A multifaceted pharmacist intervention to improve antihypertensive adherence: a cluster-randomized, controlled trial (HAPPy trial).

WHAT IS KNOWN AND OBJECTIVES: About half of all patients taking antihypertensives discontinue treatment by 12 months. There is potential for substantial health gains at both individual and population levels through improved treatment adherence. The objective was to evaluate a community pharmacist intervention to improve adherence with antihypertensive medicines with a view to improving blood pressure (BP) control. DESIGN: prospective, non-blinded, cluster-randomized, controlled trial. PARTICIPANTS: adults with primary hypertension who obtained antihypertensives in the previous 6 months. Patients with poor refill adherence were preferentially identified with the help of a purpose-built software application. INTERVENTION: package comprising BP monitor; training on BP self-monitoring; motivational interviewing; medication use review; prescription refill reminders. FOLLOW-UP: six months. PRIMARY OUTCOME: change in proportion self-reporting medication adherence. Secondary outcome: BP changes. RESULTS: Participants (n = 395; intervention - 207; control - 188) had a mean age of 66.7 years; 51.1% were males. The proportion of adherent participants increased in both groups but was not significantly different between groups [57·2% to 63·6% (control) vs. 60·0% to 73·5% (intervention), P = 0·23]. The mean reduction in systolic BP was significantly greater in the intervention group (10·0 mmHg vs. 4·6 mmHg; P = 0·05). The proportion of patients who were non-adherent at baseline and adherent at 6 months was 22·6% (95%CI 5·1-40·0%) higher in the intervention group (61·8% vs. 39·2%, P = 0·007). Among participants with baseline BP above target, reduction of systolic BP was significantly greater in the intervention group [by 7·2 mmHg (95%CI 1·6-12·8 mmHg); (P = 0·01)]. Among participants non-adherent at baseline and above target BP, the proportion reporting adherence at 6 months was significantly greater in the intervention group [56·8% vs. 35·9%, P = 0·039). WHAT IS NEW AND CONCLUSION: This community pharmacist intervention resulted in improved adherence to antihypertensive medication and reduced systolic BP.

The sustainability of a community pharmacy intervention to improve the quality use of asthma medication.

WHAT IS KNOWN AND OBJECTIVE: A previously published asthma intervention used a software application to data mine pharmacy dispensing records and generate a list of patients with potentially suboptimal management of their asthma; in particular, a high rate of provision of reliever medication. These patients were sent educational material from their community pharmacists and advised to seek a review of their asthma management from their general practitioner. The intervention resulted in a 3-fold improvement in the ratio of dispensed preventer medication (inhaled corticosteroids) to reliever medication (short-acting beta-2 agonists). This follow-up study aimed to determine the long-term effects of the intervention programme on the preventer-to-reliever (P:R) ratio. METHODS: The same data mining software was modified so that it could re-identify patients who were originally targeted for the intervention. Community pharmacists who participated in the previous intervention installed the modified version of the software. The dispensing data were then de-identified, encrypted and transferred via the Internet to a secure server. The follow-up dispensing data for all patients were compared with their pre- and post-intervention data collected originally. RESULTS AND DISCUSSION: Of the 1551 patients who were included in the original study, 718 (46·3%) were eligible to be included in the follow-up study. The improved P:R ratio was sustained for at least 12 months following the intervention (P < 0·01). The sustained increase in the P:R ratio was attributed to significant decreases in the average daily usage of reliever medication (P < 0·0001). WHAT IS NEW AND CONCLUSION: The follow-up study demonstrated a sustained improvement in the ratio of dispensed preventer medication to reliever medication for asthma. The intervention has the potential to show long-lasting and widespread improvements in asthma management, improved health outcomes for patients, and ultimately, a reduced burden on the health system.

Attitudes of Australian pharmacists towards practice-based research.

