Documenting the use of computers in Swedish Health Care up to 1980.

OBJECTIVES: This paper describes a documentation project to create, collect and preserve previously unavailable sources on informatics in Sweden (including health care as one of 16 subgroups), and making them available on the Web. Time was critical as the personal documentation and artifacts of early pioneers could be irretrievably lost. The criteria for participation were that a person had developed a system in a clinical environment which was used by others prior to 1980. METHODS: Participants were interviewed and asked for early documentation such as notes, minutes from meetings, drawings, test results and early models - together with related artifacts. The approach included traditional oral history interviews, collection of autobiographies and new self-structuring and time saving methods, such as witness seminars and an Internet-based repository of their recollections (the Writers' Web). RESULTS: The combination of methods obtained new information on system errors, and challenges in reaching the goals due partly to inadequacies of the early technology, and partly to the insufficient understanding of the complexity of the many problems which needed to be solved before a useful electronic patient record could be realized. A very important result was the development of a method to collect information in an easier, faster and much less expensive way than using the traditional scientific method, and still reach results that are qualitative and quantitative for the purpose of documenting the early period of computer-based health care technology. The witness seminars and the Writers' Web yielded especially large amounts of hitherto-unknown information. With all material in one database available to everyone on the Web, it is accessed very frequently - especially by students, researchers, journalists and teachers. CONCLUSIONS: Study of the materials explains and clarifies the reasons behind the delays and difficulties that have been encountered in developing electronic patient records, as described in an article [3] published in the IMIA Yearbook 2006.

Bioimpedance spectroscopy: a new tool to assess early esophageal changes linked to gastroesophageal reflux disease?

Bioimpedance spectroscopy can identify pathological changes related to precancerous lesions of the cervix uteri and esophagus. It therefore has the potential to detect early reflux-related changes in the esophageal mucosa, such as dilated intercellular spaces. The reliable detection of dilated intercellular spaces at the time of endoscopy would yield a significant diagnostic advantage for separating patients with functional heartburn from the large proportion of patients with gastroesophageal reflux symptoms but no macroscopic esophagitis or pathological acid exposure. The bioimpedance of the esophageal mucosa, measured with a small caliber probe, was evaluated in a series of preclinical experiments. First, sections of rabbit esophageal epithelium were mounted in Ussing chambers and exposed to solutions at pH 7.4 or pH 1.5 for 45 minutes. Impedance measurements were taken at varying probe pressures. Second, rabbit esophageal epithelia were perfused for 45 minutes in situ with pH 1.1 or control solutions and impedance measurements taken. Samples from both in vitro and in situ experiments were taken for morphological examination by light microscopy. Finally, esophageal bioimpedance was measured in awake dogs with permanent esophagocutaneous stoma. The in situ experiments demonstrated that morphological changes in the esophageal mucosa could be discerned by the use of bioimpedance spectroscopy. The variability in resistivity was species-independent but was affected by the pressure applied to the probe. The results suggest that evaluation of bioimpedance spectroscopy for use in a clinical setting is warranted. Small morphological differences in the esophageal mucosa may be detected by the use of bioimpedance spectroscopy.

Magnetic resonance imaging for preoperative staging of rectal cancer in clinical practice: high accuracy in predicting circumferential margin with clinical benefit.

OBJECTIVE: The aims were to determine agreement between staging of rectal cancer made by magnetic resonance imaging (MRI) and histopathological examination and the influence of MRI on choice of radiotherapy (RT) and surgical procedure. METHOD: In this retrospective audit, preoperative MRI was performed on 91 patients who underwent bowel resection, with 93% having total mesorectal excision. Tumour stage according to mural penetration, nodal status and circumferential resection margin (mCRM) involvement was assessed and compared with histopathology. RESULTS: Five radiologists interpreted the images. Overall agreement between MRI and histopathology for T stage was 66%. The greatest difficulty was in distinguishing between T1, T2 and minimal T3 tumours. The accuracy for mCRM (MRI) was 86% (78/91),with an interobserver variation between 80% and 100%. In the 13 cases with no agreement between mCRM and pCRM (pathological), seven had long-term RT and nine en bloc resections, indicating that the margins initially were involved with an even higher accuracy for mCRM. Preoperative short-term RT was routine, but based on MRI findings, choice of RT was affected in 29 cases (32%); 17 patients had no RT and 12 long-term RT. The surgical procedure was affected in 17 cases (19%) with planned perirectal en bloc resections in all. CRM was involved (< or = 1 mm) in 14.7% of the 34 cases in which MRI had an effect upon choice of RT and/or surgery compared with 8.8% of the remaining 57 cases where it had no impact. CONCLUSION: Magnetic resonance imaging predicted CRM with high accuracy in rectal cancer. MRI could be used as a clinical guidance with high reliability as indicated by the low figures of histopathologically involved CRM.

