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Pharmacokinetics of clinafloxacin after single and multiple doses.

Clinafloxacin (CI-960) is a potent broad-spectrum, fluoroquinolone antibiotic that has been studied for parenteral and oral administration in patients with serious infections. The objectives of these studies were to examine the pharmacokinetics and safety of clinafloxacin following administration of single and twice-daily intravenous (i.v.) and oral doses to volunteers. Plasma and urine samples were assayed by validated liquid chromatographic methods, and pharmacokinetic parameter values were determined by noncompartmental methods. Safety was evaluated by clinical observation and laboratory tests. Absorption was rapid after oral administration, with maximum concentrations in plasma (C(max)) generally occurring within 2 h. Concentrations in plasma declined biexponentially, with an average terminal half-life of 4 to 6 h after single doses and 5 to 7 h after multiple doses. Increases in C(max) and area under the concentration-time curves (AUC) were generally proportional to the dose. The volume of distribution was much greater than total body water. Approximately 40 to 75% of the clinafloxacin doses were excreted unchanged into urine. Absolute bioavailability of orally administered clinafloxacin was approximately 90% and did not change with increasing dose. Therefore, switching patients from i.v. to oral dosing should achieve similar concentrations in plasma. The tolerability of clinafloxacin was acceptable. No serious adverse events occurred. C(max) values and minimum plasma clinafloxacin concentrations during multiple dosing exceeded MICs for a wide range of organisms.

Administration, Oral↗

Review of company postmarketing surveillance studies.

OBJECTIVES: To review postmarketing surveillance studies sponsored by the pharmaceutical industry since the introduction of voluntary guidelines in 1987 and to evaluate their contribution to monitoring drug safety. DESIGN: Retrospective analysis of the information submitted to the Medicines Control Agency on postmarketing surveillance studies. SETTING: United Kingdom. MAIN OUTCOME MEASURES: Study designs, projected and actual sample sizes, provision of interim and final reports, number of suspected serious adverse reactions reported, identification of new drug safety hazards. RESULTS: 31 studies had been conducted under the guidelines, of which 27 were prospective and four retrospective. Nine studies had at least one comparator group, the remainder were uncontrolled. The median projected sample size for the studies was 5600 patients. Only five studies had achieved at least 75% of the projected sample size. 11 studies had been abandoned, predominantly because of difficulties in recruitment, and 15 were ongoing. One study had identified an important new safety hazard. CONCLUSIONS: Company postmarketing surveillance studies have made only a limited contribution to the assessment of drug safety, principally because of weak study designs and difficulties in recruitment. The guidelines require modification to take this experience into account.

Drug Industry↗

Workplace monitoring for volatile organic compounds using thermal desorption-gas chromatography-mass spectrometry.

The interest in the identification of volatile organic compounds in the workplace has been a major focus of many National Institute for Occupational Safety and Health (NIOSH) field studies. A primary technique for sampling and analysis of these compounds is summarized by NIOSH Manual of Analytical Methods (NMAM) 2549. This is a screening method that uses a multi-bed sorbent to trap a wide variety of compounds and compound classes. Thermal desorption techniques are used as a first attempt to characterize potential contaminants in a workplace and to determine what future sampling and analyses must be performed. Field examples are provided to show the versatility of thermal desorption methods and techniques. Due to their sensitivity, thermal desorption tube methods are sometimes required in order to measure the workplace concentrations of unusual compounds. In other situations, the exposures are too high or varied to make thermal desorption tubes practical. In these cases, the identification of contaminants with thermal desorption tubes leads to new method developments for the quantification of specific compounds using more conventional solid sorbent-solvent desorption based methods.

Air Pollution, Indoor↗

Chorionic villus sampling: experience with 3016 cases performed by a single operator.

