Abstract: BACKGROUND: Multiple medications is a well-known potential risk factor in terms of patient's health. The aim of the present study was to estimate the prevalence of dispensed drugs and multiple medications in an entire national population, by using individual based data on dispensed drugs. METHODS: Analyses of all dispensed out-patient prescriptions in 2006 from the Swedish prescribed drug register. As a cut-off for multiple medications, we applied five or more different drugs dispensed (DP >or= 5) at Swedish pharmacies for a single individual during a 3-month, a 6-month, and a 12-month study period. For comparison, results were also calculated with certain drug groups excluded. RESULTS: 6.2 million individuals received at least one dispensed drug (DP >or= 1) during 12 months in 2006 corresponding to a prevalence of 67.4%; 75.6% for females and 59.3% for males. Individuals received on average 4.7 dispensed drugs per individual (median 3, Q1-Q3 2-6); females 5.0 (median 3, Q1-Q3 2-7), males 4.3 (median 3, Q1-Q3 1-6).The prevalence of multiple medications (DP >or= 5) was 24.4% for the entire population. The prevalence increased with age. For elderly 70-79, 80-89, and 90-years, the prevalence of DP >or= 5 was 62.4, 75.1, and 77.7% in the respective age groups. 82.8% of all individuals with DP >or= 1 and 64.9% of all individuals with DP >or= 5 were < 70 years. Multiple medications was more frequent for females (29.6%) than for males (19.2%). For individuals 10 to 39 years, DP >or= 5 was twice as common among females compared to males. Sex hormones and modulators of the genital system excluded, reduced the relative risk (RR) for females vs. males for DP >or= 5 from 1.5 to 1.4. The prevalence of DP >or= 1 increased from 45.1 to 56.2 and 67.4%, respectively, when the study period was 3, 6, and 12 respectively months and the corresponding prevalence of DP >or= 5 was 11.3, 17.2, and 24.4% respectively. CONCLUSION: The prevalence of dispensed drugs and multiple medications were extensive in all age groups and were higher for females than for males. Multiple medications should be regarded as a risk in terms of potential drug-drug interactions and adverse drug reactions in all age groups.

Abstract: BACKGROUND: The introduction of electronic transfer of prescriptions (ETP) or ePrescriptions in ambulatory health care has been suggested to have a positive impact on the prescribing and dispensing processes. Thereby, implying that ePrescribing can improve safety, quality, efficiency, and cost-effectiveness. In December 2007, 68% of all new prescriptions were transferred electronically in Sweden. The aim of the present study was to assess the quality of ePrescriptions by comparing the proportions of ePrescriptions and non-electronic prescriptions necessitating a clarification contact (correction, completion or change) with the prescriber at the time of dispensing. METHODS: A direct observational study was performed at three Swedish mail-order pharmacies which were known to dispense a large proportion of ePrescriptions (38-75%). Data were gathered on all ePrescriptions dispensed at these pharmacies over a three week period in February 2006. All clarification contacts with prescribers were included in the study and were classified and assessed in comparison with all drug prescriptions dispensed at the same pharmacies over the specified period. RESULTS: Of the 31225 prescriptions dispensed during the study period, clarification contacts were made for 2.0% (147/7532) of new ePrescriptions and 1.2% (79/6833) of new non-electronic prescriptions. This represented a relative risk (RR) of 1.7 (95% CI 1.3-2.2) for new ePrescriptions compared to new non-electronic prescriptions. The increased RR was mainly due to 'Dosage and directions for use', which had an RR of 7.6 (95% CI 2.8-20.4) when compared to other clarification contacts. In all, 89.5% of the suggested pharmacist interventions were accepted by the prescriber, 77.7% (192/247) as suggested and an additional 11.7% (29/247) after a modification during contact with the prescriber. CONCLUSION: The increased proportion of prescriptions necessitating a clarification contact for new ePrescriptions compared to new non-electronic prescriptions indicates the need for an increased focus on quality aspects in ePrescribing deployment. ETP technology should be developed towards a two-way communication between the prescriber and the pharmacist with automated checks of missing, inaccurate, or ambiguous information. This would enhance safety and quality for the patient and also improve efficiency and cost-effectiveness within the health care system.

