promoted or their age at promotion to either associate professor or professor. Despite these findings, the responses to a questionnaire indicated that former faculty members perceived clinician-teachers as less likely than researchers to be promoted. Those who were promoted had had about twice as many articles published in peer-reviewed journals as those who were not promoted. We recommend improved counseling of medical school faculty members and more extensive discussion of the criteria for promotion and the chances of academic success.

In a prospective, randomized, double-blind study, we compared cefotaxime with nafcillin plus tobramycin in the treatment of serious bacterial infections. Of 195 patients with suspected or proven infections who were not neutropenic, definite bacterial infections were identified in 81; 34 of 38 patients given cefotaxime and 26 of 43 given nafcillin plus tobramycin (p less than 0.01) responded to treatment. The difference in response rates occurred primarily in patients with rapidly fatal underlying disease or with an infection outside the urinary tract. A logistic regression analysis showed that treatment with cefotaxime was still associated with a higher response rate after adjusting for several potential confounding factors. Among patients treated for 3 days or more, our criteria for nephrotoxicity were met in 2 of 68 (2.9%) given cefotaxime and 16 of 57 (28.1%) given nafcillin plus tobramycin (p less than 0.001). Prolongation of the prothrombin time and enterococcal colonization did not occur more frequently with cefotaxime. We conclude that cefotaxime may be more effective and less toxic than nafcillin plus tobramycin for patients with serious bacterial infections.

We conducted a prospective, randomized, double-blind comparison of intravenous penicillin and cefamandole in the therapy of pneumococcal pneumonia. Patients received either 1 g of cefamandole or 600,000 U of aqueous penicillin G every 6 h. Of the 100 patients entered into the study, 96 had clinical and radiographic evidence of pneumonia. Microbial etiology was determined from the results of sputum and blood cultures and/or sputum Gram stains. Streptococcus pneumoniae was pathogenic in 49 patients, of whom 24 received cefamandole and 25 received penicillin. There was no statistically significant difference in the response or cure rate. Of the 100 patients, 93 were treated for 3 days or more and were evaluated for adverse effects and toxicity. There was no significant difference between cefamandole-treated and pencillin-treated patients in the incidence of colonization, superinfection, phlebitis, thrombocytosis, decrease in hematocrit, or elevated liver function tests. Eosinophilia occurred more frequently in patients treated with penicillin (20 of 42) than in those treated with cefamandole (11 of 42 (chi square, P < 0.05). Only one patient receiving cefamandole developed a positive direct Coombs test. No patient in either group developed meningitis. We conclude that, with the doses and route of administration employed in this study, cefamandole is as effective as penicillin in the therapy of pneumococcal pneumonia without an increased incidence of colonization, superinfection, or adverse effects.

Study Objective: To determine whether dextran sulfate (molecular weight, 7000 to 8000 daltons; 17% to 20% sulfur), a synthetic heparin analogue with anti-human immunodeficiency virus (HIV) activity in vitro, is absorbed after oral administration., Design: Open-label, single-center study in two parts. The first part was a bioavailability study in which six subjects received a single 1800-mg oral dose and a single 225- or 300-mg intravenous dose. The second part was a study of the dose-response relation between dextran sulfate and total plasma lipolytic activity in which twelve subjects were given a single infusion of either 0.05, 0.5, 5, or 50 mg of dextran sulfate., Subjects: Eighteen healthy volunteers., Measurements and Main Results: In the bioavailability study, plasma and urine dextran-sulfate concentrations were measured by a competitive binding assay after each dose. In addition, two bioassays were used to assess plasma concentrations: plasma lipolytic activity and activated partial thromboplastin time (APTT). After the oral dose, plasma concentrations were not measurable with the competitive binding assay (lower limit of sensitivity, 1 microgram/mL); less than 0.5% of the dose was recovered in the urine, the APTT did not increase, and the median increase in the plasma lipolytic activity was only twofold (maximum increase, 11-fold). In contrast, after the intravenous dose of 225 mg, peak plasma concentrations by competitive binding assay were 26 to 35 micrograms/mL (median, 28 micrograms/mL); 25% to 29% (median, 25%) of the dose was recovered in the urine; the APTT increased to 3.5 to 9.2 times the baseline value (median increase, 6.9 times), and the plasma lipolytic activity increased by 185 to 548 times the baseline value (median increase, 438 times). In the dose-response study, intravenous doses as low as 0.5 mg produced significant increases in the plasma lipolytic activity. There was a steep dose-response curve between 0.5 and 50 mg., Conclusion: Dextran sulfate is very poorly absorbed after oral administration.