Variability of disease activity in patients with hereditary angioedema type 1/2: longitudinal data from the Icatibant Outcome Survey.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-1/2) is a chronic and debilitating disease. The unpredictable clinical course represents a significant patient burden. OBJECTIVE: To analyse longitudinal registry data from the Icatibant Outcome Survey (IOS) in order to characterize temporal changes in disease activity in patients with HAE-1/2. METHODS: Icatibant Outcome Survey (NCT01034969) is an international observational registry monitoring the clinical outcomes of patients eligible for icatibant treatment. The current analyses are based on data collected between July 2009 and July 2019. Retrospective data for attacks recorded in the 12 months prior to IOS enrolment and for each 12-month period up to 7 years were analysed. RESULTS: Included patients reported angioedema attacks without long-term prophylaxis (LTP; n = 315) and with LTP (n = 292) use at the time of attack onset. Androgens were the most frequently used LTP option (80.8%). At the population level, regardless of LTP use, most patients (52-80%) reporting <5 attacks in Year 1 continued experiencing this rate; similarly, many patients (25-76%) who reported high attack frequency continued reporting ≥10 attacks/year. However, year on year, 31-51% of patients experienced notable changes (increase/decrease of ≥5 attacks) in annual attack frequency. Of patients who reported an absolute change of ≥10 attacks from Year 1 to 2, 17-50% continued to experience a change of this magnitude in subsequent years. CONCLUSION: At the population level, attack frequency was generally consistent over 7 years. At the small group level, 28.8-34.5% of patients reported a change in attack frequency of ≥5 attacks from Year 1 to Year 2; up to half of these patients continued to experience this magnitude of variation in disease activity in later years, reflecting high intra-patient variability.

Management of patients with hereditary angioedema in Germany: comparison with other countries in the Icatibant Outcome Survey.

BACKGROUND: The Icatibant Outcome Survey (IOS; NCT01034969) is a Shire-sponsored, international, observational study monitoring the safety and effectiveness of icatibant, a bradykinin B2 receptor antagonist approved for the acute treatment of adults with hereditary angioedema with C1 inhibitor deficiency (HAE-C1-INH). OBJECTIVE: To report IOS data comparing demographic and icatibant treatment outcomes in patients with HAE-C1-INH from Germany to HAE-C1-INH patients from 11 other IOS countries. METHODS: A descriptive, retrospective, comparative analysis of data from 685 IOS patients with HAE-C1-INH from seven centres in Germany (n = 93) vs. centres from Austria, Brazil, Czech Republic, Denmark, France, Greece, Israel, Italy, Spain, Sweden and the United Kingdom (n = 592, July 2009-January 2017). Icatibant treatment outcomes were retrieved from patients with complete attack outcome data for time to treatment, time to resolution and attack duration (160 attacks in 42 German patients and 1442 attacks in 251 patients from other IOS countries). RESULTS: German patients reported significantly fewer severe/very severe attacks (38.7% vs. 57.5%, respectively; P < 0.001). The proportion of attacks treated with a single icatibant injection was significantly higher in German patients (97.1% vs. 91.6%, P = 0.0003). The median time to treatment (0.0 h vs. 1.5 h), time to resolution (3.0 h vs. 7.0 h) and attack duration (4.3 h vs. 10.5 h) in German patients vs. other IOS countries were all significantly shorter (all P < 0.0001). No meaningful differences were identified between patients from Germany and other countries with regard to sex, median age at enrolment, median age at symptom onset and median age at diagnosis. CONCLUSION: German IOS patients share similar demographic characteristics to patients from other IOS countries yet treat their attacks with icatibant significantly earlier and have markedly fewer severe or very severe attacks. Factors including regional access to and availability of icatibant may drive these outcomes and warrant further investigation.

The Icatibant Outcome Survey: experience of hereditary angioedema management from six European countries.