Abstract: Catheterization of the male urethra might cause harm and discomfort for the patient. Computer-based simulator training might improve the skills of students as well as professional nurses. This study aims to study the feasibility of a new portable computer-based male urethral catheterization simulator, Urecath (Melerit Urecath Vision((R))). The simulator consists of three software modules: teaching (explains the different procedures in the catheterization), learning (game settings with practice and self-assessments tests), and simulator module that is connected to a box with a model of a penis where syringes and the urinary catheter can be inserted. Registered nurses (n=23), nurse assistants (n=14), nurse students (n=12), and a nurse assistant student (n=1) participated in a simulation session and answered 30 questions about the feasibility of the simulator. The participants appreciated the different modules, particularly the teaching and learning modules. The simulator module was appreciated for its cross-sectional views and feedback but was found to lack a tactile component; there was too little and no varying resistance when inserting the catheter. The participants perceived the present prototype of Urecath as a valuable education tool. The male urethral catheterization simulator prototype Urecath has advantages in its present shape but to be an alternative to existing training options for practicing male urethral catheterization, it should be complemented with a tactile mode and degrees of difficulty.

Abstract: BACKGROUND: Health care personnel need access to updated information anywhere and at any time, and a Personal Digital Assistant (PDA) has the potential to meet these requirements. A PDA is a mobile tool which has been employed widely for various purposes in health care practice, and the level of its use is expected to increase. Loaded with suitable functions and software applications, a PDA might qualify as the tool that personnel and students in health care need. In Sweden today, despite its leadership role in mobile technologies, PDAs are not commonly used, and there is a lack of suitable functions and software applications. OBJECTIVE: The aim of the present review was to obtain an overview of existing research on the use of PDAs among personnel and students in health care. METHODS: The literature search included original peer-reviewed research articles written in English and published from 1996 to 2008. All study designs were considered for inclusion. We excluded reviews and studies focusing on the use of PDAs in classroom situations. From March 2006 to the last update in May 2008, we searched PubMed, CINAHL, Cochrane, IngentaConnect, and a local search engine (ELIN@Kalmar). We conducted a content analysis, using Nielsen's Model of System Acceptability as a theoretical framework in structuring and presenting the results. RESULTS: From the 900 references initially screened, 172 articles were selected and critically assessed until 48 articles remained. The majority originated in North-America (USA: n=24, Canada: n=11). The categories which emerged from our content analysis coincided to a certain extent to Nielsen's Model of System Acceptability (social and practical acceptability), including usefulness (utility and usability) subcategories such as learnability, efficiency, errors, and satisfaction. The studies showed that health care personnel and students used PDAs in patient care with varied frequency. Most of the users were physicians. There is some evidence that the use of a PDA in health care settings might improve decision-making, reduce the numbers of medical errors, and enhance learning for both students and professionals, but the evidence is not strong, with most studies being descriptive, and only 6 randomized controlled trials. Several special software programs have been created and tested for PDAs, and a wide range of situations for their use have been reported for different patient groups. Drug and medical information were commonly accessed by PDA users, and the PDA was often viewed as the preferred tool when compared to paper-based documents. Some users regarded the PDA easy to operate, while others found it difficult in the beginning. CONCLUSIONS: This overview of the use of PDAs revealed a positive attitude towards the PDA, which was regarded as a feasible and convenient tool. The possibility of immediate access to medical information has the potential to improve patient care. The PDA seems to be a valuable tool for personnel and students in health care, but there is a need for further intervention studies, randomized controlled trials, action research, and studies with various health care groups in order to identify its appropriate functions and software applications.

Abstract: BACKGROUND: The Internet is increasingly used for health matters including Ask the doctor services. AIM: To describe users and usage pattern of text-based medical consultation with family physicians on the Internet. METHODS: Descriptive analysis of the first 4 years' use of a Swedish Ask the doctor service concerning number of inquiries, age and gender of inquirers. Time of day and week, types of medical inquiries, and use in relation to population density was analyzed during the last year of the study. RESULTS: We found a considerable number of users, with 38,217 inquiries submitted to the service. Three-fourths of the inquirers were women, thus exceeding the gender difference seen in regular health care. The typical user was a woman aged 21-60 years. The service was used any time day or night, 7 days a week. Almost half of the inquiries were submitted during evenings and nights. Most areas of medicine were represented in the inquiries, reflecting the fact that there was no control of what an inquiry should include. The use was widespread over the country but more frequent per capita in more densely populated areas as defined by postal code. CONCLUSION: In the study of a service for text-based consultations with family physicians on the Internet, we found a geographically widely distributed use, slowly but gradually increasing during a 4-year period. The use increased more rapidly among young and middle-aged women. Asynchronous text-based consultation is likely to expand in the near future.