OBJECTIVE: To describe our experience with 3016 first-trimester chorionic villus sampling (CVS) procedures, all performed by a single operator, to assess the influence of operator experience on the safety and efficacy of CVS. METHODS: Transcervical or transabdominal CVS procedures were performed on 3016 patients between the gestational ages of 9-12 weeks. The sampling success rate, procedure complications, cytogenetic results, and pregnancy outcomes were tabulated and analyzed. RESULTS: Samples adequate for diagnosis were obtained in 99.7% of the cases. The mean (+/- standard deviation) number of insertions per procedure was 1.1 +/- 0.4. The percentage of procedures in which the sample was obtained with a single insertion increased from 51% in the first 100 cases to 96% in the last 2516 cases. There were 56 (1.94%) first- and second-trimester pregnancy losses among 2892 pregnancies intended to continue. This loss rate compares with published baseline risk figures for miscarriage of approximately 2-3%. No difference in pregnancy loss rate followed one or two catheter or needle insertions, but the need for three insertions was associated with a significantly increased loss rate (6.7 versus 1.9%; chi 2 = 4.35, P < .05). CONCLUSION: Operator experience plays a significant role in the safety and efficacy of CVS.

Abortion, Spontaneous↗

[Microbiological verification of a self control plan for a hospital food service].

During the past years, it has been an increment of food related infectious diseases. In order to avoid micro biological food contamination, adherence to good manufacturing is required through control measures of food safety practices. Updated national and European regulations underline the need to apply the HACCP system, overcoming the old concept of sample control on the end user product. This work shows results of microbiological controls made along the whole productive chain. Measurements are made using biomolecular techniques (PFGE) in order to assess the management of the micro biological risk of the self control plan applied to a hospital food service of Naples. The use of the PFGE applied on some micro-organisms gram negative potentially pathogen, underlines the circulation, continued in time, of these micro-organisms within the cooking area. In addition, cross contamination between several matrixes of samples has been detected.

Consumer Product Safety↗

Establishment of microbiological safety criteria for foods in international trade. International Commission on Microbiological Specifications for Foods.

Microbiological safety is achieved by applying good hygienic practices throughout the food chain, "from farm to fork". Governmental food control is traditionally based on inspection of the facilities where foods are handled, and on testing food samples. Testing is usually applied to imported foods, when no information concerning the safety of a consignment is available. The microbiological safety is judged by means of microbiological criteria. Such criteria should, in the context of the WTO/SPS measures, be scientifically justified, and established according to the principles described by the Codex Alimentarius. However, microbiological testing is not a very reliable tool for consumer protection; the emphasis is currently shifting to the application of food safety management tools such as the Hazard Analysis Critical Control Point system (HACCP).

Food Contamination↗

Short-term results of scleral intraocular lens fixation in children.

PURPOSE: To study the safety and efficacy of scleral intraocular lens (IOL) fixation in children. SETTING: A university practice. METHODS: This retrospective review evaluated the results and complications in 6 consecutive eyes of 3 children who had anterior vitrectomy, with or without lensectomy, and scleral IOL fixation to correct ectopia lentis or aphakia. RESULTS: At a mean follow-up of 17.3 months (range 13 to 21 months), all eyes had a stable and well-positioned posterior chamber IOL and good visual improvement. The only complication was asymptomatic pupillary capture of the IOL in 3 eyes. Reversal of the pupillary capture was achieved by pupil dilation with the patient in a supine position. CONCLUSIONS: The preliminary results of scleral IOL fixation in children are encouraging. The procedure's application in well-selected cases can be considered. However, its long-term safety and efficacy must be further assessed through studies with larger sample sizes and a longer follow-up.

Aphakia, Postcataract↗

Critique of 1985 ACGIH report on particle size-selective sampling in the workplace.