BACKGROUND: Hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) is a rare, potentially fatal, bradykinin-mediated disease. Icatibant is a bradykinin B2 receptor antagonist originally approved in 2008 in the European Union and 2011 in the United States as an acute therapy option for HAE attacks in adults. OBJECTIVE: To compare demographics, disease characteristics and treatment outcomes of icatibant-treated HAE attacks in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey across six European countries: Austria, France, Germany, Italy, Spain and the UK. METHODS: The Icatibant Outcome Survey [IOS; Shire, Zug, Switzerland (NCT01034969)] is an international observational study monitoring the safety and effectiveness of icatibant. Descriptive, retrospective analyses compared IOS country data derived during July 2009-April 2015. RESULTS: Overall, 481 patients with C1-INH-HAE provided demographic data. A significant difference across countries in age at onset (P = 0.003) and baseline attack frequency (P < 0.001) was found although no significant differences were found with respect to gender (majority female; P = 0.109), age at diagnosis (P = 0.182) or delay in diagnosis (P = 0.059). Icatibant was used to treat 1893 attacks in 325 patients with majority self-administration in all countries. Overall, significant differences (all P < 0.001) were found across countries in time to treatment [median 1.8 h; median range: 0.0 (Germany-Austria) to 4.4 (France) h], time to resolution [median 6.5 h; median range: 3 (Germany-Austria) to 12 (France) h] and attack duration [median 10.5 h; median range: 3.1 (Germany-Austria) to 18.5 (France) h]. CONCLUSION: These data form the first European cross-country comparison of disease characteristics and icatibant use in patients with C1-INH-HAE who are enrolled in IOS. International variation in icatibant practice and treatment outcomes across the six European countries assessed highlight the need to further investigate the range of country-specific parameters driving regional variations in icatibant use.

Comparing acquired angioedema with hereditary angioedema (types I/II): findings from the Icatibant Outcome Survey.

Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1-INH-HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1-INH-AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1-INH-AAE and compare disease characteristics with those with C1-INH-HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6-month intervals during patient follow-up visits. In the icatibant-treated population, 16 patients with C1-INH-AAE had 287 attacks and 415 patients with C1-INH-HAE types I/II had 2245 attacks. Patients with C1-INH-AAE versus C1-INH-HAE types I/II were more often male (69 versus 42%; P = 0·035) and had a significantly later mean (95% confidence interval) age of symptom onset [57·9 (51·33-64·53) versus 14·0 (12·70-15·26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1-INH-AAE versus C1-INH-HAE types I/II (mean 12·3 months versus 118·1 months; P = 0·006). Patients with C1-INH-AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0·064). Overall, angioedema attacks were more severe in patients with C1-INH-HAE types I/II versus C1-INH-AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0·001). Median total attack duration was 5·0 h and 9·0 h for patients with C1-INH-AAE versus C1-INH-HAE types I/II, respectively.

Long-term safety of icatibant treatment of patients with angioedema in real-world clinical practice.

The Icatibant Outcome Survey (IOS) is an observational study monitoring safety and effectiveness of icatibant in the real-world setting. We analyzed safety data from 3025 icatibant-treated attacks in 557 patients (enrolled between July 2009 and February 2015). Icatibant was generally well tolerated. Excluding off-label use and pregnancy, 438 patients (78.6%) did not report adverse events (AEs). The remaining 119 (21.4%) patients reported 341 AEs, primarily gastrointestinal disorders (19.6%). Of these, 43 AEs in 17 patients (3.1%) were related to icatibant. Serious AEs (SAEs) occurred infrequently. A total of 143 SAEs occurred in 59 (10.6%) patients; only three events (drug inefficacy, gastritis, and reflux esophagitis) in two patients were considered related to icatibant. Notably, no SAEs related to icatibant occurred in patients with cardiovascular disease, nor in those using icatibant at a frequency above label guidelines. Additionally, no major differences were noted in AEs occurring in on-label vs off-label icatibant users.

Redimune NF Liquid, a ready-to-use, high-concentration intravenous immunoglobulin therapy preparation, is safe and typically well tolerated in the routine clinical management of a broad range of conditions.