BACKGROUND AND OBJECTIVE: The aim was to conduct a national cross-sectional survey of randomly selected Australian pharmacists to determine their attitudes towards and involvement in pharmacy practice research. This included the canvassing of perceived barriers and potential solutions to promote research activity in pharmacy practice. METHODS: A questionnaire was developed around those used in UK and Australasian studies of general practitioners' attitudes towards research. Questions assessed attitudes to research, involvement in research, barriers and facilitators to involvement, self-assessed understanding of research terminology, and access to and use of electronic bibliographic databases. One thousand pharmacists were randomly and proportionately selected from the State and Territory Pharmacy Board registers to receive the anonymous questionnaire by mail. Non-respondents were sent a follow-up reminder and second copy of the questionnaire after 3 weeks. RESULTS: A response rate of 37% was achieved. Approximately, one-third of responding pharmacists were presently, or had been, involved in research activities, and generally reported positive experiences. Lack of time and never being approached or not being aware of the opportunities were major barriers to pharmacist participation in research. Approximately, one-third of the pharmacists were not interested in participating in research. There was low usage of publicly available electronic bibliographic databases and of scientific journals. Although there was overwhelming recognition of the value of research to the profession, few pharmacists possessed a good understanding of key terms related to research and evidence-based practice (e.g. P-value or number needed to treat). CONCLUSION: There was overwhelming recognition of the value of research to the pharmacy profession. Important factors encouraging individual pharmacists to participate in research were a desire to improve the profession, the opportunity to learn more about disease management and to provide enhanced services to patients, and personal interest.

Statistical modeling and analyses of a base-specific Salmonella mutagenicity assay.

Statistical features of a base-specific Salmonella mutagenicity assay are considered in detail, following up on a previous report comparing responses of base-specific Salmonella (Ames II) strains with those of traditional tester strains. In addition to using different Salmonella strains, the new procedure also differs in that it is performed as a microwell fluctuation test, as opposed to the standard plate or preincubation test. This report describes the statistical modeling of data obtained from the use of these new strains in the microwell test procedure. We emphasize how to assess any significant interactions between replicate cultures and exposure doses, and how to identify a significant increase in the mutagenic response to a series of concentrations of a test substance.

Transcriptional activity of quinone methides derived from the tumor promoter butylated hydroxytoluene in HepG2 cells.

Butylated hydroxytoluene (BHT) is a pulmonary toxin and tumor promoter in mice presumably due to the formation of two quinone methides (QMs) that alkylate cellular nucleophiles. The activation of stress genes by these electrophilic metabolites was investigated with an assay system consisting of 14 recombinant cell lines derived from the human hepatoma line HepG2, each carrying a unique promoter or response element construct fused to the reporter gene for chloramphenicol acetyl transferase (CAT). The largest responses to QMs occurred in cells containing either the metallothionein IIA, glutathione S-transferase Ya, or 70 kDa heat shock protein promoter, or the xenobiotic response element. The other cell lines exhibited only small or no effects. These results are consistent with transcriptional activities reported for several other electrophiles known to undergo covalent interactions with proteins.

Paediatric exploratory ingestions of paracetamol.

AIM: To review paediatric exploratory ingestions of paracetamol presenting to Christchurch Hospital Emergency Department. METHOD: A retrospective review of all paediatric patients presenting with paracetamol ingestion over a 12 month period. RESULTS: During the study period there were 88 paediatric presentations for possible toxic ingestions involving paracetamol and 85 of these were exploratory self-ingestion. The male to female ratio was 43:42 and the mean age was 35 months. Paracetamol suspension was ingested in 79/85 cases and tablets in 6/85. The mean four hour plasma level was 162 mumol/L and all levels were well below the possible toxic level (1300 mumol/L). There was very poor correlation between estimated dose ingested and plasma level. CONCLUSION: Toxicity from paediatric exploratory ingestion of paracetamol is extremely rare. To reduce the potential for poisoning, bottles and prescriptions of paracetamol should have less than a total dose of 4 g. The authors recommend that unwitnessed exploratory ingestions of paracetamol in children require no treatment if the estimated maximum ingested dose is below 140 mg/kg. Above this dose, treatment is based on the result of a plasma paracetamol level drawn four hours after ingestion. Gastrointestinal decontamination should be reserved for the rare occasions of a definite witnessed ingestion of a dose exceeding 140 mg/kg.

Comparison of responses of base-specific Salmonella tester strains with the traditional strains for identifying mutagens: the results of a validation study.