The criteria recently proposed by ACGIH for judging the acceptability of respirable and other dust fraction samplers are analyzed. Implications on the sampling of workplace aerosol are determined. With the consideration of both bias and imprecision, the overall accuracy limited by the criteria is estimated for the sampling of coal mine dust as characterized by various researchers. The accuracy limits thus found appear to be excessively broad. As an example with actual workplace dust distributions in the sampling of a single aerosol (mass median diameter = 18.6 micrometers and geometric standard deviation = 2.3) with respirable dust concentration near 2 mg/m3, two samplers acceptable according to the proposed criteria could be found giving respirable dust measurements equal to 0.71 mg/m3 and 4.3 mg/m3 (even after excluding 5% of the low and high measurements from each sampler, respectively). Large variation in samplers acceptable according to the criteria is found for many other distributions as well; this indicates that tighter requirements are necessary. Seldom attained are both the single-sample +/- 25% accuracy at the 95% confidence level required of sampling/analytical methods endorsed by the National Institute for Occupational Safety and Health (NIOSH) and the tighter ISO dust fraction measurement requirement that 67% of the measurements of a sampled dust fall within 10% of a true value. Suggestions are given for sharpening the criteria without eliminating all samplers from acceptability.

Aerosols↗

Assessment of the microbial integrity, sensu G.S. Wilson, of piped and bottled drinking water in the condition as ingested.

The second half of the 20th century witnessed substantial progress in the assurance and verification of microbiological integrity, i.e., safety and sensory quality, of drinking water. Enteropathogenic agents, such as particular viruses and protozoa, not previously identified as transmitted by industrially provided water supplies, were demonstrated to cause disease outbreaks, when ingested with piped water. The potential harm posed by carry-over of orally toxic metabolites of organisms, producing 'algal' (cyanophytic) blooms, was considered. In addition, earlier observations on the colonization of attenuated drinking water bodies by a variety of oligotrophic Gram-negative bacteria were confirmed and extended. This new evidence called for updating both water purification technologies and analytical methodology, serving to verify that goals had been attained. For the former purpose, the hazard analysis empowering control of critical practices (HACCP) strategy, introduced about 1960 in industrial food processing, was successfully adopted. Elimination, devitalization or barrier technologies for the more recently identified water-borne pathogens were elaborated, taking account of the hazard of production of chlorinated compounds with alleged adverse health effects. Biofilm formation throughout water distribution networks was brought under control by strict limitation of concentrations of compounds, assimilable by oligotrophic bacteria. Upon acknowledging that direct detection tests for pathogens were futile, because of their most sporadic and erratic distribution, Schardinger's marker organism concept was anew embraced, rigorously revised and substantially enlarged. Misleading designations, like searches for 'faecal coliforms' were replaced by boundary testing for Escherichia coli and appropriate Enterococcus spp. In addition, though still to be perfected, detection protocols for relevant bacteriophages or index viruses and, to a certain extent, also for spores of aerobic and anaerobic sporing rods were also elaborated. In all monitoring account was taken of sublethally injured target organisms, surviving purification technologies, though not deprived of their ecological significance. A need remains for a rigorously standardized operating procedure (SOP) for colony counts of psychrotrophic, oligotrophic Gram-negative rod-shaped bacteria ('heterotrophic plate count'), which constitute a useful criterion of indicator value. As in the contemporary HACCP approach to food safety, guidelines for assessing success or failure in control of integrity (Water Safety Objectives) were empirically elaborated. These rely on surveys on water samples, originating from drinking water supplies, previously verified as complying with longitudinally integrated HACCP-based purification technologies. Structured Academic dissemination of these innovations, through professional microbiologists to operator and executive levels, is recommended. Web based Distance Learning MSc Programmes, like the one, since the academic year 2003-2004, offered by the University of Hertfordshire, Hatfield, UK, may contribute to such endeavours. Though the complete Course is centered around Food Safety, the Modules in-Residence Practicals and Science and Technology of Drinking Water can be studied as an entity while being employed.

Bacteria↗

Multiple microelectrode-recording system for human intracortical applications.

The human brain is dominated by the neocortex, a large folded surface, whose cellular and synaptic elements are arranged in layers. Since cortical structure is relatively constant across its surface, local information processing can be inferred from multiple laminar recordings of its electrical activity along a line perpendicular to its surface. Such recordings need to be spaced at least as close together as the cortical layers, and need to be wideband in order to sample both low frequency synaptic currents as well as high-frequency action potentials. Finally, any device used in the human brain must comply with strict safety standards. The current paper presents details of a system meeting these criteria, together with sample results obtained from epileptic subjects undergoing acute or chronic intracranial monitoring for definition of the epileptogenic region.

