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A controlled study of the efficacy and safety of mianserin and amitriptyline in depressive inpatients.

As with other second-generation antidepressants, the antidepressive efficacy of mianserin was investigated in double-blind control group studies, mostly under outpatient conditions. This study tested the antidepressive efficacy and safety of mianserin as compared to amitriptyline in a sample of 51 depressed inpatients suffering from major depression. No statistically significant difference was found with regard to the main efficacy outcome criterion, the HAMD. The tolerability results demonstrated a superiority of mianserin with respect to vegetative symptoms and especially with respect to dryness of the mouth.

Adult↗

Preliminary assessment of atmospheric methylcyclopentadienyl manganese tricarbonyl and particulate manganese in selected urban sites.

Methylcyclopentadienyl manganese tricarbonyl (MMT: C9H7MnO3) is an organometallic additive that has been used since 1976 as an octane enhancer in Canadian unleaded gasoline. Very few studies have determined its atmospheric concentrations and only one study offers recent data on its ambient level. This preliminary study aims to assess atmospheric concentrations of MMT and respirable and total Mn (Mn(R) and Mn(T) in selected sites, at two underground car parks and one gasoline station, related to high levels of automobile traffic. It is also an investigation of the applicability of the current analytical method. In total, 34 air samples were collected using a Gil-Air portable pump during 4 consecutive days and then were analyzed by neutron activation analysis. The concentrations vary between 40 and 104 ng/m3 for Mn(R), 146 and 204 ng/m3 for Mn(T) and 6 and 128 ng/m3 for MMT (including ultrafine particulates, Mn(UF). Of the 12 Mn(R) results, 7 showed concentrations greater than the U.S. EPA reference concentration (RfC = 50 ng/m3). The ratios of Mn(R) to Mn(T) varied from 0.20 to 0.65 with a mean of 0.38. The results for MMT and Mn(UF) raise serious doubts about the specificity of the sampling and chemical analysis methodology proposed by the Occupational Safety and Health Administration (OSHA) for MMT in air.

Air Pollutants↗

Reproducibility in quality control of protein (Western) immunoblot assay for antibodies to human immunodeficiency virus.

The protein (Western) immunoblot assay (IB) for antibodies to human immunodeficiency virus, like other laboratory procedures, sometimes gives variable results. In the Transfusion Safety Study, indistinguishable aliquots of four quality control (QC) samples have been routinely submitted for IB with each group of patient specimens. A false negative IB result was obtained for 1.7% of 179 assays of two known positive (QC) standards and a false positive result for 2.0% of 101 assays of two known negative (QC) standards. In addition, a test panel of 24 samples was sent on a single occasion to three widely used laboratories. A false positive result was reported by one laboratory and a false negative by a second. Although generally reliable, IB results may occasionally be in error. There is much more technical variability in the relative frequencies of antigen-antibody bands than has been recognized. These interlaboratory and intralaboratory comparisons show quality control checks are essential for all laboratories, and more than one specimen should be tested if its applicability to a specific patient is questionable. Specific bands are sufficiently inconstant for the same specimen to make appearance or disappearance on successive specimens prognostically unreliable.

Blotting, Western↗

Subchronic toxicity studies on perfluorooctanesulfonate potassium salt in cynomolgus monkeys.

