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PubMed1998

Herpes simplex virus DNA packaging without measurable DNA synthesis.

Herpes simplex virus (HSV) type 1 DNA synthesis and packaging occur within the nuclei of infected cells; however, the extent to which the two processes are coupled remains unclear. Correct packaging is thought to be dependent upon DNA debranching or other repair processes, and such events commonly involve new DNA synthesis. Furthermore, the HSV UL15 gene product, essential for packaging, nevertheless localizes to sites of active DNA replication and may link the two events. It has previously been difficult to determine whether packaging requires concomitant DNA synthesis due to the complexity of these processes and of the viral life cycle; however, we have recently described a model system which simplifies the study of HSV assembly. Cells infected with HSV strain tsProt.A accumulate unpackaged capsids at the nonpermissive temperature of 39 degrees C. Following release of the temperature block, these capsids proceed to package viral DNA in a single, synchronous wave. Here we report that, when DNA replication was inhibited prior to release of the temperature block, DNA packaging and later events in viral assembly nevertheless occurred at near-normal levels. We conclude that, under our conditions, HSV DNA packaging does not require detectable levels of DNA synthesis.

Animals↗
PubMed1998

In vitro packaging of adeno-associated virus DNA.

We have developed an in vitro procedure for packaging of recombinant adeno-associated virus (AAV). By using AAV replicative-form DNA as the substrate, it is possible to synthesize an infectious AAV particle in vitro that can be used to transfer a marker gene to mammalian cells. The packaging procedure requires the presence of both the AAV Rep and capsid proteins. Two kinds of in vitro products can be formed which facilitate DNA transfer. Both are resistant to heat and have a density in cesium chloride gradients that is indistinguishable from that of the in vivo-synthesized wild-type virus. This indicates that the particles formed have the appropriate protein-to-DNA ratio and a structure that shares the heat resistance of mature AAV particles. The two types of particles can be distinguished by their sensitivity to chloroform and DNase I treatment. The chloroform-resistant product is, by several criteria, an authentic AAV particle. In addition to having the correct density and being resistant to treatment with chloroform, DNase I, and heat, this particle is efficiently synthesized only if the AAV genome contains intact terminal repeats, which are known to be required for AAV packaging. It is also precipitated by a monoclonal antibody that recognizes mature virus particles but not bound by an antibody that recognizes monomeric or denatured capsid proteins. The chloroform-resistant species is not made when aphidicolin is present in the reaction mixture, suggesting that active DNA replication is required for in vitro packaging. In contrast, the chloroform-sensitive product has several features that suggest it is an incompletely assembled virus particle. It is sensitive to DNase I, does not require the presence of AAV terminal repeats, and is capable of transferring DNA that is theoretically too large to package. Sucrose gradient centrifugation of the in vitro-synthesized products reveals that the particles have sedimentation values between 60S and 110S, which is consistent with partially assembled and mature AAV particles. The in vitro packaging procedure should be useful for studying the mechanism by which a human icosahedral DNA virus particle is assembled, and it may be useful for producing recombinant AAV for gene therapy. The chloroform-sensitive particle may also be useful for transferring DNA that is too large to be packaged in mature recombinant AAV.

Adenosine Triphosphate↗
PubMed1999

A lentivirus packaging system based on alternative RNA transport mechanisms to express helper and gene transfer vector RNAs and its use to study the requirement of accessory proteins for particle formation and gene delivery.

A lentivirus-based packaging system was designed to reduce the chance of recombination between helper and gene transfer vector sequences by using the constitutive transport element (CTE) derived from Mason-Pfizer monkey virus for expression of the viral proteins and the Rev-Rev response element (RRE) combination for expression of the gene transfer vector. Using this approach, we evaluated a series of human immunodeficiency virus type 1 packaging constructs that express one or more accessory proteins (Vif, Vpr, and Vpu), in addition to the Gag and Pol proteins, for particle formation and virus stock production for gene transfer. Constructs that also express Vpr or both Vpr and Vpu produced more particles, as measured by a p24 assay, than did plasmids that did not contain these sequences. Transactivation experiments showed that the packaging plasmids that encode Vpr or both Vpr and Vpu also expressed a functional single-exon Tat protein. For these constructs, high-titer virus stocks could be prepared in the absence of a cotransfected Tat-expressing plasmid. Amphotropic-envelope-pseudotyped virus stocks prepared with all of the packaging constructs, irrespective of whether any of the accessory proteins were coexpressed, were equally efficient in transducing growth-arrested HeLa cells. The combination/mixed packaging system was compared to systems that were based on either the CTE alone or Rev and RRE for expression of both the packaging plasmid as well as the gene transfer vector. The combination/mixed packaging system was comparable to the other systems for production of virus stocks, suggesting that this design may prove to be safer for the eventual deployment of lentivirus vectors for therapeutic purposes.