Action Potentials↗

Concentration of caesium-137, cobalt-60 and potassium-40 in some wild and edible plants around the nuclear power plant in Bulgaria.

The activities of 137Cs, 60Co and 40K were determined in samples of wild (Taraxacum officinale, Plantago lanceolata and Populus nigra 'Italica') and edible (vegetable, corn, fruit) plants as well as soil collected from the 30 km safety zone of the Bulgarian NPP "Kozloduy" and comparisons with earlier measurements and analyses of samples from other regions and with literature values were performed. The derived transfer factors for 137Cs and 40K from soil to plants ranged between 0.002 and 0.009 for 137Cs, and between 0.09 and 0.35 for 40K. The individual effective dose (calculated from the present results and data on the activity of other foodstuffs and from information about dietary habits) comprises 4.5% of the annual dose limit.

Bulgaria↗

A culture of patient safety in nursing homes.

BACKGROUND: Few accounts of patient safety initiatives in nursing homes exist. OBJECTIVE: To (1) determine safety culture scores for nursing homes and (2) compare these results with existing data from hospitals. METHODS: Data were collected from a nationally representative sample of nursing homes (n = 2840 completed surveys and a response rate of 71%). From these nursing homes, administrators completed The Hospital Survey On Patient Safety Culture (HSOPSC) instrument. RESULTS: 11 of the 12 HSOPSC subscale scores from the nursing home sample were considerably lower than the benchmark hospital scores. In addition, almost all item scores from nursing homes were considerably lower than the benchmark hospital scores. These results indicate that a less well-developed safety culture exists in nursing homes. CONCLUSIONS: The results clearly show that the patient safety culture scores of nursing homes are considerably lower than those of hospitals. Residents of nursing homes may be at risk of harm as a result of patient safety errors.

Adult↗

Pharmacokinetics and safety of single intravenous infusions of the adenosine agonist, AMP 579, in patients with end-stage renal insufficiency.

The pharmacokinetics of an adenosine agonist (AMP 579) were characterized in patients with end-stage renal disease compared to sex- and age-matched healthy volunteers. All study participants were administered single AMP 579 doses of 50 micrograms/kg as a 6-hour, constant-rate intravenous infusion. Serial blood samples were obtained for measurement of plasma AMP 579 concentration, and predose samples were collected for determination of AMP 579 plasma protein binding. The safety of AMP 579 administration in renally impaired patients also was evaluated. AMP 579 was rapidly cleared from the systemic circulation in all subjects as plasma concentrations were below the limit of detection by 2 to 4 hours after terminating the infusion. Noncompartmental analysis yielded mean values for the plasma AMP 579 concentration at the end of the 6-hour infusion (C6 h) of 9.6 and 10.5 ng/mL and for systemic clearances (Cl) of 0.91 and 0.72 L/h/kg in renally impaired patients and healthy volunteers, respectively. Mean volumes of distribution (Vss) in the renally impaired and healthy volunteers were 0.92 and 0.84 L/kg, and terminal elimination half-life values (t1/2) were 1.61 and 1.33 hours, respectively. The extent to which AMP 579 is bound to plasma protein was not altered in renally impaired patients since the free fractions were 4.0% and 3.4% for renally impaired and healthy volunteers, respectively. It was concluded that the pharmacokinetic parameters of AMP 579 were similar in both groups. The 6-hour AMP 579 infusion was generally well tolerated by both renal patients and healthy volunteers. There were no serious adverse events, and there were only two mild adverse events in 1 renally impaired patient judged possibly related to the study drug that quickly resolved. There were no clinically significant changes in laboratory values or clinical evaluations during the study. There was a slight increase in heart rate during the infusion of similar magnitude for both the renal patients and healthy volunteers. These data suggest that AMP 579 may be administered to renally impaired patients with minimal cardiovascular effects and adverse events. These results in end-stage renal patients (worst-case scenario) indicate that dose adjustment in patients with renal insufficiency of any degree is not indicated in future studies of AMP 579.