This study was conducted to determine the earliest measurable response of primates to low-level perfluorooctanesulfonate (PFOS) exposure and to provide information to reduce uncertainty in human health risk assessment. Groups of male and female monkeys received 0, 0.03, 0.15, or 0.75 mg/kg/day potassium PFOS orally for 182 days. Recovery animals from each group, except the 0.03 mg/kg/day dose group, were monitored for one year after treatment. Significant adverse effects occurred only in the 0.75 mg/kg/day dose group and included compound-related mortality in 2 of 6 male monkeys, decreased body weights, increased liver weights, lowered serum total cholesterol, lowered triiodothyronine concentrations (without evidence of hypothyroidism), and lowered estradiol levels. Decreased serum total cholesterol occurred in the 0.75 mg/kg/day dose group at serum PFOS levels > 100 ppm. Hepatocellular hypertrophy and lipid vacuolation were present at term in the 0.75 mg/kg/day dose group. No peroxisomal (palmitoyl CoA oxidase) or cell proliferation (proliferating cell nuclear antigen immunohistochemistry) was detected. Complete reversal of clinical and hepatic effects and significant decreases in serum and liver PFOS occurred within 211 days posttreatment. Liver-to-serum PFOS ratios were comparable in all dose groups, with a range of 1:1 to 2:1. Serum concentrations associated with no adverse effects (0.15 mg/kg/day) were 82.6 +/- 25.2 ppm for males and 66.8 +/- 10.8 ppm for females. Comparison of serum PFOS concentrations associated with no adverse effect in this study to those reported in human blood samples (0.028 +/- 0.014 ppm) indicated an adequate margin of safety.

Administration, Oral↗

The efficacy and safety of olanzapine for the treatment of geriatric psychosis.

Elderly psychiatric patients often present with psychotic symptoms that need antipsychotic treatment. Olanzapine is one of the atypical antipsychotics with efficacy for psychotic symptoms and a safer side-effect profile than typical antipsychotics. This study was conducted to assess the efficacy and safety of olanzapine for treatment of geriatric psychosis. The sample population comprised 94 acute-ward patients who were 65 years of age or older. Clinical assessment was conducted at baseline and also at 4 weeks after commencement of olanzapine treatment, with use of the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Improvement (CGI-I) instruments. A 4-week therapeutic evaluation was completed for 80 patients, 73 of whom (91.3%) experienced mild to substantial improvement as determined from the CGI-I. A mean 52.6% reduction from baseline was also determined from the BPRS. The mean daily dosage of olanzapine in the fourth week was 10.1 +/- 5.3 mg/d (range, 2.5-20.0). Higher olanzapine dosages were administered for patients with functional psychoses than for an analogous group with organic mental disorders. Adverse effects were monitored for all 94 patients, the most common of which were somnolence (18.1%), dizziness (18.1%), and weakness of legs or bradykinesia (16.0%). Body weight and fasting triglyceride and sugar levels were significantly elevated after olanzapine treatment (2.2, 39.9, and 8.9% from baseline, respectively). It seems reasonable to suggest that olanzapine is efficacious for geriatric patients with psychosis and that the dosage should be diagnosis-dependent.

Acute Disease↗

Clinical relevance of therapeutic drug monitoring of digoxin and gentamicin in the saliva of children.

Digoxin and gentamicin are widely used in pediatric medicine, and therapeutic monitoring is mandatory because of their narrow margin of safety and wide interpatient and intrapatient pharmacokinetic variabilities. Saliva sampling may be of potential interest, especially in children, in whom blood sampling is often difficult. In 11 children treated with digoxin for various cardiac conditions, and in 24 children treated with gentamicin (14 patients were administered gentamicin three times a day, and 10 once-daily), drugs levels were measured in plasma and saliva. There was no correlation between plasma total or free digoxin concentrations and saliva levels, precluding the clinical use of the saliva test for digoxin. No correlation was found between plasma gentamicin concentrations and saliva levels when the drug was administered three times a day; however, good correlation was found when the drug was administered once-daily (r2 = 0.89, p < 0.0001). Saliva may be used as a noninvasive method of measuring gentamicin serum concentrations to guide dosage adjustments in patients administered the drug once-daily.

Anti-Bacterial Agents↗

Bioidentical hormone therapy: a review.