Inclusion of electric octupole contributions explains the fast radiative decays of two metastable states in Ar+.

A laser probing investigation has yielded the lifetimes of the 3s(2)3p(4)(1D)3d (2)G(7/2,9/2) metastable doublet states of Ar+. The results, obtained with the CRYRING ion storage ring of Stockholm, are 3.0+/-0.4 and 2.1+/-0.1 s, respectively. Comparisons with theoretical values calculated with two independent theoretical approaches, i.e., the pseudorelativistic Hartree-Fock method and the multiconfiguration Breit-Pauli approach, have allowed us to establish the unexpected and extraordinary strong contribution of an electric octupole (E3) transition to the ground state, in addition to the M1 decay channels to the 3d ;{2,4}F states and the E2 contributions to the 4s 2P, 2D states.

High-resolution ROMA CGH and FISH analysis of aneuploid and diploid breast tumors.

Combining representational oligonucleotide microarray analysis (ROMA) of tumor DNA with fluorescence in situ hybridization (FISH) of individual tumor cells provides the opportunity to detect and validate a wide range of amplifications, deletions, and rearrangements directly in frozen tumor samples. We have used these combined techniques to examine 101 aneuploid and diploid breast tumors for which long-term follow-up and detailed clinical information were available. We have determined that ROMA provides accurate and sensitive detection of duplications, amplifications, and deletions and yields defined boundaries for these events with a resolution of <50 kbp in most cases. We find that diploid tumors exhibit fewer rearrangements on average than aneuploids, but rearrangements occur at the same locations in both types. Diploid tumors reflect at least three consistent patterns of rearrangement. The reproducibility and frequency of these events, especially in very early stage tumors, provide insight into the earliest chromosomal events in breast cancer. We have also identified correlations between certain sets of rearrangement events and clinically relevant parameters such as long-term survival. These correlations may enable novel prognostic indicators for breast and other cancers as more samples are analyzed.

Importance of an M2 depopulating channel for a Kr II metastable state.

An experimental investigation of the radiative lifetime of the metastable 4s24p4(3P)4d4D7/2 level in Kr II shows an unusual situation regarding the importance of an M2 depopulation channel. While the first order M1 and E2 channels are expected to contribute in a dominant way to the decay, the experimental result, obtained using a laser probing technique on a stored ion beam, tau = 0.57+/-0.03 s, is far too short to be due to these channels according to our relativistic multiconfiguration Dirac-Fock calculation. Only if second order contributions to the decay branches (including essentially the M2 contribution) are taken into account in the calculations could the unexpected short lifetime be explained.

Radiative lifetime of a bound excited state of Te-.

We report on the first experimental study of the lifetime of a bound excited state of a negative ion. A new experimental technique was developed and used to measure the radiative lifetime of the 5p(5) (2)P(1/2) level of Te-. The experiment was performed in a magnetic storage ring, where a laser beam was applied along one of the straight sections. In the experiment the population of the excited J=1/2 level was probed each time the Te- ions passed through the laser field. A decay curve was built up by sampling the population of the excited level of the Te- ions as a function of time after injection into the ring. A multiconfiguration Dirac-Hartree-Fock calculation was performed in conjunction with the experiment. The calculation yielded a radiative lifetime of 0.45 s, in excellent agreement with the measured value of 0.42(5) s.