Abstract: BACKGROUND: Many patients receive health care in different settings. Thus, a limitation of clinical care may be inaccurate medication lists, since data exchange between settings is often lacking and patients do not regularly self-report on changes in their medication. Health care professionals and patients are both interested in utilizing electronic health information. However, opinion is divided as to who should take responsibility for maintaining personal health records. In Sweden, the government has passed a law to enforce and fund a national register of dispensed medications. The register comprises all individuals with dispensed medications (6.4 million individuals, September 2006) and can be accessed by the individual online via "My dispensed medications". The individual has the right to restrict the accessibility of the information in health care settings. OBJECTIVE: The aim of the present study was to evaluate the users' attitudes towards their access to "My dispensed medications" as part of a new interactive Internet service on prescribed medications. METHOD: A password-protected Web survey was conducted among a first group of users of "My dispensed medications". Data was anonymously collected and analyzed with regard to the usefulness and design of the Web site, the respondents' willingness to discuss their "My dispensed medications" with others, their reasons for access, and their source of information about the service. RESULTS: During the study period (January-March, 2007), all 7860 unique site visitors were invited to answer the survey. Invitations were accepted by 2663 individuals, and 1716 responded to the online survey yielding a view rate of 21.8% (1716/7860) and a completion rate of 64.4% (1716/2663). The completeness rate for each question was in the range of 94.9% (1629/1716) to 99.5% (1707/1716). In general, the respondents' expectations of the usefulness of "My dispensed medications" were high (total median grade 5; Inter Quartile Range [IQR] 3, on a scale 1-6). They were also positive about the design of the Web site (total median grade 5; IQR 1, on a scale 1-6). The high grades were not dependent on age or number of drugs. A majority of the respondents, 60.4% (1037/1716), had learned about "My dispensed medications" from pharmacies. 70.4% (1208/1716) of all respondents said they visited "My dispensed medications" to get control or an overview of their drugs. Getting control was a more common (P < .001) answer for the elderly (age 75 or above), whereas curiosity was more common (P < .001) for the younger age group (18-44 years). CONCLUSION: We found that users of the provider-based personal medication record "My dispensed medications" appreciated the access to their record. Since we found that the respondents liked the design of the Web site and perceived that the information was easy to understand, the study provided no reason for system changes. However, a need for more information about the register, and to extend its use, was recognized.

Abstract: To achieve a safer future prescribing, the Swedish government has introduced a mandatory registration of all drugs dispensed at pharmacies. The medication history in the register may be accessed online by registered individuals, prescribers and pharmacists. After 15 months of action, the prevalence of individuals with dispensed drugs in the Swedish population was 71.0% (6,424,487/9,047,752); women 78.8% and men 63.1%. The incidence rate for individuals with dispensed drugs was estimated as 12.4 (1,000*111,960/9,047,752) per month and 1, 000 inhabitants. The mean number of dispensed prescriptions was 12.1 (median 6, Q1-Q3 2-15) per individual. For the elderly (age group 80-89), the mean number of dispensed prescriptions was 27.8 during the study period (median 24,Q1-Q3 13-38); women 28.8 and men 26.1. When introducing a National Pharmacy Register, containing personal drug information for the majority of the population, issues on security, confidentiality and ethics have to be taken into consideration. The lack of widespread secure digital signatures in health care may delay general availability. To clinically evaluate individual medication history, the relatively high prevalence of dispensed drugs in the population, seems to justify the National Pharmacy Register.

Abstract: INTRODUCTION: Healthcare organisations are nowadays expecting the support of IT in the daily routines. Personal digital assistants (PDAs) are in use in some healthcare organisations but in an irregular and unplanned way. The aim of the present study was to describe nurses' and nurse students' demands of functions and usability in a PDA. METHODS: Interviews were made with 12 nurses at the County Hospital of Kalmar and a questionnaire was given to nurse students (n=84) in their last, i.e. third, year at the Department of Health and Behavioural Sciences, University of Kalmar. RESULTS: There was a need for nurses to make the information in general more rich and efficient by means of a PDA. In a PDA, the nurses and nurse students expected access to information about the patients, knowledge resources and functions for their daily work. CONCLUSIONS: The nurses and nurse students had high expectations of a PDA for information retrieval. A PDA has the potential to be accepted as a supportive tool in healthcare organisations if it contains the demanded content which must be adapted to the users' needs and the general IT-system used, and the PDA must have a user friendly design.