Gene Expression↗
PubMed1999

Packaging cell lines for simian foamy virus type 1 vectors.

Foamy viruses are nonpathogenic retroviruses that offer several unique opportunities for gene transfer in various cell types from different species. We have previously demonstrated the utility of simian foamy virus type 1 (SFV-1) as a vector system by transient expression assay (M. Wu et al., J. Virol. 72:3451-3454, 1998). In this report, we describe the first stable packaging cell lines for foamy virus vectors based on SFV-1. We developed two packaging cell lines in which the helper DNA is placed under the control of either a constitutive cytomegalovirus (CMV) immediate-early gene or inducible tetracycline promoter for expression. Although the constitutive packaging expressing cell line had a higher copy number of packaging DNA, the inducible packaging cell line produced four times more vector particles. This result suggested that the structural gene products in the constitutively expressing packaging cell line were expressed at a level that is not toxic to the cells, and thus vector production was reduced. The SFV-1 vector in the presence of vesicular stomatitis virus envelope protein G (VSV-G) produced an insignificant level of transduction, indicating that foamy viruses could not be pseudotyped with VSV-G to generate high-titer vectors. The availability of stable packaging cell lines represents a step toward the use of an SFV-1 vector delivery system that will allow scaled-up production of vector stocks for gene therapy.

Animals↗
PubMed2003

Sequences downstream of the 5' splice donor site are required for both packaging and dimerization of human immunodeficiency virus type 1 RNA.

Two copies of human immunodeficiency virus type 1 RNA are incorporated into each virus particle and are further converted to a stable dimer as the virus particle matures. Several RNA segments that flank the 5' splice donor site at nucleotide (nt) 289 have been shown to act as packaging signals. Among these, RNA stem-loop 1 (SL1) (nt 243 to 277) can trigger RNA dimerization through a "kissing-loop" mechanism and thus is termed the dimerization initiation site. However, it is unknown whether other packaging signals are also needed for dimerization. To pursue this subject, we mutated stem-loop 3 (SL3) (nt 312 to 325), a GA-rich region (nt 325 to 336), and two G-rich repeats (nt 363 to 367 and nt 405 to 409) in proviral DNA and assessed the effects on RNA dimerization by performing native Northern blot analyses. Our results show that the structure but not the specific RNA sequence of SL3 is needed not only for efficient viral RNA packaging but also for dimerization. Mutations of the GA-rich sequence severely diminished viral RNA dimerization as well as packaging; the combination of mutations in both SL3 and the GA-rich region led to further decreases, implying independent roles for each of these two RNA motifs. Compensation studies further demonstrated that the RNA-packaging and dimerization activity of the GA-rich sequence may not depend on a putative interaction between this region and a CU repeat sequence at nt 227 to 233. In contrast, substitutions in the two G-rich sequences did not cause any diminution of viral RNA packaging or dimerization. We conclude that both the SL3 motif and GA-rich RNA sequences, located downstream of the 5' splice donor site, are required for efficient RNA packaging and dimerization.

Animals↗
PubMed2003

Packaging of brome mosaic virus RNA3 is mediated through a bipartite signal.

The three genomic and a single subgenomic RNA of brome mosaic virus (BMV), an RNA virus infecting plants, are packaged by a single-coat protein (CP) into three morphologically indistinguishable icosahedral virions with T = 3 quasi-symmetry. Genomic RNAs 1 and 2 are packaged individually into separate particles whereas genomic RNA3 and subgenomic RNA4 (coat protein mRNA) are copackaged into a single particle. We report here that packaging of dicistronic RNA3 requires a bipartite signal. A highly conserved 3' tRNA-like structure postulated to function as a nucleating element (NE) for CP subunits (Y. G. Choi, T. W. Dreher, and A. L. N. Rao, Proc. Natl. Acad. Sci. USA 99:655-660, 2002) and a cis-acting, position-dependent packaging element (PE) of 187 nt present in the nonstructural movement protein gene are the integral components of the packaging core. Efficient incorporation into BMV virions of nonviral RNA chimeras containing NE and the PE provides confirmatory evidence that these two elements are sufficient to direct packaging. Analysis of virion RNA profiles obtained from barley protoplasts transfected with a RNA3 variant lacking the PE provides the first genetic evidence that de novo synthesized RNA4 is incompetent for autonomous assembly whereas prior packaging of RNA3 is a prerequisite for RNA4 to copackage.