OBJECTIVE: The terms "natural" or "bioidentical" hormone therapy (NHT) are used to describe hormone treatment with individually compounded recipes of certain steroids in various dosage forms, including dehydroepiandrosterone, pregnenolone, testosterone, progesterone, estrone, estradiol, and estriol. Based on the results of a person's salivary hormone levels, the final composition of the compounded dosage form is individualized to that specific person. Proponents claim that NHT is better tolerated than manufactured products. This paper is intended to review the concept of NHT and to determine whether there is sufficient scientific evidence to support its use. DESIGN: A literature search was performed in Medline using the following MeSH terms and key words: drug combinations; progestational hormones; hormone replacement therapy; endometrium; estrogen replacement therapy; climacteric; menopause; estradiol; estrogens; progesterone; drug monitoring; and drug compounding. Current Contents, International Pharmaceutical Abstracts, Cochrane Database of Systematic Reviews, Lexis Nexis, Google, Medscape, MD Consult, and clinicaltrials.gov were searched with key words. RESULTS: There are a few observational studies and clinical trials comparing conventional hormone therapy with bioidentical hormone therapy. Studies generally lacked adequate study design, including small sample sizes and comparison of inequivalent doses, to prove safety and efficacy. Little evidence was found to support individualized hormone dosing based upon saliva hormone concentrations. CONCLUSION: Evidence suggests that, although individualized hormonal products may decrease some symptoms of menopause, it seems they have no proven advantage over conventional hormone therapies and their use is not supported by evidence regarding pharmacokinetics, safety, and efficacy.

Drug Compounding↗

Quantification of Escherichia coli by kinetic 5'-nuclease polymerase chain reaction (real-time PCR) oriented to sfmD gene.

AIMS: A kinetic 5'-nuclease polymerase chain reaction (real-time PCR) for the quantification of Escherichia coli was developed. METHODS AND RESULTS: Specific primers and a fluorogenic probe oriented to sfmD gene, encoding a putative outer membrane export usher protein, were designed. The PCR system was highly specific and sensitive for E. coli, as determined with 37 non-E. coli strains (exclusivity, 100%) and 24 E. coli strains (inclusivity, 100%). When used in real-time PCR, linear calibration lines were obtained in the range from 10(2) to 10(8) CFU ml(-1) for three E. coli strains. Salmonella Enteritidis (10(6) CFU ml(-1)) or Citrobacter freundii (10(6) CFU ml(1)) had no effect on quantification of E. coli by the method. CONCLUSIONS: The developed real-time PCR is suitable for rapid quantification of E. coli. SIGNIFICANCE AND IMPACT OF THE STUDY: In connection to an appropriate sample preparation technique, the method is suitable for food safety and technological hygiene applications.

Bacterial Outer Membrane Proteins↗

Detection and quantification of Listeria monocytogenes by 5'-nuclease polymerase chain reaction targeting the actA gene.

AIMS: The aim of this study was to develop a 5'-nuclease polymerase chain reaction (PCR) for the rapid detection and quantification of Listeria monocytogenes. METHODS AND RESULTS: Specific primers and a fluorogenic probe were designed, which target a specific sequence of the actA gene encoding for a protein involved in the actin filament assembly. The PCR system was highly sensitive and specific for L. monocytogenes (inclusivity, 100%; exclusivity, 100%), which was determined using 46 L. monocytogenes and 28 non-L. monocytogenes strains. Detection limits of 10(4) cfu ml(-1) after 35 cycles and 10(2) cfu ml(-1) after 45 cycles were achieved by PCR in both real-time and end-point fluorescence measurement modes. Linear calibration lines were obtained in the range from 10(2) to 10(9) cfu ml(-1) for three L. monocytogenes strains in real-time PCR with 45 cycles. CONCLUSIONS: The developed 5'-nuclease PCR of the actA gene provides a new target for the rapid detection and quantification of L. monocytogenes. SIGNIFICANCE AND IMPACT OF THE STUDY: In conjunction with enrichment or with an appropriate quantitative sample preparation technique, the method is suitable for food safety applications.

Bacterial Proteins↗

Parents' self-reported behaviors related to health and safety of very young children.