Abstract: OBJECTIVES: The increased risk of adverse events in patients receiving potentially interacting drugs has long been recognized. The purpose of the present study was to evaluate the change in the risk of receiving potentially interacting drugs during a period covering three decades and to examine the relative risk of actual drug combinations. METHODS: The prescriptions from all individuals (about 8,000) with two or more prescriptions during three periods of 15 months, October to December 1983-1984, 1993-1994 and 2003-2004, were collected from an ongoing cohort study in the county of Jämtland, Sweden. The potential interactions were detected by a computerized system. RESULTS: The relative risk (RR) of receiving potentially interacting drugs increased for type C interactions [RR: 1.177, 95% confidence interval (CI): 1.104-1.256] and decreased for type D interactions (RR: 0.714, 95% CI: 0.587-0.868) from the period 1983-1984 to 2003-2004. Polypharmacy for the participants increased by 61%, from 9.05 filled prescriptions per subject in 1983-1984 to 10.6 in 1993-1994 and 14.6 in 2003-2004. The RR was positively correlated to the pronounced increase in polypharmacy; in addition, an exponential relationship was found for the more severe type D interactions. Few interacting drug combinations were responsible for a large proportion of the risk. CONCLUSION: We conclude that the risk of receiving potentially interacting drugs was strongly correlated to the concomitant use of multiple drugs. The pronounced increase in polypharmacy over time implies a growing reason for prescribers and pharmacists to be aware of drug interactions. Recently established national prescription registers should be evaluated for drug interaction vigilance, both clinically and epidemiologically.

Abstract: BACKGROUND: Internet consultation without a previous relationship between the doctor and the enquirer seems to be increasing in popularity. However, little is known about the advantages, disadvantages or other differences compared with regular health care when using this kind of service. OBJECTIVE: To investigate how an Internet-based Ask the Doctor service out with any pre-existing doctor-patient relationship was used and evaluated by the enquirers. METHODS: We recruited to a web-based survey users of the non-commercial Swedish Internet-based Ask the Doctor service run by family physicians. The survey was conducted between November 2001 and January 2002. Questions included both multiple choice and free text formats, and the results were analysed quantitatively and qualitatively. RESULTS: The survey was completed by 1223 participants. It was mainly women who submitted questions to the service (29% men, 71% women) and also who participated in the survey (26% men, 74% women). Most participants (77%) wrote their question at home, and 80% asked on their own behalf. Almost half of the enquiries (45%) concerned a medical matter that had not been evaluated by a medical professional before. After reading the answer, 43% of the participants indicated that they would not pursue their question further having received sufficient information in the answer provided. The service was appreciated for its convenience and flexibility, but also for reasons to do with the mode of communication such as the ability to reflect on the written answer without having to hurry and to read it more than once. CONCLUSION: In the present study, we found that an Internet-based Ask the Doctor service run by family physicians on the whole was evaluated positively by the participants both in terms of the answers and the service. Internet-based consultation may act as a complement to regular health care. In future studies, the cost-effectiveness, patient security, responsibilities of the Internet doctor and the role of Ask the Doctor services compared with regular health care should be evaluated.

Abstract: OBJECTIVE: The widespread use of pharmaceuticals prescribed by different physicians has caused the Swedish government to propose a new legislation with registration of all prescriptions dispensed at the Swedish pharmacies. In the present study, we wanted to examine the frequency, distribution and determinants of potential drug interactions. METHODS: The prescriptions from all individuals (n=8,214) with two or more prescriptions during October 2003 to December 2004 were collected from the ongoing Jämtland cohort study of a total of about 11,000 individuals. Potential drug-drug interactions were detected with a computerized interaction detection system and classified according to clinical relevance (types A-D). RESULTS: On average each individual filled 14.6 (men 14.3, women 14.8) prescriptions during the study period. 3.6% of the individuals used more than 15 different drugs. The number of detected potential drug interactions type A-D was 4,941 (men 1,949, women 2,992). The risk of receiving a potential interaction type A-D was estimated as the cumulative incidence 0.26 (2,116/8,214) overall, 0.22 (748/3,467) for men and 0.29 (1,368/4,747) for women during the 15-month study period. The age adjusted risk, RR(adj), for women was estimated as 1.30. Excluding sex hormones and modulators of the genital system, the RR(adj) was 0.96, with no elevated risk for women. For potential interactions type D, that might have serious clinical consequences, 167 (cumulative incidence 0.0203) individuals (72 men, cumulative incidence 0.0208, 95 women cumulative incidence 0.0200) were detected. The risk of receiving a combination of potentially interacting drugs was positively correlated to age and polypharmacy. The cumulative incidence for elderly was estimated as 0.36 (65-84 years) and 0.39 (85 years and above). The relative risk for individuals with 15 drugs or more was estimated as 3.67 (95% CI 3.46-3.90). CONCLUSION: In a general population there were relatively few severe potential drug interactions. The new Swedish national pharmacy register will provide health care professionals with a powerful tool to systematically review all prescriptions. An alert system should focus on the more potential drug interactions, type C-D, with close monitoring of elderly and patients with polypharmacy.