In clinical practice, intravenous immunoglobulin therapy (IVIG) is used in the management of a wide variety of medical conditions. Observational studies examining IVIG use in routine clinical practice are therefore an important means of validating findings from more strictly randomized controlled trials of patients with specific conditions. In this observational study, we examined the tolerability of a high-concentration (12%) ready-to-use liquid IVIG (Redimune NF Liquid) when used in the standard management of a diverse range of conditions (including primary immunodeficiency diseases, neurology conditions, oncology conditions and immune thrombocytopaenic purpura). IVIG regimen and dose were selected by the physician based on the summary of product characteristics. During the study, 193 infusions were administered to 51 patients in 153 infusion cycles (per infusion cycle: one to five infusions; mean dose, 347.6 mg/kg; mean duration, 202.4 min). The mean maximum infusion rate per cycle was 2.9 mg/kg/min, demonstrating that the infusion rate was often higher than that recommended in the summary of product characteristics. Redimune NF Liquid was well tolerated: there were 36 adverse reactions (at least probably associated with IVIG) in 10 patients (19.6% of sample, 0.24 per infusion cycle, 0.19 per infusion). The most common adverse reaction was headache (50% of reactions), followed by chills (13.8%). Most reactions (69%) were mild and there were no serious or unexpected reactions. In conclusion, in routine clinical practice involving patients with many different conditions, Redimune NF Liquid was well tolerated by the majority of patients.

Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study.

In patients with relapsing-remitting multiple sclerosis (MS), IVIG was shown to reduce the relapse rate and progression of disability. In patients with chronic progressive MS, a beneficial effect of IVIG was not documented in placebo controlled studies. This trial investigated the influence of IVIG in primary (PPMS) and secondary (SPMS) chronic progressive MS. Two-hundred and thirty-one patients stratified for PPMS (n=34) and SPMS (n=197) were randomly assigned to IVIG 0.4 g/kg per month or to placebo for 24 months. Primary endpoints were 1) the time to sustained progression of disease identified as worsening of the expanded disability status scale (EDSS) sustained for 3 months, and 2) the improvement of neurological functions defined by a patient's best EDSS score. Secondary endpoints were the proportion of patients with sustained progression, the relapse rate, the assessment of fine motor skills, visual evoked potentials, contrast sensitivity, depression and quality of life. Analysis of the intention-to-treat (ITT) population of combined PPMS and SPMS patients showed that the mean time to sustained progression was 74 weeks in the IVIG compared with 62 weeks in the placebo group (P=0.0406). When PPMS and SPMS patients were analysed separately, the time to sustained progression was also longer in the IVIG group, but the difference was not significant. There was no IVIG-mediated improvement in neurological functions. In the combined per protocol (PP) treated patients, IVIG treatment prolonged time to sustained progression by 13 weeks (P=0.0396). PPMS patients, but not SPMS patients showed a slight favourable IVIG effect on the best EDSS score. In the combined ITT population there were less patients with sustained progression in the IVIG than in the placebo group (P=0.028). The difference was significant in PPMS (P=0.016), but not in SPMS patients. In the combined PP population, there was a trend for a favorable IVIG effect on the rates of patients with sustained progression. In patients with PPMS, this IVIG effect reached significance (P=0.036). Other secondary endpoints did not show significant differences between treatment groups. Eighteen patients with PPMS and 102 patients with SPMS withdrew from the study for various reasons. Treatment was generally well tolerated. It was concluded that monthly IVIG infusion could delay progression of disease in patients with PPMS, and that there was a trend in favour of IVIG treatment in patients with SPMS.

Pharmacokinetics and safety of recombinant anti-RhD in healthy RhD-negative male volunteers.