This survey documented self-reported health and safety behaviors of parents of children enrolled in Head Start programs. The sample consisted of eight preschool programs (n = 1143) from different geographical areas of the country. This survey obtained baseline data on parent self-reported behavior as it relates to priority issues in child health and safety. A 25-item questionnaire assessed parents' behavior related to injury prevention, fire and electrical safety, firearm storage, poison prevention, automobile safety, and child supervision. More than 90% of parents reported they use car seats, teach handwashing and pedestrian safety, and keep medicine and alcohol out of children's reach. Fewer than 60%, however, reported they keep guns and bullets stored separately and locked, possess a working fire extinguisher, or have the poison control telephone number available. Findings provide direction for emphasis for those developing or implementing a comprehensive family health education program.

Adult↗

Phase I study of MetXia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma.

PURPOSE: MetXia-P450 is a novel recombinant retroviral vector that encodes the human cytochrome P450 type 2B6 gene (CYP2B6), Escherichia coli lacZ, and neomycin resistance marker genes. Cytochrome P450 enzymes are primarily expressed in the liver and convert the prodrug cyclophosphamide to an active phosphoramide mustard and acrolein. Gene-based delivery of CYP2B6 to the tumor site leads to local prodrug activation and higher concentrations of the active metabolites at the target site. EXPERIMENTAL DESIGN: MetXia-P450 was directly injected into metastatic cutaneous tumor nodules on days 1 and 2 and nodules biopsied on day 7. Oral cyclophosphamide (100 mg/m(2)) was administered between days 8 and 22. Subsequent cycles of oral cyclophosphamide were repeated for 2 of 4 weeks. Gene transfer levels in biopsy samples were measured by histologic and quantitative PCR analyses. Safety assessments were made using PCR for vector dissemination to the blood after injection and using PCR and serologic analyses to detect replicating virus. Secondary end points included clinical response, toxicity, and evaluation of antitumor immune responses by measurement of carcinoembryonic antigen and 5T4 antibodies. RESULTS: Twelve patients with breast cancer (n = 9) and melanoma (n = 3) received three dose levels of MetXia-P450 ( approximately 8 x 10(5), approximately 8 x 10(6), and approximately 8 x 10(7) lacZ transferring units/mL). The product was safe and well tolerated. The lacZ transgene was detected in biopsy material by immunohistochemistry in 10 of 12 patients and integrated viral sequences by PCR in 3 of 6 patients. One (8%) patient with breast cancer had a partial response and received 7 months of oral cyclophosphamide. Four (33%) patients had stable disease for > or =3 months and the rest had progressive disease. Preliminary immunologic analyses were suggestive of an antitumor response in two patients (partial response in one patient and stable disease in one patient). CONCLUSION: MetXia was safe and well tolerated. Gene transfer was detected at all dose levels, and the initial suggestion of an antitumor response indicates that MetXia-P450 should undergo further clinical assessment.

Administration, Oral↗

Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903, in healthy volunteers.

AP1903 is a novel gene-targeted drug that is being developed for use in drug-regulated cell therapies. An intravenous, single-blind, placebo- and saline-controlled, ascending-dose study was performed to evaluate the safety, tolerability, and pharmacokinetics of AP1903. Twenty-eight normal healthy male volunteers were randomized into five dosage groups of AP1903 (0.01, 0.05, 0.1, 0.5, and 1 mg/kg). Within each group, 4 volunteers received a single dose of AP1903, 1 volunteer received an equal volume of placebo, and 1 received an equal volume of normal saline. The only exception was in the 0.5 mg/kg group, in which 4 volunteers were dosed: 3 received AP1903 and 1 received normal saline. All dosages were administered as intravenous infusions over 2 hours. Clinical safety parameters were monitored, and serial blood and urine samples were collected for analysis of AP1903. No drug-related adverse events were observed at any of the dose levels with the possible exception of facial flushing in 1 volunteer at the 1.0 mg/kg dose level. AP1903 plasma levels were directly proportional to the administered dose, with mean Cmax values ranging from approximately 10 to 1,275 ng/mL over the 0.01 to 1.0 mg/kg dose range. Following the infusion period, blood concentrations revealed a rapid distribution phase, with plasma levels being reduced to approximately 18%, 7%, and 1% of the maximal concentration at 0.5, 2, and 10 hours postdose, respectively. AP1903 was shown to be safe and well tolerated at all dose levels and demonstrated a favorable pharmacokinetic profile at doses well above the anticipated therapeutic dose.