Base Sequence↗
PubMed2005

Packaging capacity of adeno-associated virus serotypes: impact of larger genomes on infectivity and postentry steps.

The limited packaging capacity of adeno-associated virus (AAV) precludes the design of vectors for the treatment of diseases associated with larger genes. Autonomous parvoviruses, such as minute virus of mice and B19, while identical in size (25 nm), are known to package larger genomes of 5.1 and 5.6 kb, respectively, compared to AAV genomes of 4.7 kb. One primary difference is the fact that wild-type (wt) AAV utilizes three capsid subunits instead of two to form the virion shell. In this study, we have characterized the packaging capacity of AAV serotypes 1 through 5 with and without the Vp2 subunit. Using reporter transgene cassettes that range in size from 4.4 to 6.0 kb, we determined that serotypes 1 through 5 with and without Vp2 could successfully package, replicate in, and transduce cells. Dot blot analysis established that packaging efficiency was similar for all vector cassettes and that the integrity of encapsidated genomes was intact regardless of size. Although physical characterization determined that virion structures were indistinguishable from wt, transduction experiments determined that all serotype vectors carrying larger genomes (5.3 kb and higher) transduced cells less efficiently (within a log) than AAV encapsidating wt size genomes. This result was not unique to reporter genes and was observed for CFTR vector cassettes ranging in size from 5.1 to 5.9 kb. No apparent advantage in packaging efficiency was observed when Vp2 was present or absent from the virion. Further analysis determined that a postentry step was responsible for the block in infection and specific treatment of cells upon infection with proteasome inhibitors increased transduction of AAV encapsidating larger DNA templates to wt levels, suggesting a preferential degradation of virions encapsidating larger-than-wt genomes. This study illustrates that AAV is capable of packaging and protecting recombinant genomes as large as 6.0 kb but the larger genome-containing virions are preferentially degraded by the proteasome and that this block can be overcome by the addition of proteasome inhibitors.

Animals↗
PubMed2005

In vivo studies of genomic packaging in the dsRNA bacteriophage Phi8.

BACKGROUND: Phi8 is a bacteriophage containing a genome of three segments of double-stranded RNA inside a polyhedral capsid enveloped in a lipid-containing membrane. Plus strand RNA binds and is packaged by empty procapsids. Whereas Phi6, another member of the Cystoviridae, shows high stringency, serial dependence and precision in its genomic packaging in vitro and in vivo, Phi8 packaging is more flexible. Unique sequences (pac) near the 5' ends of plus strands are necessary and sufficient for Phi6 genomic packaging and the RNA binding sites are located on P1, the major structural protein of the procapsid. RESULTS: In this paper the boundaries of the Phi8 pac sequences have been explored by testing the in vivo packaging efficacy of transcripts containing deletions or changes in the RNA sequences. The pac sequences have been localized to the 5' untranslated regions of the viral transcripts. Major changes in the pac sequences are either tolerated or ameliorated by suppressor mutations in the RNA sequence. Changes in the genomic packaging program can be established as a result of mutations in P1, the major structural protein of the procapsid and the determinant of RNA binding specificity. CONCLUSION: Although Phi8 is distantly related to bacteriophage Phi6, and does not show sequence similarity, it has a similar genomic packaging program. This program, however, is less stringent than that of Phi6.

Bacteriophages↗
PubMed1995

Fertility of bull semen packaged in .25- and .5-milliliter french straws.