In this first-in-man study, we assessed the pharmacokinetics, safety and tolerability of MonoRho, a human recombinant monoclonal anti-RhD immunoglobulin G1 (IgG1) antibody. Eighteen RhD-negative healthy male volunteers were randomized in two groups to receive a single administration of 300 micro g of MonoRho either intravenously or intramuscularly. There were no symptoms of allergic or anaphylactic type reaction in any subject, and there was no evidence of any MonoRho-related changes in laboratory safety parameters. None of the subjects mounted a detectable immune response to MonoRho. Serum samples were obtained up to 91 days after injection to measure anti-D IgG concentrations by flow cytometry. After intramuscular administration of MonoRho, anti-D IgG concentrations gradually increased reaching peak levels after a mean of 3.4 days. After 3 weeks, the mean anti-D IgG concentrations after intravenous and intramuscular administration became virtually equal to each other and remained so thereafter. In both the treatment groups, the mean elimination half-life was about 18 days and thus similar to that described for plasma-derived anti-D IgG. The bioavailability of MonoRho after intramuscular administration was estimated as 46%. The excellent tolerability and safety of MonoRho as well as its expected elimination half-life supports the continued clinical development of this compound.

Efficacy, tolerability, safety and pharmacokinetics of a nanofiltered intravenous immunoglobulin: studies in patients with immune thrombocytopenic purpura and primary immunodeficiencies.

BACKGROUND AND OBJECTIVES: A nanofiltration step with the capacity to reduce blood-borne pathogens was introduced into the manufacturing process of intravenous immunoglobulin (IVIG). In order to demonstrate the efficacy, safety and pharmacokinetics of the modified product, we conducted Phase II/III studies comparing the nanofiltered IVIG (IVIG-N) with its parent product, Sandoglobulin, in patients with chronic immune thrombocytopenic purpura (ITP) and primary immunodeficiencies (PID). MATERIALS AND METHODS: Patients with ITP (n = 27) with platelet counts of < 20 x 10(9)/l were treated with Sandoglobulin or IVIG-N infusions at a dose of 0.4 g/kg body weight on five consecutive days. The primary efficacy end-point was the number of patients with an increase in platelet counts to > 50 x 10(9)/l. Secondary end-points were time to and duration of response, and regression of bleeding. Patients with PID (n = 36) were treated for 6 months with Sandoglobulin or IVIG-N at doses of 0.2-0.8 g/kg, infused at 3- or 4-week intervals. The primary end-point was the number of days absent from school/work. Secondary end-points were hospitalization, use of antibiotics and feeling of well-being. In both studies, tolerability was assessed by recording of adverse events and laboratory determinations. Viral safety was ascertained by serology supplemented with nucleic acid detection methods. Pharmacokinetics were analysed in patients with PID using serum concentration-time data for immunoglobulin G (IgG), and IgG antibodies to hepatitis B surface antigen (anti-HBsAg). RESULTS: In the ITP study, the primary end-point was met by 12/16 patients on IVIG-N and by 10/10 patients on Sandoglobulin (P = 0.123). A shift towards lesser bleeding intensity was seen in both groups. In the PID study, seven of 18 patients on IVIG-N and six of 16 patients on Sandoglobulin missed days at work/school, with monthly mean absences of 0.4 and 0.5 days (P = 0.805). The feeling of well-being was comparable in both groups. In the ITP study, adverse events with a causal relationship to medication were suspected in six patients on IVIG-N and in seven on Sandoglobulin. In the PID study, three patients on IVIG-N and two on Sandoglobulin experienced possible drug-related adverse events. In both studies, serological and polymerase chain reaction (PCR) tests gave evidence for virus safety. Pharmacokinetics showed constant peak and trough serum IgG levels in all patients, indicating almost steady-state conditions for both formulations. The overall half-life (t1/2) for total IgG was 33 +/- 17 days in the IVIG-N arm and 25 +/- 16 days in the Sandoglobulin arm; for anti-HBsAg t1/2, values were 17 +/- 7 and 17 +/- 9 days, respectively. CONCLUSIONS: IVIG-N is efficacious, well tolerated and safe in patients with ITP and PID. Its pharmacokinetic properties were comparable to those of Sandoglobulin.

Product equivalence study comparing the tolerability, pharmacokinetics, and pharmacodynamics of various human immunoglobulin-G formulations.