Adult↗

Residual hazard assessment related to handling of antineoplastic drugs: safety system evolution and quality assurance of analytical measurement.

Despite improvement of operating procedures and publication of safety guidelines, contamination is still observed in healthcare settings where antineoplastic drugs (ADs) are handled. Even after cleaning work areas, some residual contamination may still be present. Zero percent contamination is not a realistic goal, but the scientific community should set zero contamination as its main goal. The strategies to reach this objective may be traced based on the followings: (a) a wider number of drugs should be monitored; (b) safety equipment and devices must be available to the workers; (c) the likely source of widespread contamination in workplaces is the safety cabinet; (d) direct determination of the parent drug or its metabolite in urine is the recommended approach because it provides higher sensitivity and specificity; (e) reliable analytical methods are necessary to measure the extent of contamination; and (f) analytical methods intended to be applied for routine testing must be assessed through method validation studies. These studies rely on the determination of overall method performance parameters including uncertainty measurement. Our laboratory has developed and validated a number of analytical methods for the determination of several drugs in environmental and biological samples. Surveys were carried out in several hospitals, and there has been progressive, significant decrease in the number of positive samples, mostly due to the improvement of working procedures and safety measures.

Antineoplastic Agents↗

Pharmacokinetics of oseltamivir in young and very elderly subjects.

BACKGROUND: Pharmacokinetic studies of oseltamivir in very elderly patients (> or = 80 y) have not previously been performed. OBJECTIVE: To compare the pharmacokinetics of oseltamivir and the active carboxylate metabolite in healthy young and very elderly Japanese subjects. METHODS: Young (20-35 y, fasting, n = 7) and very elderly subjects (> or = 80 y, fed, n = 5) were enrolled in single-center studies and received a single oral dose of oseltamivir 75 mg. Plasma and urine samples were collected (24 h) for pharmacokinetic analysis, and safety was assessed. RESULTS: The time to maximum plasma concentration (tmax) for oseltamivir was delayed in the very elderly compared with the young subjects (2.30 vs 0.71 h, respectively). Furthermore, oseltamivir maximum plasma concentration (Cmax) and AUC(inf) were 52% and 80% higher, respectively, in the very elderly compared with the young subjects. Oral clearance was 45% lower in elderly patients, possibly due to the effects of administration of oseltamivir with a meal. For the active metabolite, oseltamivir carboxylate, Cmax and AUC(inf) values were, respectively, 22% and 91% higher in the very elderly subjects than in the young subjects, while oral clearance was 50% lower in the elderly population. The increased exposure of the active metabolite is likely to correlate with an age-related decline in renal function. For both oseltamivir and the active metabolite, there was large interpatient variability in the Cmax values. The data reported here indicate that oseltamivir would be effective in both of these populations, as trough concentrations for the active metabolite at 12 and 24 hours exceeded the 50% inhibitory concentration against the neuraminidase of influenza A and B isolates by more than 50-fold. Oseltamivir was well tolerated in both groups. CONCLUSIONS: Exposures (AUC(inf)) to both the parent drug and active metabolite were increased by more than 80% in the small number of very elderly subjects presented here. However, oseltamivir was well tolerated by these subjects.

Adult↗

Universal health care coverage for children: impact on pediatric health care providers.

A Northern California county expanded health coverage to cover nearly all children in the state through a new insurance program. In two years, 75,500 children entered a health care system near capacity. We hypothesized that the influx of thousands of previously uninsured children into the health system would affect providers in many ways. This cross-sectional study sought to investigate how this influx affected provider practices, job satisfaction, access to specialists, and overarching views about the program. Qualitative analyses of expert interviews were performed. Providers reported improved access to health care, specialists, and medications for patients. They cited increased job satisfaction for providers due to fewer limits on care, improved referral process, and decreased patient family financial stress. Providers noted the persistence of long appointment wait times for specialist care. After moving to near universal coverage, safety net providers described increased job satisfaction. Because this study examined safety-net providers, future research requires a more representative sample of providers.