The fertility of bull semen packaged in .25- and .5-mL french straws was compared. One ejaculate from each of five Holstein bulls was split, extended to 10 x 10(6) spermatozoa/inseminate dose in whole homogenized milk, packaged in .25- and .5-mL french straws, frozen in liquid nitrogen (LN) vapor, and stored in LN. Semen was thawed at 37 degrees C for 30 s. Synchronized heifers (n = 1,360) were inseminated (during a 12-mo period) with semen packaged in either a .25- or .5-mL french straw. Blood was collected on the day of insemination and the serum was assayed for progesterone. Heifers with blood progesterone levels of > 1 ng/mL were eliminated from the data. Blood was collected at 30 to 45 d after insemination and the serum was assayed for the presence of bovine pregnancy-specific protein B (bPSPB) by RIA to determine pregnancy. Conception was 63.6 and 62.0% (P = .55) for semen packaged in the .25- and .5-mL french straws, respectively. There was neither a bull x packaging unit interaction (P = .49) nor a day of insemination x packaging unit interaction (P = .87). Conception among bulls ranged from 57.1 to 68.0% (P = .19). No evidence was found that meteorological factors influenced conception. Under the conditions of this experiment, semen packaged in the .25- and .5-mL french straw had similar fertility.

Animals↗
PubMed1983

Influence of cooling rates and extenders upon post-thaw viability of bovine spermatozoa packaged in .25- and .5-ml French straws.

Post-thaw survival of bovine spermatozoa was compared for semen packaged in either .25- or .5-ml French straws and frozen at three different cooling rates in moving N2 vapor. Using a split ejaculate technique, nine ejaculates were extended in heated skim milk, egg yolk-citrate and egg yolk-Tris and packaged in .25- and .5-ml French straws. Semen packaged in the .25- and .5-ml straws was frozen simultaneously at initial N2 vapor temperatures of -140, -110 or -80 C. Semen was thawed in a water bath at 35 C for 1 min. Recovery of spermatozoa was evaluated immediately post-thaw (0 h) and again after 3 h of incubation at 37 C. Motility estimates and motility counts were made using phase contrast microscopy; percentage of spermatozoa possessing intact acrosomes was quantitated using differential interference contrast microscopy. There was a packaging unit X cooling rate interaction (P less than .05) for all three viability measures. However, there was no consistent trend with regard to cooling rate or packaging unit among the three extenders examined. Post-thaw viability for each characteristic varied (P less than .01) among extenders, but not for cooling rate or packaging unit (P greater than .05). Spermatozoa extended and frozen in egg yolk-Tris had greater (P less than .05) post-thaw viability than those extended in skim milk or egg yolk-citrate regardless of cooling rate or volume of the seminal package.

Acrosome↗
PubMed2006

Analysis of German package inserts.

OBJECTIVE: Package inserts have an important impact on patients compliance and thus on the effectiveness of drug use. Despite efforts of the European or national regulatory authorities and manufacturers to improve the readability and comprehensiveness of package inserts, they are still the subject of critical discussion. MATERIAL AND METHODS: 68 German package inserts were chosen for a detailed analysis of their quality and suitability based on a set of 104 quality criteria developed prior to the survey. RESULTS: In many cases package inserts available on the German drug market did not include important information or were difficult to read or understand. In 73.5% of cases, the daily maximum dose was missing and 63.2% gave no information on the measures to take for each of the interactions. 66.2% of package inserts provided no instructions about the correct storage and 58.8% gave no instructions on the appropriate storage temperature. In 13 cases, dosage instructions were provided only in milligrams of active substance instead of a number of tablets or volume of liquid. 98.5% of the 68 package inserts included non-quantifiable statements such as "high dosage" or "take 2 - 4 tablets, 1 - 3 times daily". 97.1% contained repetitious information, 83.8% included advertising elements and 8.8% contained contradictory information. CONCLUSION: Package inserts must be optimized and tested by selected groups of patients prior to approval of the drug. This will avoid misunderstandings and lack of information and ensure that use of the drug will give the best possible outcome and avoid safety risks.

Comprehension↗
PubMed1995

Maldives. Package on population education for special interest groups developed.