A pharmacoscintigraphic evaluation of oral budesonide given as controlled-release (Entocort) capsules.

AIMS: To investigate the gastrointestinal pharmacokinetics of controlled-release (Entocort) and standard budesonide capsules. METHODS: Six Crohn's disease patients and eight healthy controls were given controlled-release capsules containing budesonide and an inert 111In label, following breakfast. In the patients, a standard capsule containing deuterium-labelled budesonide was given simultaneously. In the controls, on a separate occasion, the controlled-release capsules were given in the fasting state. Gastrointestinal transit was recorded by a gamma camera. Plasma budesonide and deuterium-labelled budesonide were used to estimate drug release, and urine cortisol was used to assess systemic effects. RESULTS: Budesonide delivery to the ileo-colonic region was significantly greater after the intake of the controlled-release capsules [69%; 95% confidence interval (CI), 54-84] than after the standard capsules (30%; 95% CI, 15-45) (P = 0.005). Fasting had little impact on uptake. The transit and pharmacokinetics of budesonide were similar in both subject groups, although systemic availability was higher in patients (21%; 95% CI, 13-33) than in controls (12%; 95% CI, 10-14) (P = 0.009). Urinary cortisol was, however, similar in both groups. CONCLUSIONS: A major fraction of budesonide is released in the ileum and throughout the colon, the intended target for the controlled-release formulation. The prandial state has little effect on budesonide uptake.

Pharmacokinetics of budesonide controlled ileal release capsules in children and adults with active Crohn's disease.

BACKGROUND: Systemic glucocorticosteroid therapy is effective in Crohn's disease, but is associated with side-effects. Budesonide has high topical anti-inflammatory activity, but considerably lower systemic activity than other oral glucocorticosteroids. AIM: To evaluate the systemic exposure to budesonide (controlled ileal release capsules) in children and adults with active Crohn's disease, and to assess the suppression of plasma cortisol. METHODS: In an open label study, patients (eight children and six adults) with active Crohn's disease received 9 mg budesonide (Entocort capsules) orally once daily for 7 days. Plasma concentrations were determined on the seventh day of administration, and pharmacokinetic parameters were calculated. For reference, 0.5 mg budesonide was given intravenously separately. Plasma cortisol levels were compared with the pre-treatment baseline values. RESULTS: Systemic exposure to budesonide (AUC0-24 h) after 1 week of oral administration was 41 +/- 21 nmol/L x h (mean +/- s.d.) in children and 35 +/- 20 nmol/L x h in adults. The estimated systemic availability in children was 9 +/- 5% and in adults 11 +/- 7%. The mean plasma cortisol (AUC0-24 h) decreased by 64 +/- 18% in children and by 50 +/- 27% in adults. CONCLUSIONS: The systemic exposure, systemic availability and cortisol suppression after oral administration of 9 mg budesonide were similar in children and adults with active Crohn's disease. Budesonide was well tolerated and no clinically important safety-related findings were identified.

Effect of food on the pharmacokinetics of budesonide controlled ileal release capsules in patients with active Crohn's disease.

AIM: To study the influence of food on the systemic availability of budesonide in patients with active Crohn's disease. METHODS: Eight patients with an established diagnosis of Crohn's disease each received 9 mg budesonide controlled ileal release (CIR) capsules (Entocort capsules) orally on two separate occasions: once in a fasting state and once after a heavy breakfast. For reference, deuterium-labelled ((2)H(8)) budesonide, 0.5 mg, was given intravenously. Plasma concentrations of budesonide and (2)H(8)-budesonide were determined for 12 h, and their pharmacokinetic parameters were calculated. RESULTS: Average systemic availability of budesonide during fasting conditions was 10.7%, area under the curve was 27.5 nmol/L x h and peak plasma concentration was 4.1 nmol/L. Corresponding postprandial values were 13.2%, 27.0 nmol/L x h and 3. 8 nmol/L. Food increased the mean absorption time from 4.5 to 6.8 h (P=0.0012). Body clearance of budesonide was about 25% higher after eating (P=0.0015). CONCLUSIONS: Food had little influence on systemic availability and peak plasma concentrations of budesonide administered in CIR capsules. Absorption was retarded postprandially, likely due to delayed gastric emptying. Budesonide in CIR capsules can be administered at the same dose regardless of prandial status in patients with Crohn's disease.