In this randomized, double-blind, parallel-group study, a commercially available human immunoglobulin-G product, IVIG, was compared with two test formulations: (1) IVIG-N, which is a nanofiltered formulation of IVIG, and (2) IVIG-L, which is a nanofiltered, liquid, ready-for-use IgG formulation containing nicotinamide, L-proline, and L-isoleucine as stabilizers. Three groups of 10 healthy subjects each received a single 0.6 g/kg dose of one of the formulations infused over 3.5 to 6.8 hours, depending on the total volume to be infused. Blood samples were obtained over a 6-week period to assess pharmacokinetics, immunogenicity, and the pharmacodynamic effects on leukocytes and TNF-alpha. A blood sample was taken at 6 months for a viral safety check. Administrations were generally well tolerated with only one reference IVIG infusion stopped prematurely due to headache. The IgG Cmax and AUC over the 6-week blood sampling period from both test formulations satisfied equivalence criteria compared with the reference formulation. In subjects receiving IVIG-L, peak concentrations of the stabilizer nicotinamide ranged from 0.34 to 0.47 mmol/L and of nicotinamide-N-oxide from 0.03 to 0.04 mmol/L, which are below those reported to cause adverse events. During the infusion of IVIG, leukocyte counts initially declined from a baseline of 5.7 +/- 1.1 x 10(9)/L to 3.7 +/- 0.8 x 10(9)/L at 2 to 4 hours and returned to baseline by 24 hours. TNF-alpha levels, reflecting activation of the monocyte-macrophage system by the infused IVIG, rose from a baseline of 13 +/- 4 pg/mL to a peak of 272 +/- 324 pg/mL at 2 to 4 hours and returned to baseline by 24 hours. These patterns were generally similar for the test formulations, with the exception that the increase in TNF-alpha levels was dampened for IVIG-N, although this was not statistically significant. There was no evidence of immunogenicity or viral transmission from any of the formulations. Hence, these three formulations were generally well tolerated, yielded similar systemic exposure to IgG over a 6-week period after administration, and did not give rise to immunogenicity or viral safety concerns.

M2 receptor binding of the selective antagonist AF-DX 384: possible involvement of the common allosteric site.

The hypothesis was tested that M2-selective antagonists partially utilize the allosteric site of muscarinic M2 receptors. The interactions of the allosteric agent W84 (hexane-1, 6-bis[dimethyl-3'-phthalimidopropyl-ammonium bromide]) were studied with the M2/M4-selective AF-DX 384 [(+/-)-5, 11-dihydro-11-([(2-(2-[(dipropylamino)methyl]-1-piperidinyl)ethyl)amino]carbonyl)-6H-pyrido(2,3-b)(1,4)-benzodiazepine-6-one], the nonselective N-methylscopolamine (NMS), and a number of other muscarinic antagonists. In isolated paced guinea pig atria, the antagonistic effect of W84 against oxotremorine- and arecaidine propargyl ester-induced negative inotropic actions reached a limiting value at higher W84 concentrations, revealing negative cooperativity (factors of cooperativity alpha = 311 and alpha = 495, respectively). The antagonistic potency of W84 in this M2 receptor model (W84 binding constant KA approximately 160 nM) was higher than at M1/M4-like receptors of rabbit vas deferens (KB approximately 800 nM) and at M3 receptors of guinea pig ileum (KB approximately 4,000 nM). In paced atria, combinations of W84 with muscarinic antagonists yielded more-than-additive antagonistic effects against oxotremorine in case of conventional antagonists such as NMS (alpha = 18) but less-than-additive effects with the M2-preferring AF-DX 384 (alpha = 444). In guinea pig heart homogenates, the equilibrium binding of [3H]NMS was only partially inhibited by W84 (alpha = 2.4), whereas [3H]AF-DX 384 binding could be suppressed completely (alpha = 194). The difference in cooperativity reflects that W84 inhibits [3H]NMS dissociation with a approximately 40-fold higher potency (ECdiss = 900 nM) than [3H]AF-DX 384 dissociation (ECdiss = 33,300 nM). [3H]NMS dissociation also could be retarded by AF-DX 384 (ECdiss = 22,000 nM), probably via an interaction with the site used by W84. The results suggest that the binding domain of AF-DX 384 partially overlaps with the common allosteric site of the M2 receptor protein.