The Population Education Program of the Non-Formal Education Center has developed a package of Population Education for Special Interest Groups comprising a learning package and fieldworker's guide. The learning package is especially developed for teaching population education for out-of-school populations. Special interest groups in Maldives include newly married couples, adolescents, and working youth. Produced under the guidance of UNESCO, Bangkok, the package contains 36 different materials such as posters, charts, leaflets, booklets, stories, and illustrated booklets which may be taught in 36 to 45 periods. The materials deal with eight themes, namely, family size and family welfare, population and resources, delayed marriage and parenthood, responsible parenthood, population-related values and beliefs, women in development, AIDS/STD, and respect for old people. Accompanying the learning package is the fieldworker's guide used to teach the package. It contains individual guides for each of the 36 learning materials. The guide gives the titles of the materials, format, objectives of the materials, messages, target groups, and an overview of the content of each learning materials. The methodologies used for teaching the learning materials include role playing, group discussion, questioning, brainstorming, survey, creative writing, problem-solving and evaluation. The package will be used by fieldworkers to conduct island-based population education courses.

Asia↗
PubMed2005

[Improvement of package insert CYP information for prescription drugs marketed in Japan].

In clinical practice, one drug is frequently used in combination with one or more other drugs, rather than as a sole regimen, and therefore healthcare providers need to carefully consider drug interactions. As mechanisms of drug interactions, metabolic enzymes of drugs are seen as one of the most likely interactive sites, where a majority of drugs are metabolized by cytochrome P450 (CYP). For this reason, providing appropriate information on CYP in package inserts is of grave importance. In fact, the package insert is the primary tool for supplying information on drugs to healthcare providers. The present study was designed to determine how many package inserts of prescription drugs marketed in Japan were providing CYP information. We searched the April 2003 version of "Drugs in Japan DB," which listed 2,022 prescription drugs, and found that only 239 package inserts (11.8%) mentioned CYP information and that only 194 (9.6%) specified CYP isozymes. To assess the improvement of package inserts, we searched "Drugs in Japan DB" from the January 2000 version to the April 2003 version. We found that CYP information had increased year by year (eg, 7.8-11.8% annually). For newly approved drugs, an analysis of the relationship between approval year and CYP information in package inserts (April 2003 version) revealed that recently approved drugs had more CYP information (eg, 45.5-51.3% of drugs in 1999-2002, compared to 6.8-26.1% in 1991-1996). A search for regulatory review documents for new drugs approved from 1999 to 2002 suggested that this recent improvement could be related to the increased number of studies identifying CYP isozymes involved in the metabolism or interaction with other drugs. Another reason for the recent improvement may be the fact that the guideline for package inserts for prescription drugs was revised in 1997, and the guidelines for drug interaction and pharmacokinetic studies were published between 1997 and 1999.

Cytochrome P-450 Enzyme System↗
PubMed1988

Safe and efficient ecotropic and amphotropic packaging lines for use in gene transfer experiments.

The construction of a retrovirus packaging cell line which produces high-titer, helper-free retrovirus is an essential prerequisite for experiments whose goal is gene therapy. We have constructed an ecotropic packaging cell line, GP + E-86, and an amphotropic packaging cell line, GP + envAm12, in which the viral gag and pol genes are on one plasmid and the viral env gene is on another plasmid. Both plasmids contain deletions of the psi packaging sequence and the 3' LTR. The fragmented helper virus genomes, when introduced into 3T3 cells, produce titers of delta neo or N2 retrovirus which are comparable to titers produced from packaging cells containing the helper virus genome on a single plasmid. We have found no evidence for the generation of wild-type retrovirus using the GP + E-86 and GP + envAm12 packaging lines, either alone or in combination with the N2 retroviral vector. These results indicate that these packaging lines are safe and efficient for use in experiments designed for murine (using GP + E-86) and human (using GP + envAm12) gene therapy.

Animals↗
PubMed1995

Randomised controlled field trial of two antenatal care packages in rural south India.

A randomised community intervention trial was undertaken in 12 subcentres in Karur health unit district, Tamil Nadu, to compare the efficacy of two antenatal care packages. A newly recommended 'high-risk' strategy package and a uniform package recommended by the Tamil Nadu Government were each implemented in 4 randomly selected subcentres by the study team, and the latter was also delivered by routine health services in the 4 remaining subcentres. Analyses were based on 294 pregnant women on the high-risk package (HR), 242 on the Tamil Nadu Government (TNG) package and 335 women in the control series. The HR package reduced the differences between the high-risk women and the others in mean haemoglobin and the percentages with preventable neonatal morbidity and low birth weight, and consequently the overall outcome was better in the HR series than in the TNG series. Finally, the results with the TNG package were better when it was implemented by the study team than by the routine health services, in terms of preventable maternal morbidity and preventable perinatal morbidity, but there was no impact on birth weight.