Women react with more myocardial ischemia and angina pectoris during elective percutaneous transluminal coronary angioplasty.

BACKGROUND: Women have been considered to be at higher risk of complications relating to percutaneous transluminal coronary angioplasty (PTCA) than are men. One reason for this sex-related difference could be the ischemic response of myocardium during the procedure. OBJECTIVE: To investigate whether there are sex-related differences in ischemic response of myocardium during elective PTCA. METHODS: Consecutive patients (n = 192, of whom 48 were women), were subjected to vectorcardiography during the PTCA procedure. Vectorcardiographic variables, magnitude of ST-segment vector (ST-VM), and magnitude of ST-segment vector change (STC-VM) were studied. RESULTS: Women were older (63 +/- 10 versus 56 +/- 10 years, P< 0.001) than men in our study and more often had diabetes mellitus and hypertension. Women less often had stents implanted (24 versus 50%, P < 0.01) and they were subjected to fewer balloon inflations (P < 0.001), with a total inflation time shorter than that for men (P< 0.001). Maximum STC-VM was 25% greater for women (P < 0.05). Women reported greater maximum pain (P < 0.05) and nitroglycerine was more frequently used for them during PTCA (P < 0.05). Occurrence of episodes of residual ischemic STC-VM (the difference between total number of episodes and number of balloon inflations) was more common for women (3 +/- 5 versus 1 +/- 3, P< 0.01). Duration of residual ischemic STC-VM episodes (the difference between total duration of episodes and duration of balloon inflations) was longer for women than it was for men (242 +/- 275 versus 148 +/- 233 s, P < 0.05). In a stepwise multivariate analysis and for a matched case-control group, episodes of residual STC-VM and duration of residual STC-VM episodes still indicated that there was an independent sex-related difference (P < 0.01 and P < 0.01, respectively). CONCLUSIONS: Women more commonly develop vectorcardiographic signs of severe myocardial ischemia, more frequently experience episodes of ischemia and report more severe angina pectoris during elective PTCA than do men.

Prognostic value of ischemia monitoring with on-line vectorcardiography in patients with unstable coronary artery disease.

AIM: The aim of this study was to determine whether on-line vectorcardiography (VCG) gives independent prognostic information, regarding death, myocardial infarction (MI), and revascularization in patients with unstable coronary artery disease, i.e. unstable angina or non-Q-wave MI. METHODS AND RESULTS: One hundred and fifty patients (mean age 69 +/- 10), participating in a randomized study of low-molecular-weight heparin in unstable coronary artery disease, were studied with on-line VCG recordings for 24 h. During a 5-6-month follow-up, 11 patients died, 14 suffered a nonfatal MI and 31 were revascularized. Univariate predictors of death were diabetes mellitus (p < 0.01), maximum ST vector magnitude (ST-VM; p < 0.001), maximum ST change vector magnitude (STC-VM; p < 0.001), number of ST-VM (p < 0.01) and STC-VM episodes (p < 0.001). In multivariate analysis, the number of STC-VM episodes (p < 0.01) and diabetes mellitus (p < 0.02) each gave independent prognostic information regarding death. When all cardiovascular events were combined, the inability to perform an exercise test (p < 0.05), maximum value of ST-VM (p < 0.01) and STC-VM (p < 0.001), the number of episodes of STC-VM (p < 0.001) and ST-VM (p < 0.001) all gave prognostic information. In multivariate analysis, the inability to perform an exercise test and the number of STC-VM episodes were independent predictors. CONCLUSION: VCG monitoring during the first 24 h of hospitalization for unstable coronary artery disease gives independent prognostic information.

Diabetes mellitus is a strong negative prognostic factor in patients with myocardial infarction treated with thrombolytic therapy.