The ability of a TA7000 series of Salmonella his- mutant tester strains to detect mutagens as classified by the traditional tester strains (TA100, TA98, TA1535, TA1537, TA97, TA102 and TA104) was evaluated using 30 coded chemicals, 5 of which were duplicates with different code numbers. The TA7000 series of tester strains were TA7001, TA7002, TA7003, TA7004, TA7005 and TA7006, each of which reverts by a specific base substitution. In addition, each chemical was tested in a mixture of the base-specific strains (the Mix), plus the traditional strains, TA98 and TA1537. A liquid version of the Salmonella mutagenicity assay was performed in microtiter plates to allow partial automation for increased throughput. The results were compared to those in the National Toxicology Program (NTP) database, which were obtained from the traditional strains in the preincubation assay. In the two strains common to both protocols, TA98 and TA1537, the agreement was 80% and 85%, respectively. When compared to the NTP results for TA100, the Mix gave a 72% concordance, while the addition of the frameshift tester strain, TA98, increased the agreement to 76%. The overall agreement on positive or negative classifications of mutagenicity was 88% for the 25 chemicals tested. There were three notable exceptions to the overall agreement. Benzaldehyde was detected as a mutagen in TA7005 in contrast to its classification as a non-mutagen in the NTP database. This does not necessarily contradict the NTP results because the base-specific strains may respond to different mutagens. Two weak mutagens in the NTP database, 1-chloro-2-propanol and isobutyl nitrite, were not detected as mutagens in the base-specific new strains in the liquid protocol. While there are a number of major differences in the two assays, it was concluded that the results from each procedure are comparable.

Development and evaluation of a computer-assisted instruction package in clinical pharmacology for nursing students.

Recent reports commissioned by the Australian Government have highlighted the need to improve medication use in both community and hospital settings. Nurses are placed ideally to promote safe and effective drug use. The aim of this project was to develop and evaluate a computer-assisted instruction package, to help undergraduate nursing students improve their knowledge of clinical pharmacology, and to enhance their ability to contribute to the quality use of medications. In a collaborative project, staff of the Tasmanian Schools of Pharmacy and Nursing have produced the program PharmaCAL, using HyperCard 2.2 for the Apple Macintosh. A wide range of clinical pharmacology units are covered extensively, concentrating on drugs in common use and based on body systems: cardiovascular pharmacology (including hypertension, cardiac failure and angina); respiratory pharmacology; alimentary tract pharmacology (including peptic ulcer, diarrhea, and constipation); central nervous system pharmacology (analgesia, anxiety and insomnia, depression, psychoses, and epilepsy); antibiotic chemotherapy; and diabetes mellitus. Many color illustrations have been included. Each unit has a set of multiple choice questions to provide feedback to students. The package was evaluated in two ways. First, a questionnaire was used to assess users' opinions of the package. Second, a validated multiple choice test on clinical pharmacology and therapeutics was administered to 24 third-year nursing students before and after a set of sessions using the package and to a control group of 28 nursing students who were not exposed to the PharmaCAL package. The package generally was well received by the nursing students. Clinical pharmacology test scores significantly improved after using the package and were significantly higher than for the control group of students. The program is a useful adjunct to the existing nursing curriculum. It also could be used in postgraduate nursing education and other health sciences.

Nutritional assessment in elderly care--a team approach.

This work began in February 1996 when nationally questions were being asked about the nutritional care patients were receiving in hospital. Within the Elderly Care Unit the multi-disciplinary team was also questioning the nutritional care patients received. The main concern raised was the lack of consistent nutritional assessment occurring within the unit. A multi-disciplinary nutritional group was formed to address this area of concern. It developed an assessment tool that identifies those patients at risk and provides guidelines for appropriate action.

Identification of functional conserved residues of CTP:glycerol-3-phosphate cytidylyltransferase. Role of histidines in the conserved HXGH in catalysis.