Attitude of Health Personnel↗

A convenient method for synthesis of cyclic peptide libraries.

Cyclic peptides have been reported to bind to multiple, unrelated classes of receptor with high affinity. Owing to the robustness of amide bond chemistry, the ability to explore extensive chemical diversity by incorporation of unnatural and natural amino acids, and the ability to explore conformational diversity, through the incorporation of various constraints, arrays of cyclic peptides can be tailored to broadly sample chemical diversity. We describe the combination of a safety catch linker with a directed-sorted procedure for the synthesis of large arrays of diverse cyclic peptides for high-throughput screening.

Amino Acids↗

Dialysis unit and patient characteristics associated with reuse practices and mortality: 1989-1993.

The diverse patient and dialysis unit characteristics in the United States pose challenges for assessing the safety and efficacy of reuse practices. A 10% random sample of period-prevalent hemodialysis patients from units practicing conventional dialysis (<25% of patients with high-efficiency/high-flux dialysis) were analyzed. The data included 13,926 patient observations in 1989-1990 and 20,422 in 1991-1993. Centers for Disease Control and Prevention and Health Care Financing Administration facility survey Medicare data were analyzed with a Cox regression model, evaluating the risk of reuse compared with no reuse and adjusting for comorbidity, unit characteristics, and profit status. In 1989-1990, freestanding and hospital-based units that did not reuse dialyzers were not significantly different from each other in mortality rates. In 1991-1993, however, no-reuse, freestanding, for-profit units had higher risks (relative risk [RR] = 1.23, P = 0.003) compared with no-reuse, hospital-based, nonprofit units. No-reuse, hospital-based, for-profit units, in contrast, were associated with a lower mortality risk (RR = 0.70, P = 0.0001). An isolated higher risk associated with peracetic acid manual reuse in freestanding units (1989-1990) was identified in for-profit units only. In the 1991-1993 period, an increased mortality risk was noted in hospital-based, nonprofit units practicing formaldehyde automatic reuse, and in freestanding, for-profit units using glutaraldehyde, which accounted for <5% of all units. All other interactions of reuse germicide and technique were not different from no-reuse. The varying mortality rates identified in both no-reuse and reuse units using conventional dialysis suggest that other factors, such as dialysis therapy and anemia correction (both known predictors of patient survival), have a greater influence on U.S. mortality than reuse germicides and techniques.

Adult↗

Polypectomy of adenomas in the prevention of colorectal cancer: 10 years' follow-up of the Telemark Polyp Study I. A prospective, controlled population study.

BACKGROUND: The efficacy of polypectomy in preventing colorectal cancer (CRC) has never been demonstrated in a controlled, prospective study. This must be done by randomization within a population with a high prevalence of colorectal polyps, and the feasibility and safety of endoscopic screening examination is a prerequisite for this type of study. METHODS: The present study is a randomized, controlled study of the feasibility and safety of flexible sigmoidoscopic screening of a normal population sample of 799 men and women aged 50-59 years, findings at 2 and 6 years' colonoscopic follow-up, and the appearance of clinical colorectal cancer (CRC) after 10 years. RESULTS: The attendance rate was high, and there were no complications. After 10 years 1 of 400 in the screening group had developed CRC (in the group of 76 (19%) not attending for screening examination). Four of 399 controls developed CRC. CONCLUSIONS: Poor yield of polyps at follow-up, slow growth of in situ polyps, and no clinical CRC among screenees after 10 years provides support to infrequent or no colonoscopic follow-up after initial polypectomy in individuals with otherwise average risk of CRC.

Adenomatous Polyposis Coli↗