Adult↗

Galantamine pharmacokinetics, safety, and tolerability profiles are similar in healthy Caucasian and Japanese subjects.

The aim of this study was to compare the pharmacokinetics of galantamine in healthy Japanese and Caucasian subjects and assess the safety and tolerability of galantamine in both ethnic groups. Parallel groups of healthy Japanese (n = 13; 6 males and 7 females)and Caucasian (n = 12; 6 males and 6 females) subjects matched for weight and age received single oral doses of galantamine 4 mg, or galantamine 8 mg, or placebo in a double-blind, three-way crossover trial according to a randomized dosing schedule. Concentrations of galantamine and norgalantamine were determined in plasma and urine samples taken up to 48 and 24 hours after dosing, respectively. Safety and tolerability were monitored throughout the trial by recording adverse events, laboratory tests, and cardiovascular parameters. The mean plasma concentration-time profiles of galantamine were very similar after single doses of galantamine (4 and 8 mg), and there was an approximate dose proportionality of galantamine pharmacokinetic parameters in both Caucasian and Japanese ethnic groups. The mean (+/- SD) pharmacokinetic parameters in the two ethnic groups did not show any clinically relevant differences. The ratios for the area under the plasma-concentration curve from time zero to infinity (AUC)0-infinity) in Japanese:Caucasian subjects with 4 and 8 mg doses were 103% (90% confidence interval [CII = 92-116) and 107% (90% CI = 94-121), respectively. Ratios for maximum plasma concentration (Cmax) values were 107% (90% CI= 90-127) and 108% (90% CI= 95-123), respectively. These ratios and associated 90% CIs were within the 80% to 125% range limit of bioequivalence. Analysis of variance (ANOVA) showed that these ratio values demonstrated no statistically significant difference between the two ethnic groups. There was no overt difference in the adverse event profile in Japanese subjects compared with Caucasian subjects. There were no serious adverse events, and no subjects discontinued from the study because of adverse events. No consistent or clinically relevant pattern of blood chemistry, hematology, or cardiovascular changes was seen. These results suggest that the pharmacokinetic profiles of galantamine after single-dose administration are not statistically significantly different between Caucasian and Japanese groups. Galantamine was well tolerated. The safety and tolerability of galantamine were very similar in the two ethnic groups.

Adult↗

Prescription drug samples--does this marketing strategy counteract policies for quality use of medicines?

Prescription drug samples, as used by the pharmaceutical industry to market their products, are of current interest because of their influence on prescribing, and their potential impact on consumer safety. Very little research has been conducted into the use and misuse of prescription drug samples, and the influence of samples on health policies designed to improve the rational use of medicines. This is a topical issue in the prescription drug debate, with increasing costs and increasing concerns about optimizing use of medicines. This manuscript critically evaluates the research that has been conducted to date about prescription drug samples, discusses the issues raised in the context of traditional marketing theory, and suggests possible alternatives for the future.

Advertising↗

Microbiological quality and safety of ready-to-eat cooked foods from a centralized school kitchen in Argentina.