[Granular corneal dystrophy or Groenouw's disease type 1. A challenge to Norwegian biochemists, geneticists and ophthalmologists]. / Granulaer hornhinnedystrofi eller Groenouws sykdom type 1. En utfordring til norske biokjemikere, genetikere og øyeleger.

A Norwegian family with granular corneal dystrophy was described by Saebø (2) as early as 1939. One of the branches in this family is further described in the present work. The sickness, which is autosomal dominant, occurred with high penetrance, especially in generation IV and V, with as many as 12 of 16 affected in generation V. In the youngest generation described only 10 of 23 are affected. The reason for this cannot be predicted from the present work. The results in this generation are more uncertain than in the others because of the age of the patients. If we include the work done by Saebø, a total of 45 of 73 children are affected (62%). Further work is needed. Ophthalmologists, biochemists and persons working on genetics should make a joint effort to study the reason for the formation and the composition of the granulae on the corneas of these patients.

Dose-related control of allergic rhinitis symptoms by a H1-receptor antagonist. Finding the proper doses [correction of dosis] of dimethindene maleate in patients with allergic rhinitis.

The aim of the study was to evaluate the efficacy and duration of two doses of dimethindene, in a sustained release pellet formulation, with a standardized grass pollen provocation model (Vienna Challenge Chamber, VCC). The study of 12 grass pollen-allergic volunteers (verified by case history, skin prick test and RAST) was carried out in a placebo-controlled, double-blind, cross-over design. 12 h before a 4-hour continuous challenge with permanent 1,000 Dactylis grass pollen/m3 of air in the VCC, 4 or 8 mg of dimethindene (Fenistil pellets) or an identically appearing placebo was administered in three sessions. Nasal flow and resistance, nasal secretion and subjective symptoms were recorded at 15-min intervals during this long-term challenge under reproducible conditions. In comparison to placebo, dimethindene leads to a statistically significant reduction (p < 0.05) in nasal response and clinical symptoms for at least 16 h after treatment. The efficacy of 8 mg dimethindene was superior to that of 4 mg dimethindene; however, the differences between both active treatments were not statistically significant. Therefore 4 mg dimethindene once a day is adequate for usual pollinotic disease conditions.

The identification of leaf thionin as one of the main jasmonate-induced proteins of barley (Hordeum vulgare).

Jasmonic acid (JA) and its methyl ester (JA-Me) are able to introduce the accumulation of several specific polypeptides in cut leaf segments of barley. Two of the most prominent JA-induced proteins of M(r) 15,000 and 23,000 have been characterized by isolating and sequencing complete cDNA sequences. While the sequence of the M(r) 23,000 polypeptide shows no similarity to published sequences, the sequence of the M(r) 15,000 polypeptide corresponds to the higher-molecular-weight precursor of a leaf thionin previously characterized. Transcripts for the M(r) 23,000 and M(r) 15,000 polypeptides accumulate in leaf segments shortly after the beginning of JA treatment. JA and JA-Me induce the appearance of the two proteins not only in leaf segments but also in intact barley seedlings. However, in seedlings the accumulation of JA-induced proteins occurs much more slowly and requires high concentrations of volatile JA-Me. Thus, in barley it seems unlikely that volatile JA-Me is involved in the interaction between different members of this species, as has been proposed recently for tomato seedlings.

Behavioural and school adjustment of 12-13-year old internationally adopted children in Norway: a research note.

Rutter's scales for parents and teachers were used to assess the behavioural and emotional adjustment of 151 12-13-year old internationally adopted children. Additional questions about school adjustment were added to the teachers' questionnaire. The majority of the adopted children were found to be well adjusted. However, the adopted children were given higher mean scores both for the full scale and on a "hyperactive" subscale than a comparison group of non-adopted children. More adopted than non-adopted children had problems with arithmetic. Adopted boys had higher mean scores than adopted girls on both Rutter scales. Age at adoption was unrelated to outcome.