The CTP:glycerol-3-phosphate cytidylyltransferase (GCT) of Bacillus subtilis has been shown to be similar in primary structure to the CTP:phosphocholine cytidylyltransferases of several organisms. To identify the residues of this cytidylyltransferase family that function in catalysis, the conserved hydrophilic amino acid residues plus a conserved tryptophan of the GCT were mutated to alanine. The most dramatic losses in activity occurred with H14A and H17A; these histidine residues are part of an HXGH sequence similar to that found in class I aminoacyl-tRNA synthetases. The kcat values for H14A and H17A were decreased by factors of 5 x 10(-5) and 4 x 10(-4), respectively, with no significant change in Km values. Asp-11, which is found near the HXGH sequence in the cytidylyltransferases but not aminoacyl-tRNA synthetases, was also important for activity, with the D11A mutation decreasing activity by a factor of 2 x 10(-3). Several residues found in the sequence RTEGISTT, a signature sequence for this cytidylyltransferase family, as well as other isolated residues were also shown to be important for activity, with kcat values decreasing by factors of 0.14-4 x 10(-4). The Km values of three mutant enzymes, D38A, W74A, and D94A, for both CTP and glycerol-3-phosphate were 6-130-fold higher than that of the wild-type enzyme. Mutant enzymes were analyzed by two-dimensional NMR to determine if the overall structures of the enzymes were intact. One of the mutant enzymes, D66A, was defective in overall structure, but several of the others, including H14A and H17A, were not. These results indicate that His-14 and His-17 play a role in catalysis and suggest that their role is similar to the role of the His residues in the HXGH sequence in class I aminoacyl-tRNA synthetases, i.e. to stabilize a pentacoordinate transition state.

Detection of peroxisome proliferators using a reporter construct derived from the rat acyl-CoA oxidase promoter in the rat liver cell line H-4-II-E.

Peroxisome proliferators are nongenotoxic carcinogens capable of causing rapid transcriptional activation of genes comprising the rodent beta-oxidation pathway. Numerous compounds, such as hypolipidemic drugs, herbicides, plasticizers, and analgesics have been identified as peroxisome proliferators in rodents. We have developed a whole-cell in vitro assay to detect peroxisome proliferators in approximately 48 h. A promoter::chloramphenicol acetyltransferase (CAT) fusion construct for rat acyl-CoA oxidase (ACOX), the rate-limiting enzyme in the peroxisomal beta-oxidation pathway, was stably transfected into the rat liver cell line H-4-II-E. Treatment of the recombinant cell line (ACOX::CAT) with peroxisome proliferators, WY 14,643, clofibrate, di(2-ethylhexyl) phtalhate, and acetylsalicylic acid resulted in differential increases of CAT protein 48 h after exposure. Nonsteroidal anti-inflammatory drugs including ibuprofen, fenbupen, naproxen, and acetaminophen also up-regulated ACOX::CAT. Phorbol 12-myristate 13-acetate, a nongenotoxic carcinogen that is not classified as a peroxisome proliferator, also resulted in a slight induction of ACOX::CAT, consistent with the role of cell proliferation in tumor progression. The carcinogenic compounds 4-nitroquinoline N-oxide, ethyl methanesulfonate, diethylstilbestrol, and 2-aminoanthracene did not induce ACOX::CAT. Although the significance of peroxisome proliferators and their impact on humans is still unknown, the ability to identify them is of interest to the pharmaceutical and chemical industries. This assay was able to detect known peroxisome proliferators tested in approximately 48 h of exposure and to distinguish them from genotoxic carcinogens.

The Internet. Part-II. A home care nursing clinical resource.

Part I of this series discussed the many features of the internet and how to access this powerful tool. This article will focus on using the Internet's World Wide Web (WWW) as a home care nursing reference and way to access nursing, health-care, and home care knowledge. This article will also describe a few WWW sites that provide nursing and home care information for the practitioner and informational sites for families and caregivers.

Stress responses to DNA damaging agents in the human colon carcinoma cell line, RKO.