The purpose of this study was to evaluate the microbiological and sensory quality as well as the safety of ready-to-eat (RTE) cooked foods prepared in and distributed from a centralized kitchen to schools in Argentina. A total of 101 cooked food samples delivered as hot RTE cooked foods (group A) and as RTE cooked foods at room temperature (group B) and 140 surface swab environment samples were collected from February to November 1999. Petrifilm plates were used for aerobic (PAC), coliform (PCC), and Escherichia coli (PEC) counts. Standard methods were used to determine Enterobacteriaceae (EntC) and thermotolerant coliform counts (TCC). Samples were also tested for the presence of Salmonella spp., Staphylococcus aureus, Bacillus cereus, and Clostridium perfringens. Food temperatures just before samples were put into containers ranged from 80 to 98 degrees C and from 28 to 32 degrees C for group A and group B, respectively. For group A food samples, PAC ranged from 1.04 to 3.50 log CFU/g, and PCC, PEC, TCC, and EntC were not detected. For group B food samples, PAC ranged from 3.63 to 6.48 log CFU/g, PCC ranged from 1.90 to 5.36 log CFU/g, TCC ranged from 1.30 to 3.95 log CFU/g, and EntC ranged from 3.60 to 5.46 log CFU/g. Of the foodborne pathogens, only B. cereus was isolated (63.4% of samples) in both food groups (<4 log CFU/g). The microbiological and sensory quality and the safety of group A foods were satisfactory. Large numbers of PAC and EntC detected in group B foods show that better control is needed to avoid potential foodborne diseases.

Argentina↗

Occupational exposures to air contaminants at the World Trade Center disaster site--New York, September-October, 2001.

Amid concerns about the fires and suspected presence of toxic materials in the rubble pile following the collapse of the World Trade Center (WTC) buildings on September 11, 2001, the New York City Department of Health (NYCDOH) asked CDC for assistance in evaluating occupational exposures at the site. CDC's National Institute for Occupational Safety and Health (NIOSH) collected general area (GA) and personal breathing zone (PBZ) air samples for numerous potential air contaminants. This report summarizes the results of the assessment, which indicate that most exposures, including asbestos, did not exceed NIOSH recommended exposure limits (RELs) or Occupational Safety and Health Administration (OSHA) permissible exposure limits (PELs). One torch cutter was overexposed to cadmium; another worker was overexposed to carbon monoxide (CO) while cutting metal beams with an oxyacetylene torch or a gasoline-powered saw, and two more were possibly overexposed to CO. NIOSH recommended that workers ensure adequate on-site ventilation when using gas-powered equipment and use rechargeable, battery-powered equipment when possible.

Air Pollutants↗

Single-center experience with tacrolimus-based immunosuppressive regimens in renal transplantation.

The efficacy and safety of tacrolimus (FK506; Prograf) were determined in 28 adult kidney transplant patients (20 males and 8 females), aged 18-68 years (mean+/-S.D.: 46.9+/-4.03 years). Induction therapy was ATG-F (n=23), daclizumab (n=3), or none (n=2), and maintenance immunosuppression consisted of tacrolimus, combined with mycophenolate mofetil (MMF; n=26) or azathioprine (AZA; n=2) and prednisone (Pred). In seven patients, cyclosporine A microemulsion (Neoral) was replaced by tacrolimus for acute rejection (AR; three patients), slow graft function (SGF, two patients) and Neoral side effects (two patients). Acute rejection occurred in five patients (17.8%), three of whom were steroid-resistant treated with a second course of ATG-F. Infection occurred in 10 patients (35.7%) with a total of 15 infectious episodes, comprising bacterial (73%) and viral (27%) infections related to CMV. Other side effects related to tacrolimus were hypertension in four patients (14%) and post-transplantation hyperglycemia in nine patients (32%), three of whom required insulin therapy. In addition, hypercholesterolemia and hypertriglyceridemia occurred in six (21%) and eight patients (28.5%), respectively. The patient's hospital stay was 12.7+/-1.3 days (range: 8-24 days), and mean serum creatinine upon discharge, and at 1, 3 and 6 months following transplantation were: 2.1+/-0.5, 1.47+/-0.21, 1.41+/-0.53 and 1.23+/-0.11 mg/dl, respectively. The 6-month actuarial patient and graft survival rates were 100%. While tacrolimus is an effective calcineurin inhibitor for kidney transplantation (KT), severe acute rejection seen is related to highly sensitized patients, and the CMV infections noted were related to the presence of more CMV-negative recipients receiving kidneys from CMV-positive donors. Longer follow-up with a larger patient sample is needed to fully assess both the efficacy and safety of tacrolimus, including its metabolic effects.

Acute Disease↗