Abstract: BACKGROUND: The internet is increasingly used for health matters, including consulting a doctor. Primary care physicians (general practitioners) will probably be involved in performing text-based consultations on the internet as a complement to physical meetings. In the present study, we explored the experiences of GPs already performing consultations on the internet: the challenges, worries and educational demands of the task. MATERIALS AND METHODS: A questionnaire was given to 21 GPs performing consultations on the internet for a public, non-commercial 'ask the doctor' service. The questionnaire was carried out at a meeting or sent by mail. The doctors answered a total of 28 questions, 12 of which included graded alternatives. RESULTS: The participating GPs were stimulated and challenged by performing consultations on the internet with previously unknown enquirers, in spite of limitations caused by the lack of personal meetings and physical examinations. The participants experienced a high educational value as a result of the problem-based learning situation induced by unfamiliar questions. The asynchronous feature was appreciated as it allowed time to reflect and perform relevant information searches before replying. Prior training and long-term experience as a family doctor were recommended before embarking on this method of consultation. CONCLUSIONS: We conclude that the GPs studied experienced their new role as internet doctors mainly in a positive way, with some limitations. With the increase in consultations on the internet, training in this technique should be integrated into the curricula of medical schools and of continuous professional development (CPD).

Abstract: BACKGROUND: In 1998 the Swedish noncommercial public health service Infomedica opened an Ask the Doctor service on its Internet portal. At no charge, anyone with Internet access can use this service to ask questions about personal health-related and disease-related matters. OBJECTIVE: To study why individuals choose to consult previously-unknown doctors on the Internet. METHODS: Between November 1, 2001, and January 31, 2002 a Web survey of the 3622 Ask the Doctor service users, 1036 men (29%) and 2586 (71%) women, was conducted. We excluded 186 queries from users. The results are based on quantitative and qualitative analysis of the answers to the question "Why did you choose to ask a question at Infomedica's 'Ask the Doctor' service?" RESULTS: 1223 surveys were completed (response rate 36 %). Of the participants in the survey 322 (26%) were male and 901 (74%) female. As major reasons for choosing to consult previously-unknown doctors on the Internet participants indicated: convenience (52%), anonymity (36%), "doctors too busy" (21%), difficult to find time to visit a doctor (16%), difficulty to get an appointment (13%), feeling uncomfortable when seeing a doctor (9%), and not being able to afford a doctors' visit (3%). Further motives elicited through a qualitative analysis of free-text answers were: seeking a second opinion, discontent with previous doctors and a wish for a primary evaluation of a medical problem, asking embarrassing or sensitive questions, seeking information on behalf of relatives, preferring written communication, and (from responses by expatriates, travelers, and others) living far away from regular health care. CONCLUSIONS: We found that that an Internet based Ask the Doctor service is primarily consulted because it is convenient, but it may also be of value for individuals with needs that regular health care services have not been able to meet.

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Abstract: BACKGROUND: The aim of this study was to investigate the prevalence of allergic rhinitis and atopy in adolescents and whether air pollution in their schools contributed to allergic sensitization. METHODS: Analyses were performed in 1992-1994 on 511 18-year-old students at four schools and on the indoor air and floor dust of their classrooms. The students underwent skin-prick tests (SPTs) and a nasal lavage and answered a computer-based questionnaire containing questions on allergy and nasal symptoms. RESULTS: Atopy, defined as at least one positive SPT response, was found among 37% of the students, with no difference between students of the four schools, regardless of whether the data were adjusted for gender, hereditary disposition to allergy, and smoking habits. The number of students who had positive SPT and reported nasal symptoms when exposed to possible allergens, which were found among 35%, did not differ between the schools. No correlation was found between the prevalence of atopic individuals and the levels of different indoor air pollutants in the schools. CONCLUSION: The prevalence of allergic rhinitis among adolescents is very high and suggests that it is, at least at the time of our study and in comparison with other studies, still increasing. Our results indicate that the indoor air and floor dust at the schools of the students do not contribute to allergic sensitization.

Abstract: Continuing professional development (CPD) is a joint responsibility of the individual physician and the employer. CPD should focus on identification and documentation of the learning needs of the individual, based on professional demands. Reflection, feedback and evaluation of the results are central elements of the process. Efficient learning demands active participation; modern information technology is now becoming more widely available.