DNA damage results from a wide variety of external agents such as chemicals and radiation. The consequences of exposure to agents that damage DNA have been traditionally studied from the perspective of cell survival and mutagenesis. Mutations are late endpoints of DNA damage. Cells respond to the earlier stages of DNA damage by inducing the expression of several genes, including those specific of the nature of the lesion. These early transcriptional responses are likely to predetermine the later fate of the damaged cell. Genes activated during this early response include those involved in DNA repair, replication, and growth control. We are interested in the transcriptional mechanisms by which cells respond to DNA damaging agents. To facilitate the measurement of gene induction, we used seven different reporter constructs integrated stably into the RKO cell line derived from a human colon carcinoma. These constructs were derived from promoters and/or response elements isolated from genes associated with DNA damage responses in human cells, and were fused to the bacterial reporter gene, choramphenicol acetyl transferase (CAT). The cell lines generated in this manner contain the promoters and/or response elements representing DNA polymerase beta, p53, gadd (growth arrest and DNA damage) 45 and 153, c-fos, TPA response element, and tissue-type plasminogen activator. These recombinant cell lines were assembled in a 96-well microtiter plate permitting their simultaneous exposure to compounds and subsequent CAT protein measurement. This assembly has been designated the CAT-Tox (D) assay. These cell lines were exposed to different classes of DNA damaging agents including those which covalently join bases to form dimers (e.g., UVC irradiation), generate DNA adducts by alkylation (e.g., methylmethane sulfonate [MMS], ethylmethane sulfonate [EMS], N-methyl-N-nitro-N-nitrosoguanine [MNNG], dimethylnitrosamine [DMN]), cross-link DNA (e.g., mitomycin C), and inhibit DNA replication by intercalative (e.g., actinomycin D) and nonintercalative (e.g., hydroxyurea) mechanisms. The transcriptional responses were measured as a function of the accumulation of CAT protein using antibodies against CAT protein in a standard ELISA. Endogenous cellular responses were evaluated for a number of the genes represented in the assay at both the mRNA and protein levels by Northern and Western blot analysis, respectively. These data corroborate the stress-induced responses measured by CAT ELISA in the CAT-Tox (D) assay, demonstrating the usefulness of this assay as a rapid and sensitive method for detection of DNA damaging agents in human cells.

The CAT-Tox (L) assay: a sensitive and specific measure of stress-induced transcription in transformed human liver cells.

Identifying and measuring the molecular mechanisms of toxicity is an important goal in hazard assessment. We have developed an assay in transformed human liver cells to simultaneously measure the transcriptional responses of 14 stress promoter- or response element-chloramphenicol acetyl transferase (CAT) fusion constructs that are stably integrated into the HepG2 cell line. This assay can measure a wide spectrum of stresses, both toxic and nontoxic, such as protein and protein biosynthesis perturbations, DNA damage, heavy metals, and planar aromatic hydrocarbons. We found that each promoter or response element can be induced by one or more of four chemicals that were tested in the assay. These results have been interpreted in light of the current models of action for each compound. The responses of this assay system can distinguish among compounds that are closely related in their structure and have been shown previously to elicit similar biological activities in simple assay systems. We have designated this technique the CAT-Tox (L)iver assay. It measures a broad range of cellular stresses and toxicants at levels that were comparable to or below those of established methods. The induction profiles generated using the CAT-Tox (L) assay can help to elucidate the molecular mechanisms by which chemicals exert their actions on human cells. These profiles can be indicative of both toxic and nontoxic processes that are occurring in the cell. We propose that this cellular stress assay can serve as a screen for a variety of substances at the molecular level.

Aquatic surface respiration, buoyancy control and the evolution of air-breathing in gobies (Gobiidae: Pisces)

The role of a buccal gas bubble, held while performing aquatic surface respiration (ASR; ventilating the gills with surface water during hypoxia), was examined in benthic, intertidal Australian gobies (Favonigobius tamarensis, F. exquisitus, Pseudogobius olorum, Chlamydogobius sp., Mugilogobius paludis, Cryptocentroides cristatus and Arenigobius bifrenatus). Analyses of the forces of lift and weight of the head and body during ASR indicate a hydrostatic role for the bubble. During ASR, lift from the bubble was sufficient to provide neutral or positive buoyancy to the head, anchoring the mouth at the water surface. A buoyancy role was confirmed by experiments demonstrating the ability of some species to alter bubble volume, to compensate either for different body positions or for water densities (salinities). Use of the bubble for aerial respiration by Cryptocentroides, Mugilogobius, Chlamydogobius and Arenigobius was confirmed in hypoxia by the presence of blood-filled capillaries in the buccal subepithelium (mean air­blood barrier less than 30 µm) in areas of the buccal cavity that contacted the bubble. Blood-filled capillaries were rare or absent in normoxia in all species except Mugilogobius. Cutaneous respiration was inferred from the presence of blood-filled capillaries in the dermis and epidermis of emersed portions of the head in Mugilogobius, Chlamydogobius and Arenigobius. The buccal bubble has respiratory and hydrostatic roles and there is support for the hypothesis that ASR and the buoyancy regulation (air-gulping) required to perform it effectively are prerequisite steps in the evolution of air-breathing in these gobies.