Birth Weight↗
PubMedDate not supplied

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.

Analysis of Variance↗
PubMed2005

Unit-dose packaged drugs for treating malaria.

BACKGROUND: Unit-dose packaging of antimalarial drugs may improve malaria cure by making it easier for patients to take their treatment correctly. OBJECTIVES: To summarize the effects of unit-dose packaged treatment on cure and treatment adherence in people with uncomplicated malaria. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group Specialized Register (November 2004), CENTRAL (The Cochrane Library Issue 4, 2004), MEDLINE (1966 to November 2004), EMBASE (1980 to November 2004), LILACS (November 2004), conference proceedings, and reference lists of articles. We also contacted pharmaceutical companies, organizations, and researchers in the field. SELECTION CRITERIA: Randomized controlled trials (RCTs), cluster-RCTs, quasi-RCTs, and controlled before-and-after studies of unit-dose packaged drugs for treating uncomplicated malaria. DATA COLLECTION AND ANALYSIS: We independently assessed study eligibility and methodological quality, and extracted data for an intention to treat analysis, where possible. We combined binary data using relative risk (RR) and the fixed-effect model, and presented them with 95% confidence intervals (CI). We attempted to contact study authors for additional information. MAIN RESULTS: Three quasi-RCTs (895 participants) and one cluster-RCT (6 health facilities) met the inclusion criteria. Trials were of poor methodological quality, and none adequately assessed treatment failure. Unit-dose packaged drugs (in conjunction with prescriber training and patient information) appeared to be associated with higher participant-reported treatment adherence in all trials.A meta-analysis of two trials (596 participants) showed that participant-reported treatment adherence was higher with blister-packed tablets compared with tablets in paper envelopes (RR 1.18, 1.12 to 1.25). Two trials using tablets in sectioned polythene bags as the intervention also noted an increase in participant-reported treatment adherence: the cluster-RCT (6 clusters) compared it with tablets in paper envelopes, and the other trial compared it with syrup in bottles (RR 2.15, 1.76 to 2.61; 299 participants). AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the effect of unit-dose packaged antimalarial drugs on treatment failure. Unit-dose packaging supported by prescriber training and patient information appears to improve participant-reported treatment adherence, but these data come from trials with methodological limitations.

Antimalarials↗
PubMed2006

Reminder packaging for improving adherence to self-administered long-term medications.

BACKGROUND: Current methods of improving medication adherence for health problems are mostly complex, labour-intensive, and not reliably effective. Medication 'reminder packaging' which incorporates a date or time for a medication to be taken in the packaging, can act as a reminder system to improve adherence. OBJECTIVES: The objective of this review was to determine the effects of reminder packaging to enhance patient adherence with self-administered medications taken for one month or more. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library Issue 3, 2004), MEDLINE, EMBASE, CINAHL and PsycINFO from the start of the databases to 1 September 2004. We also searched the internet, contacted packaging manufacturers, and checked abstracts from the Pharm-line database and reference lists from relevant articles. We did not apply any language restrictions. SELECTION CRITERIA: We selected randomised controlled trials with at least 80% follow up, comparing a reminder packaging device with no device in participants taking self-administered medications for a minimum of one month. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed studies for inclusion, assessed quality, and extracted data from included studies. Where considered appropriate, data were combined for meta-analysis, or were reported and discussed in a narrative. MAIN RESULTS: Eight studies containing data on 1,137 participants were included. Six intervention groups in four trials provided data on the percentage of pills taken. Reminder packaging showed a significant increase in the percentage of pills taken, weighted mean difference 11% (95% confidence interval (CI) 6% to 17%). Notable heterogeneity occurred among these trials I(2 )= 96.3%. Two trials provided data for the proportion of self-reported adherent patients, reporting a reduction in the intervention group which was not statistically significant, odds ratio = 0.89 (95% CI 0.56 to 1.40). No appropriate data were available for meta-analysis of different clinical outcomes, the most common of these being blood pressure (three out of eight trials). Other clinical outcomes reported were glycated haemoglobin, serum Vitamin C and E levels, and self-reported psychological symptoms (one trial each). AUTHORS' CONCLUSIONS: Reminder packing may represent a simple method for improving adherence for patients with selected conditions examined to date. Further research is warranted to improve the design and targeting of these devices.

Drug Packaging↗