Abstract: At the recommendation of the Swedish Government, the Council for the Renewal of Undergraduate Education was established in 1990. In 1993 the Council was declared a permanent National Agency by Swedish Parliament and became part of the newly established National Agency for Higher Education in 1995. The purpose of the Council for Renewal of Undergraduate Education is to promote and support endeavors to develop quality and renewal of undergraduate education. In particular the council awards grants to development activities. Once a year, teachers at Swedish universities, university colleges and professional schools can apply for funding. Applications are accepted for projects directed towards undergraduate education in all disciplines. The Council selects 15-20 projects and each project is funded for 1-3 years. An advisory group--MEDCAL (Computer Assisted Learning (CAL) in MEDicine, Odontology and Veterinary Medicine)--consisting of representatives from all universities supports the Council with registration and evaluation of programs, offers their opinions on the production of CAL and collaborates with similar organizations in other countries, e.g. Australia, Denmark, Germany, Great Britain and USA. In all, 12 projects within the frame of MEDCAL will be reported.

Abstract:

Abstract: The nasal mucosa harbors sensory nerves containing neuropeptides such as substance P (SP), which are released by capsaicin. The neuropeptides are degraded by peptidases, e.g., neutral endopeptidase (NEP) that is present in the nasal mucosa. We studied the effect of enzymatically active recombinant NEP (rNEP) on neuropeptide-evoked secretion of nasal fluid and plasma exudation in rats. rNEP administered intranasally (i.n.) reduced the capsaicin-evoked nasal fluid secretion but failed to reduce the secretion evoked by SP (exogenous) under the experimental conditions used. rNEP reduced the increase in nasal plasma exudation evoked by capsaicin (endogenous neuropeptides). Because rNEP reduced neuropeptide-mediated nasal fluid secretion and plasma exudation in the rat, we suggest that peptidase activity in the nasal mucosa will determine the magnitude of the response to locally released neuropeptides.

Abstract: The concentration of biomarkers from vessels and inflammatory cells in nasal lavage fluid reflects the degree of hyperresponsiveness in patients with allergic rhinitis. The lavage has usually been performed of both nasal cavities together after prewashings and administration of decongestants. To improve the technique, we introduced a modification involving lavage of the nasal cavities separately without any prewashings or decongestants. We challenged 20 rhinitic subjects sensitive to timothy unilaterally with timothy extract. In nasal lavages performed before, immediately after, and 6 h after the challenge, we determined the concentrations of albumin, histamine, bradykinin, TAME (N-alpha-tosyl-L-arginine methyl ester)-esterase, and leukotriene C4 (LTC4). In eight subjects, the procedure was repeated 1 and 2 weeks later. After the challenge, albumin, bradykinin, TAME-esterase, and LTC4 in the nasal lavage fluid increased on the ipsilateral side but not on the contralateral side. Histamine did not increase after antigen challenge. After 6 h, the biomarkers were not increased. The concentrations of biomarkers did not differ between sides before the challenge and not between visits. Thus, the modified nasal lavage technique is reliable and improved compared to previous methods because it involves reproducible determinations of different biomarkers, and it is simple and easy to perform.

Abstract: Substance P (SP) evokes fluid secretion and plasma extravasation when applied to the nasal mucosa of rats. SP and another tachykinin, neurokinin A (NKA), are degraded in vitro by neutral endopeptidase (NEP) and angiotensin-1-converting enzyme (ACE). In this study, NKA or SP were applied locally to the nasal mucosa of rats. Subsequent fluid secretion was measured by a filter paper technique. Plasma exudation was derived as the recovery of intravenous (i.v.) administered 125I-albumin from the fluid-containing filter papers. In order to inhibit enzymatic degradation of the tachykinins by NEP and ACE, the rats were treated with i.v. administered phosphoramidon or captopril respectively or their combination. SP evoked fluid secretion that was augmented by phosphoramidon and further enhanced by adding captopril. NKA evoked nasal fluid secretion less effectively than SP and the effect was unaffected by peptidase inhibition. SP, but not NKA, evoked increased plasma exudation but only after pre-treatment with phosphoramidon.