OBJECTIVES: To assess the long-term prognostic values of baseline demographic data, occurrence of vectorcardiographic signs of reperfusion, left ventricular function and coronary angiographic features. DESIGN: Longitudinal study of morbidity and mortality. SETTING: Coronary care unit at Danderyd Hospital, Stockholm, Sweden. SUBJECTS: A total of 222 patients (mean age 61 years) with a suspected acute myocardial infarction treated with thrombolysis were investigated and followed for 2-5 years (mean 1216 days). MAIN OUTCOME MEASURES: Death or a new myocardial infarction. RESULTS: Age above 55 years (P < 0.05), a previous diagnosis of diabetes mellitus (P < 0.005), hypertension (P < 0.05), heart failure (P < 0.001) and myocardial infarction (P < 0.05), a previous use of beta-blockers (P < 0.05) and an ejection fraction below 60% (P < 0.01) were predictors for death or a new myocardial infarction in univariate analysis. Sex, a previous history of smoking or angina pectoris, vectorcardiographic signs of reperfusion or degree of coronary artery disease had no prognostic values. In multivariate analysis including age above 55 years, a previous diagnosis of diabetes mellitus, hypertension and myocardial infarction, and an ejection fraction below 60%, only age (P < 0.05), diabetes mellitus (P < 0. 01) and ejection fraction (P < 0.05) were predictors for death or a new myocardial infarction. CONCLUSIONS: The results of the present study emphasize the importance of diabetes mellitus as a long-term prognostic risk factor in patients with myocardial infarction treated with thrombolysis. Further studies are needed to determine the mechanisms behind this increased risk.

Prognostic role of on-line vectorcardiography as regards repeat revascularization after successful coronary angioplasty.

This study evaluated the prognostic significance of continuous on-line vectorcardiography (VCG) during elective coronary angioplasty (percutaneous transluminal coronary angioplasty, PTCA). Patients (n = 192, mean age 58 +/- 10), treated with elective and initially successful PTCA, were included. VCG monitoring was started before start of the PTCA procedure and was carried out during the entire procedure. ST vector magnitude (ST-VM) was monitored. A 6-month follow-up was obtained. Main outcome measures were the frequency of cardiac events and revascularization during follow-up. During follow-up, 1 patient died, 6 suffered a nonfatal myocardial infarction and 50 were revascularized. Angiography revealed restenosis in 88% of the patients who had a revascularization. In the total patient group, the VCG predictor of revascularization was the total ischemic time of all ST-VM episodes (p = 0.05). Clinical predictors of revascularization were diabetes mellitus (p < 0.01), a more severe type of lesion (type B; p < 0.01), percent post-PTCA stenosis (p < 0.05), nominal balloon size (p < 0.01), maximum balloon pressure (p < 0.05) and no stent implanted (p < 0.001). In a multivariate analysis all the above significant univariate variables of revascularization were entered. Total ischemic time of ST-VM (p < 0.01) was the best variable giving independent prognostic information. In the nonstent group, total ischemic time of ST-VM (p < 0.01) was the only independent predictor of a further revascularization. In conclusion, VCG monitoring during elective PTCA gives on-line information that identifies patients at an increased risk of a revascularization during 6 months after the initial procedure.

On-line vectorcardiography during elective coronary angioplasty indicates procedure-related myocardial infarction.

BACKGROUND: Increased creatine kinase concentrations after elective percutaneous transluminal coronary angioplasty (PTCA) have been shown to be associated with increased late cardiac mortality. OBJECTIVE: To evaluate the potential of continuous on-line vectorcardiography during elective PTCA to identify procedure-related myocardial infarction. METHODS: Patients (n = 192, ages 58 +/- 10 years), treated with elective and initially successful PTCA, were studied using vectorcardiogram (VCG) recordings. VCG monitoring was started 5 min before start of the PTCA and was carried out during the entire procedure, for at least 30 min after the first balloon inflation. ST-segment vector magnitude (ST-VM) and ST-segment change vector magnitude (STC-VM) were monitored. RESULTS: Fifteen (7.8%) procedure-related myocardial infarctions occurred. Indicators of procedure-related myocardial infarction were maximum value of ST-VM (P < 0.001) and STC-VM (P < 0.001), total ischemic time of all ST-VM episodes (P < 0.001) and STC-VM episodes (P < 0.001). The variable most closely related to a procedure-related myocardial infarction was the maximum STC-VM value during the procedure. With an optimized cutoff value, maximum STC-VM predicts a procedure-related myocardial infarction with a sensitivity of 93%, a specificity of 59% and a negative predictive value of 99%. Patients who had a stent implanted had significantly greater VCG values (P < 0.05-P < 0.001) than the group without a stent. There was a trend (P < 0.06) to a relation between increased creatine kinase concentration and stent implantation. In patients both with and without an implanted stent, greater STC-VM values were associated with procedure-related myocardial infarction (P < 0.01). CONCLUSION: Continuous VCG monitoring during elective PTCA is a promising method for immediate detection of patients at increased risk of procedure-related myocardial infarction.