[Treatment of acute episodes of atopic dermatitis. Double-blind comparative study with 0.05% halometasone cream versus 0.25% prednicarbate cream]. / Behandlung akuter Schübe der atopischen Dermatitis. Doppelblinde Vergleichsstudie mit 0.05%-Halometason-Creme versus 0.25%-Prednicarbat-Creme.

In a double-blind, randomized multicenter study in patients with acute episodes of atopic dermatitis, the efficacy and tolerance of 0.5% halometasone (Sicorten) cream were compared with those of 0.25% prednicarbate cream. A total of 165 patients (88 men, 77 women) were admitted to the study. The halometasone group contained 9% more cases with severe disease than did the prednicarbate group. Two daily nonocclusive applications were permitted, and treatment lasted 14 days. No difference in the onset of the effect was observed between the two groups. With respect to clinical efficacy, higher healing rates were found in the halometasone group: 50.6% versus 34.5% in the patients as a whole, and 39.5% vs. 16.2% in the subgroup of clinically severe cases. Applying stratification, a statistical difference was found in the clinically severe cases. Both creams were well tolerated; undesired side effects were observed neither with halometasone cream nor with prednicarbate cream. Cosmetic acceptance was assessed as very good by 50.6% of patients treated with halometasone cream, and 46.0% of patients treated with prednicarbate cream. Summarizing, it may be noted that halometasone cream is more effective than prednicarbate cream, and is equally well tolerated.

[A physician-staffed heart ambulance in a rural district. A 1-year trial]. / En laegeassisteret hjerteambulance i et landdistrikt. En etårig forsøgsordning.

A trial period of one year in which the ambulance service for patients with acute cardiac disease was improved is described. This trial took pace in the County of Vestsjaelland in a mixed urban and rural district with five general practices and with more than fifteen kilometres (9.4 miles) to the county hospital. Two ambulance stations were equipped with defibrillators and the staff were trained in their use. The recommendations made by a subcommittee appointed by the Danish Board of Health were thus fulfilled, but, in addition, the general practitioners/doctors-on-duty were connected with the arrangement. They were equipped with radios by which they could communicate with the ambulance stations. If the leader of the ambulance station considered, on the basis of the alarm, that a patient with acute cardiac disease was involved, the doctor-on-duty in the district concerned was contact so that he could come and participate in the treatment unless prevented by other work. An attempt was made to assess the effect of an arrangement such as this on survival of patients, the extent to which medical assistance can be obtained and the extent of the actual medical assistance. During the trial period, 158 turn-outs occurred to the approximately 30,000 population in the district concerned. The total number of emergency ambulance turn-outs was 1,200, 41 of these were patients with clinical cardiac arrest and 56 to patients with other forms of acute cardiac disease. Sixty-one patients were found to have conditions other than cardiac diseases. It proved possible to provide medical assistance in 79% of the cases.(ABSTRACT TRUNCATED AT 250 WORDS)

[Treatment of diabetes and quality of life. On possibilities of a more normalized life style using an insulin pen for multi-injection therapy]. / Diabetesbehandling og livskvalitet. Om muligheter til mer normalisert livsmønster ved bruk av mangeinjeksjonsbehandling med insulinpenn.

Forty-eight insulindependent diabetics were interviewed by a psychologist about their experiences when changing from conventional diabetes regimen to multi-injection therapy using NovoPen (a pen-like insulin injection system). They had then used the new therapy for 1 1/2 years. Most of them had made only small changes in their eating habits, but they strongly appreciated the new possibility for flexibility in eating patterns. The most mentioned advantages were: The new therapy was practical and easy to use, gave more freedom, made social life easier and improved blood glucose control. Many, mainly women, experienced less feelings of guilt, and women also placed the social advantages highest on the list of advantages. The youngest persons thought the greatest benefit was increased freedom, and persons in middle age the possibilities for improved metabolic control. Multi-injection insulin therapy is an important advancement, and is probably not acceptable to most diabetics without a practical and reliable insulin pen.