Abstract: The increase in vascular permeability associated with neurogenic inflammation in the nasal mucosa is mediated by neuropeptides such as substance P released from sensory nerves. Substance P is degraded by the peptidases neutral endopeptidase-24.11 (NEP-24.11) and angiotensin converting enzyme (ACE). In the present study, we used capsaicin to produce neurogenic inflammation in the nasal mucosa of rats, and we examined the effect of inhibition of NEP-24.11 by phosphoramidon, inhibition of ACE by captopril or inhibition of both enzymes by giving both inhibitors. Using as tracers intravenous Evans blue dye to quantify the extravasation and Monastral blue pigment to localize the sites of leakage, we examined the magnitude and distribution of capsaicin-induced plasma extravasation in the nasoturbinates, maxilloturbinates, ethmoidal turbinates and septum. Capsaicin caused a dose-dependent increase in Evans blue extravasation in the naso- and maxilloturbinates but had only a slight effect in the septum. The leaky blood vessels responsible for this plasma extravasation, as manifested by Monastral blue labeling, were most numerous in the naso- and maxilloturbinates, particularly near the front and free borders. After phosphoramidon, the leakage of Monastral blue was more widespread and extended in a more caudal direction. The response to capsaicin was augmented by phosphoramidon alone but not by captopril alone. However, in the presence of phosphoramidon, captopril further augmented the capsaicin-induced extravasation. We conclude that neurogenic inflammation in the rat nasal mucosa is greatest in the naso- and maxilloturbinates and can be modulated by NEP-24.11 and, to a lesser extent, by ACE.

Abstract: We studied the role of different tachykinin receptors in mediating neurogenic vasodilation in the nasal mucosa of anesthetized pathogen-free rats. Three successive determinations of blood flow were made by injecting radionuclide-labeled microspheres suspended in 70% dextrose into the left ventricle. A selective agonist of the tachykinin NK1 receptor increased nasal blood flow, but neurokinin NK2- and NK3-selective agonists were without effect. The natural agonist of NK1 receptors, substance P (1 microgram/kg), increased nasal blood flow, an effect that was abolished by the selective NK1 receptor antagonist (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994). Capsaicin (25 micrograms/kg), a drug that releases tachykinins from sensory nerves, increased nasal blood flow, and this effect was significantly reduced by CP-99,994. We conclude that a significant component of neurogenic vasodilation in rat nasal mucosa is due to the stimulation of NK1 tachykinin receptors.

Abstract: We used Evans blue dye to assess the effects of bradykinin on vascular extravasation in nasal mucosa of pathogen-free F344 rats. There was a dose-dependent increase in Evans blue extravasation when bradykinin was delivered by topical instillation in the nose (doses, 25-100 nmol). Only the highest intravenous doses (2 and 5 mumol/kg) of bradykinin caused increased extravasation. When bradykinin was delivered by either route, its effect on extravasation was exaggerated by pharmacological inhibition of the enzymes neutral endopeptidase (NEP) and kininase II [angiotensin-converting enzyme (ACE)]. When bradykinin was instilled locally, the effect of NEP inhibition was predominant; when bradykinin was injected intravenously, the effect of ACE inhibition was predominant. The mechanism of extravasation also varied with the mode of bradykinin delivery: when bradykinin was instilled locally in the nose, the selective neurokinin 1 (NK1) receptor antagonist CP-96,345 markedly inhibited the response, whereas it had no effect on Evans blue extravasation when bradykinin was injected intravenously. We conclude that bradykinin causes dose-related increases in Evans blue dye extravasation in the nose and that these effects are exaggerated when NEP and ACE are inhibited. Topically instilled bradykinin causes vascular extravasation to a large extent via NK1 receptor stimulation, thus suggesting a major role for tachykinins released from sensory nerve endings.

Abstract: We studied the effect of the locally administered glucocorticoid budesonide on plasma extravasation induced by capsaicin and by substance P (SP) in the nasal mucosa of pathogen-free rats. Using Evans blue dye as a tracer, we measured plasma extravasation induced by capsaicin (150 micrograms kg-1 i.v.) or SP (0.5 and 2.5 micrograms kg-1 i.v.) in the rat naso- and maxilloturbinates after pretreatment with budesonide (0.1-50 micrograms twice/day for 2 days in the right nostril; 50 micrograms only for SP) or its vehicle. We found that budesonide inhibits plasma extravasation induced by capsaicin in a dose-dependent fashion in the nasal cavity. After the highest dose (50 micrograms) of budesonide, the values of Evans blue in the nasal mucosa were not different from the values observed after capsaicin vehicle alone. Budesonide also reduced plasma extravasation induced by capsaicin in the trachea and the urinary bladder of the rats in a dose-dependent fashion. Budesonide (50 micrograms) delivered to the nose inhibited the plasma extravasation caused by 0.5 but not by 2.5 micrograms SP kg-1 in the nasal mucosa. We conclude that the postjunctional part of the neurogenic pathway is a target for glucocorticoid antiinflammatory action in the nasal mucosa, at least of the rat. Budesonide's effect on organs other than the nose can be explained by systemic absorption.

