Phase I and pharmacokinetic study of tiazofurin (TCAR,NSC 286193) administered by continuous infusion

Summary Tiazofurin (2--D-ribofuranosylthiazole-4-carboxamide, TCAR) is a synthetic C-nucleoside that demonstrated significant in vivo activity against a variety of animal tumors as well as in vitro activity against human tumor-derived cell lines. Thirteen patients were treated with TCAR administered as a 5-day continuous infusion in this Phase I trial. Seventeen complete cycles were administered in three dose levels ranging from 550 to 1450 mg/M². Dose-limiting toxicities were myelosuppression and neurotoxicity including severe lethargy. Other toxicities including superficial skin peeling, myalgias, and tearing were seen at all doses. One patient had chest pain on day 4 resulting in stopping the drug, however, there was no evidence of cardiac or pericardial disease. Uric acid levels rose within one day in the absence of allopurinol treatment. There were no treatment related deaths. HPLC measurement of drug levels demonstrated steady-state plasma levels during the infusion, and a half-life following the infusion of 7.7 ± 0.6 hours. Minor abnormalities in renal function were associated with dramatic changes in pharmacokinetics and toxicity. No clinical responses were observed in this trial.Abbreviations TCAR Tiazofurin - HPLC High performance liquid chromatography - IMPD Inosine monophosphate dehydrogenase - WBC white blood cell - CPK creatine phosphokinase - C_ss steady-state concentration     

Inconsistent effects of all-trans retinoic acid on different clones of chemically transformed rat liver epithelial cells

The effects of all-trans retinoic acid (RA) on the growth andbiochemical properties of five clonal strains of neoplasticallytransformed rat liver epithelial cells were studied. These cellstrains were derived clonally from a single line of normal diploidrat liver epithelial cells that had been transformed by treatmentwith N-methyl-N'-nitro-N-nitrosoguanidine. The results showthat RA induces inconsistent alterations in selected phenotypicproperties of these five different cell strains. Retinoic acideither depressed, enhanced or produced no effect on the colony-formingability in soft agar, on the activity of -glutamyl transpeptidase,on the amount of cell-associated fibronectin, and on the bindingcapacity of ¹²⁵I-epidermal growth factor (EGF). The only consistentcorrelation observed among cell strains was between the cellularability to grow in soft agar and the amount of cell-associatedfibronectin. Enhancement of anchorage-independent growth byretinoic acid was not mediated through changes in the numberof EGF receptors. Our data demonstrate that the responses toretinoic acid of clonal subpopulations of chemically transformedrat liver epithelial cells are inconsistent, even when the clonalsubpopulations are derived from a common precursor.     

Biochemical and morphologic studies of heterogeneous lobe responses in hepatocarcinogenesis

Experiments have demonstrated interlobe differences in the incidenceof diethylnitrosamine (DEN)-induced hepatocellular carcinoma(HCCA), with a 100% incidence in the left and right median lobesand a 30% incidence in the right anterior lobe 20 weeks afterexposure began. These tumor data provide a model to test thehypothesis that chemically induced neoplasia can be qualitativelyand quantitatively related to promutagenic DNA damage and concurrentcell replication. Experiments were performed to measure O⁴-ethyldeoxythymidine(O⁴-EtdT) (a major pro-mutagenic lesion in hepatic DNA of ratsexposed to DEN), N7-ethylguanine, cell replication and hepatocyteinitiation using the induction of growthselected -glutamyl transferase-positive(GGT+) foci in the left and right median and right anteriorhepatic lobes following 0, 3, 7, 14 or 28 days of DEN administration.Results demonstrated that O⁴-EtdT concentrations were consistentlyhigher in the left and right median versus the right anteriorhepatic lobes, while cell replication was transiently higherin the right median and right anterior lobes. Likewise, highnumbers of GGT+ foci were observed in the left and right medianlobes in DEN-exposed rats subjected to a Cayama-Farber growthselection protocol. Following administration of [¹⁴C]DEN, thedistribution of radioactivity showed a marked left lobe preferencein 4-week-old rats that had no prior exposure to DEN and in8-week-old rats exposed to DEN for 4 weeks. This study suggeststhat interlobe differences in hepatocyte initiation and theincidence of HCCA may be due in part to differences in cellreplication and in DNA alkylation resulting from differentialDEN distribution and/or metabolism.     

Measuring quality and level of care provided by family caregivers of persons with dementia: protocol for a systematic review of validated instruments

BackgroundChanges in the quality-of-life (QoL) of family caregivers as they care for their loved ones with dementia over time may affect the quality or level of care that these caregivers provide. We do not know if validated instruments exist to directly measure this quality or level of care. The purpose of this systematic review is to identify validated instruments for measuring the quality or level of care provided by family caregivers of persons with dementia.MethodsWe will include articles containing a validated instrument or questionnaire designed to measure quality or level of care provided by the aforementioned group of caregivers. The included articles may utilize the tools in primary or secondary data analyses, or evaluate the tools'' psychometric properties. The following electronic databases will be searched from inception date to the present: Medline, CINAHL Complete, Cochrane Central, and PsycINFO. We will also search the gray literature, the reference lists of included articles, and contact experts in the field to help identify relevant instruments. Included articles will be required to report on an instrument measuring at least one of the following outcomes: quality of care, level of care, appropriateness of care, amount of time spent providing care, and caregiver performance. Two reviewers will independently screen retrieved citations, extract data, and assess the methodological quality of each included article. A narrative synthesis method will be used to describe the findings.DiscussionResults of this systematic review will show whether validated instruments exist to measure the quality or level of care provided by family caregivers of persons living with dementia. This will make it possible to develop initiatives that are targeted towards improving the quality or level of care provided by family caregivers.     