Imaging of aortoiliac arterial disease. Duplex ultrasound and MR angiography versus digital subtraction angiography.

PURPOSE: To evaluate and compare the diagnostic accuracy of duplex ultrasound (US) and MR angiography (MRA) at 1.0 T in aortoiliac arterial disease using digital subtraction angiography (DSA) as the reference standard. In addition, a comparison of the 2D time-of-flight (TOF) and 3D contrast-enhanced MRA (CE MRA) techniques was performed. MATERIAL AND METHODS: Prospectively, 39 patients with symptoms of lower-extremity arterial occlusive disease were examined using US, TOF MRA, CE MRA and DSA. Significant lesions (stenosis > or =50%) and occlusions were evaluated blindly for each method. RESULTS: For all segments, the sensitivity for US, TOF MRA and CE MRA with regard to significant lesions was 0.72, 0.81 and 0.81, respectively, and the specificity for each was 0.97, 0.91 and 0.92, respectively. For significant lesions above the inguinal ligament the corresponding sensitivity was 0.84, 0.89 and 0.94 and the specificity 0.93, 0.82 and 0.73, respectively. The specificity was higher when the two MRA methods were combined. TOF MRA overgraded 7 segments as occluded. In most cases, the length of the occlusions was correctly determined on CE MRA, overestimated on TOF MRA and uncertain on US. CONCLUSION: Neither US nor MRA were sufficiently accurate to fully replace angiography. MRA was preferable to US as a non-invasive test when vascular intervention was contemplated. Although CE MRA was superior to TOF MRA, the most accurate results were achieved when the two methods were combined.

Respiratory monitoring during MR imaging. The clinical value of a new fibre-optical monitor.

PURPOSE: To assess the clinical utility of a fibre-optical monitor for respiratory monitoring in patients undergoing MR imaging without general anaesthesia. MATERIAL AND METHODS: One hundred consecutive patients were included at each of 3 MR units (300 patients in total). The technicians estimated the value of monitoring the respiratory rate on a 5-graded scale. Conditions that might complicate the MR examination were noted. RESULTS: The respiratory monitor was well tolerated by 99% of the patients. It was rated as valuable or very valuable in one-third of the total group, but in slightly more than two-thirds of the group of patients with some condition that might have complicated the MR examination. The estimated value of respiratory rate monitoring did not correlate to the age or sex of the patients, the type of examination, or to whether contrast medium was used or not, but it was significantly more often considered valuable in patients placed in the head-first position than in those placed in feet-first. CONCLUSION: Respiratory rate monitoring during MR imaging seems to be valuable in many patients, particularly if some condition that might complicate the MR examination is present.

Ischaemia monitoring with on-line vectorcardiography during dobutamine stress echocardiography in patients after an episode of unstable coronary artery disease.