Abstract:

Abstract: Nasal permeability was studied in anaesthetized rats after topical challenge with methacholine (MC), substance P (SP), or capsaicin. The drugs were applied onto strips of filter paper. After drying, they were inserted into one side of the nasal cavity while the other side received strips without drugs. The filter paper strips were used not only to stimulate secretion but also to collect the resulting fluid. FITC-albumin was given i.v. and the amount appearing in the nasal fluid was captured on the strips and measured by fluorometry. The presence of FITC-albumin in nasal secretions reflects a leakage of plasma through the capillary endothelium and the nasal epithelium. MC, SP, and capsaicin stimulated the secretion of nasal fluid. SP and capsaicin, but not MC increased the concentration of FITC-albumin in the nasal fluid.

Abstract: Histamine (dihydrochloride or free base), mannitol or sodium chloride applied topically to the nasal mucosa of anaesthetized rats stimulated the secretion of fluid in a dose-dependent manner. Compound 48/80 applied in the same way and histamine given s.c. failed to evoke secretion. The secretion evoked by topically applied histamine was resistant to pretreatment with H1 and H2 receptor antagonists i.p. Furthermore, the secretion evoked by histamine and sodium chloride was resistant to pretreatment with atropine i.p. or lidocaine topically. The secretion evoked by mannitol or by sodium chloride was not reduced by H1 receptor antagonists and was not significantly different from that obtained after challenge with histamine of equivalent osmolality. We conclude that the response to topically applied histamine reflects the hyperosmolarity of the compounds applied and not the effect of histamine on histamine receptors.

Abstract: The effect of substance P (SP) on nasal secretion was studied in dog, rat, and man. Substance P was administered topically by the use of filter papers that had been soaked with an aqueous solution of SP and dried. The SP-containing filter paper strips were applied to the nasal mucosa for five minutes. The secretion was absorbed onto the filter papers. The strips were weighed before and after the experiment. Substance P induced atropine-resistant nasal secretion in a dose-dependent manner in anaesthetized dogs and rats. In man, SP failed to evoke nasal secretion in the doses applied. Systemic effects limited the dose that could be given to man. When exposed to nasal secretions SP was rapidly degraded. This may explain the failure of SP to evoke nasal secretion in man.

Abstract: 1. The secretion of nasal fluid was studied in anaesthetized rats after topical application of capsaicin, and of calcitonin gene-related peptide (CGRP) alone or CGRP in combination with substance P (SP). The flow of nasal fluid was stimulated and the secretions collected by a filter paper technique. The concentrations of SP and CGRP in nasal biopsies were determined after topical or systemic administration of capsaicin. 2. Capsaicin (single dose administration) stimulated nasal secretion in a dose-dependent manner. The effect was inhibited by hexamethonium, lignocaine, or by the tachykinin antagonist (D-Pro2, D-Trp7,9)-SP, but not by atropine, or by a combination of the histamine H1-receptor antagonist chlorpheniramine and the H2-receptor antagonist ranitidine. 3. When applied cumulatively, capsaicin rapidly produced desensitization. The concentrations of SP and CGRP in the nasal mucosa were reduced by capsaicin 6 days after topical or s.c. administration but not 15 min after topical application of desensitizing doses. 4. CGRP did not stimulate the secretion of nasal fluid and did not alter SP-evoked nasal secretion. 5. The inhibition by hexamethonium of the capsaicin-evoked nasal secretion suggests the involvement of ganglionic reflexes. In addition, the inhibition of the response to capsaicin by (D-Pro2,D-Trp7,9)-SP and lidocaine and the depletion of SP and CGRP after capsaicin indicate the involvement of tachykinin-mediated axon reflexes.

Abstract: The diagnostic efficacy of clinical history (CH), skin prick test (SPT) and RAST was estimated in relation to nasal and conjunctival provocation tests (NPT, CPT) in 69 patients with seasonal rhinoconjunctivitis. The extracts used were freeze-dried, and biologically standardized birch and timothy allergen preparations matched to the extracts on Phadebas RAST discs. Based on single determinations the sensitivity, specificity and predictive values were calculated. There were highly significant (P less than 0.001) correlations between all parameters: NPT, CPT, CH, SPT and RAST. For birch the combination of SPT and RAST made the PTs superfluous as both sensitivity and specificity then reached 100%. With timothy the sensitivity was 97% and with the addition of CH 100%. However, the specificity was only 79% through combining CH, SPT and RAST. The present study using the same standardized allergen preparation in all tests showed a good correlation between indirect test results and provocation tests.