The implementation of an infection control bundle within a Total Care Burns Unit

AimTo evaluate the impact of the implementation of a best practice infection prevention and control bundle on healthcare associated burn wound infections in a paediatric burns unit.BackgroundBurn patients are vulnerable to infection. For this patient population, infection is associated with increased morbidity and mortality, thereby representing a significant challenge for burns clinicians who care for them.MethodsAn interrupted time series was used to compare healthcare associated burn wound infections in paediatric burn patients before and after implementation of an infection prevention and control bundle. Prospective surveillance of healthcare associated burn wound infections was conducted from 2012 to 2014. Other potential healthcare associated infection rates were also reviewed over the study period, including urinary tract infections, pneumonia, upper respiratory tract infections and sepsis. An infection prevention and control bundle developed in collaboration between the paediatric burn unit and infection control clinicians was implemented in 2013 in addition to previous standard practice.ResultsDuring the study period a total of 626 patients were admitted to the paediatric burns unit. Healthcare associated burn wound infections reduced from 34 in 2012 to 0 in 2014 following the implementation of the infection prevention and control bundle. Pneumonia and sepsis also reduced to 0 in 2013 and 2014, however one upper respiratory tract infection occurred in 2013 and urinary tract infections persisted in 2013.ConclusionThe implementation of an infection prevention and control bundle was effective in reducing healthcare associated burn wound infections, pneumonia and sepsis within our paediatric burns unit. Urinary tract infections remain a challenge for future improvement.     

Variability in cesarean delivery rates among individual labor and delivery nurses compared to physicians at three attribution time points

ObjectiveTo examine the variability in the cesarean delivery (CD) rates of individual labor and delivery nurses compared with physicians at three attribution time points.Data SourcesMedical record data from nine hospitals in Washington State from January 2016 through September 2018.Study DesignRetrospective, observational cohort design using an aggregated database of birth records.Data Collection/Extraction MethodsChart‐abstracted clinical data from a subset of nulliparous, term, singleton, vertex births attributed at admission, labor management, and delivery to nurses and physicians. Two classification methods were used to categorize nurse‐ and physician‐level CD rates at three attribution time points and the reliability of these methods compared.Principal FindingsThe sample included 12 556 births, 319 nurses, and 126 physicians. Overall, variation in nurse‐level CD rates did not differ significantly across the three attribution time points, and the extent of variation was similar to that observed in physicians. However, agreement between attribution time points varied between 35 percent and 65 percent when classifying individual nurses into the top and bottom deciles. The average reliability of nurse‐level CD rates was 32 percent at admission (IQR 22.0 percent to 38.7 percent), 32.6 percent at labor (IQR 23.1 percent to 40.9 percent), and 29.3 percent (IQR 20.9 percent to 35.8 percent) at delivery. The average reliability of physician‐level CD rates was higher: 54.2 percent (IQR 38.7 percent to 71.4 percent) at admission, 62.5 percent (IQR 49.0 percent to 79.6 percent) at labor management, and 66.1 percent (IQR 53.7 percent to 81.2 percent) at delivery.ConclusionFeedback on nurse‐level CD rates as part of routine clinical quality audits can provide insight into nurse performance in the context of other individual‐level and unit‐level information. To reliably distinguish individual nurse performance, larger sample sizes are needed.     

The Pharmacokinetics of Recombinant Human Relaxin in Nonpregnant Women After Intravenous,Intravaginal, and Intracervical Administration

The pharmacokinetics of recombinant human relaxin (rhRlx) after intravenous (iv) bolus administration and the absorption of rhRlx after intracervical or intravaginal administration were determined in nonpregnant women. The study was conducted in two parts. In part I, 25 women received 0.01 mg/kg rhRlx iv. After a minimum 7-day washout period, these women were dosed intracervically (n = 10) or intravaginally (n = 15) with 0.75 or 1.5 mg rhRlx, respectively, in 3% methylcellulose gel. Part II was a double-blind, randomized, three-way crossover study in 26 women. At 1-month intervals, each woman received one of three intravaginal treatments consisting of 0 (placebo), 1, or 6 mg rhRlx in 3% methylcellulose gel. The serum concentrations of relaxin following iv administration were described as the sum of three exponentials. The mean (±SD) initial, intermediate, and terminal half-lives were 0.09 ± 0.04, 0.72 ± 0.11, and 4.6 ± 1.2 hr, respectively. Most of the area under the curve was associated with the intermediate half-life. The weight-normalized clearance was 170 ± 50 mL/hr/kg. The observed peak concentration was 98 ± 29 ng/mL, and the weight-normalized initial volume of distribution was 78 ± 40 mL/kg, which is approximately equivalent to the serum volume. If central compartment elimination was assumed, the volume of distribution at steady state (V _ss/W) was 280 ± 100 mL/kg, which is approximately equivalent to extracellular fluid volume. V _ss/W could be as large as 1300 ± 400 mL/kg without this assumption. After intravaginal administration of the placebo gel, endogenous relaxin concentrations were evident (i.e., 20 pg/mL) in 9 of the 26 women (maximum concentrations, 23–234 pg/mL). A similar proportion of women (approximately 35–40%) exhibited measurable serum concentrations of relaxin following intravaginal rhRlx treatment; this proportion increased to 90% following intracervical rhRlx treatment. For both routes of administration, the maximum serum concentrations of relaxin were usually within the range of values observed for endogenous relaxin, suggesting that the absorption of rhRlx was minimal.