OBJECTIVES: This study investigated the ability of on-line vectorcardiography (VCG) to detect myocardial ischaemia as assessed by dobutamine stress echocardiography after an episode of unstable coronary artery disease. DESIGN: Dobutamine stress test (incrementally infused doses of 5, 10, 20, 30 and 40 microg kg(-1) per minute) was performed during simultaneous VCG monitoring. QRS vector difference (QRS-VD), ST vector magnitude (ST-VM), ST change vector magnitude (STC-VM) and T change vector magnitude (TC-VM) were monitored. A new wall motion abnormality or worsening of abnormal wall motion was regarded as indicating a positive dobutamine stress test. SUBJECTS: Fifty-five patients with unstable angina pectoris and 16 patients with an acute non-Q-wave myocardial infarction were studied 5-8 days after admission. RESULTS: A positive dobutamine stress test was observed in 37 patients (52%). The sensitivity, specificity and total accuracy of identifying patients with a positive dobutamine stress test by VCG were: 38%, 91% and 63% for QRS-VD; 59%, 88% and 73% for ST-VM; 84%, 79% and 82% for STC-VM; and 86%, 23% and 56% for TC-VM. Patients with a positive dobutamine stress test showed higher maximum VCG values than patients with a negative dobutamine stress test (QRS-VD, P < 0.01; ST-VM, P < 0.001; STC-VM, P < 0.001). The maximum VCG values were related to the number of segments showing new or worsening wall motion abnormality (QRS-VD: r=0.41, P < 0.001; ST-VM: r=0.44, P < 0.001; STC-VM: r=0.57, P < 0.001). CONCLUSION: STC-VM and ST-VM seem to be the best VCG variables for detection of myocardial ischaemia as assessed by dobutamine stress echocardiography.

Enhancing effects of monohexanoin and two other medium-chain glyceride vehicles on intestinal absorption of desmopressin (dDAVP).

The intestinal absorption enhancement of the nonapeptide [Mpa1,D-Arg8]vasopressin (dDAVP) by medium-chain glyceride vehicles was studied using an in vivo rat model. Rats were gavaged with dDAVP formulated with three different lipid vehicles: (1) monohexanoin, (2) mixed monoglycerides, diglycerides and triglycerides of hexanoic acid and (3) monoglycerides, diglycerides and triglycerides of octanoic and decanoic acids, and with saline as control. The marker absorption into blood and urine was followed for 24 hr. All lipid vehicles enhanced the oral bioavailability of dDAVP, but monohexanoin gave the highest increase, approximately 10 times that of control. In contrast to dDAVP, the stable and more lipophilic nonapeptide analog [Mpa1,D-Tyr(ethyl)2,Val4,D-Arg8]oxytocin did not show increased urine recovery when formulated with monohexanoin. A 2-fold increase in urine recovery of the inert low-molecular-weight marker [51Cr]EDTA was observed when formulated with monohexanoin. With use of the fluorescent marker Evans blue formulated with monohexanoin, an elevated accumulation of Evans blue in the mucus layer was observed after incubation in in situ loops. No mucosal damage after lipid vehicle gavage was observed by light microscopic evaluation. Medium-chain glycerides functioned well as oral absorption enhancers of the model peptide dDAVP, and monohexanoin showed the highest enhancement capacity. The mechanisms of this enhancement appear to be related to a protection against luminal dDAVP degradation, mucoadhesive properties of the vehicle and, possibly, an altered epithelial absorption pathway.

Pulmonary delivery of intratracheally instilled and aerosolized cyclosporine A to young and adult rats.

The delivery and pharmacokinetics of cyclosporine A (CyA) given locally to the airways or iv was evaluated in young and adult rats. After intratracheal (i.t.) instillation of saline suspended CyA to adult rats, the CyA plasma levels peaked at 30 min with a bioavailability of 78.1 +/- 6.9%. After the i.t. instillation of CyA with micelles forming surfactant, Cremophor EL, in adult and young rats, the plasma levels peaked at 5 min with a bioavailability of 77.5 +/- 7.2% and 66.3 +/- 4.5%, respectively. The bioavailability of aerosolized CyA was 80.1 +/- 4.1% in adults. Thus, CyA is absorbed by the lungs into the systemic circulation of the rat in high amounts, independent of age and type of delivery system. Long-term treatment with i.t. instillations did not affect body weight gain in young and adult rats, and no histopathological changes were found in the lungs. It is important to emphasize that CyA plasma clearance in young rats was lower and elimination half-life longer than in adults. The slow elimination of CyA in young rats indicated profound pharmacokinetic age differences for this species.