Hypoglycaemic effects of the novel antidiabetic agent repaglinide in rats and dogs

1. Repaglinide, a novel compound with a nonsulphonylurea structure, is currently being clinically tested as a therapeutic agent. In the present study, the hypoglycaemic effects of repaglinide in rats and dogs were investigated.
2. Whereas the R-enantiomer, AG-EE 624 ZW, showed only weak hypoglycaemic activity, the S-enantiomer, repaglinide, turned out to be a potent hypoglycaemic compound in rats after oral as well as after intravenous administration. Only 50% of the dose of repaglinide was needed to be equieffective with the racemic mixture AG-EE 388 ZW. The corresponding ED₅₀ values calculated for the effects after 120 min p.a. (intravenous administration) were 3.4 μg kg⁻¹ (repaglinide) and 6 μg kg⁻¹ (AG-EE 388 ZW).
3. When compared to glimepiride or glibenclamide, repaglinide displayed a 18 to 25 times higher potency in fasted rats. The ED₅₀ values calculated for the effects after 120 min p.a. (oral administration) were 10 μg kg⁻¹ (repaglinide), 182 μg kg⁻¹ (glimepiride) and 255 μg kg⁻¹ (glibenclamide).
4. In glucose loaded rats (0.5, 1.0, 2.0 and 3.0 g kg⁻¹ glucose, p.o.) repaglinide exerted a very strong antihyperglycaemic activity which was even more pronounced than under normoglycaemic conditions. So for a reduction in blood glucose of 1 mmol l⁻¹, 10.3, 9.3, 7.0 8.4 and 7.2 μg kg⁻¹ repaglinide were needed after glucose loads of 0.0, 0.5, 1.0, 2.0 and 3.0 g kg⁻¹, respectively.
5. In beagle dogs repaglinide again showed a pronounced hypoglycaemic effect (ED₅₀ 28.3 μg kg⁻¹) which lasted for up to 24 h. However, insulin levels were only transiently increased.
6. The in vivo data presented are well supported by recently published in vitro findings. From its activity profile, repaglinide appears to be a promising new therapeutic agent.

     

Attenuation of the cutaneous blood flow response during combined exercise and heat stress

Skin blood flow (SkBF) was measured in six male subjects using laser-Doppler velocimetry, with zero-gradient auditory canal temperature (T_ac) used as an index of body core temperature (T_c). Subjects performed incremental, upright cycling commencing at 40% peak power ( _peak: 10 min), increasing every 4 min by 5 % _peak thereafter. Trials were conducted in hot (ambient temperature (T_a) 36.7 ±0.2°C, relative humidity (rh) 46.1 ±3.2%; _peak ±S.D.), and neutral environments (T_a 19.6 ±0.3°C, rh 50.2 ±1.4%). SkBF increased with T_ac in all subjects. Attenuation of SkBF occurred at the same T_ac, relative SkBF and cardiac frequency (f _c) between environments, but at a lower exercise intensity (40.8 ±0.8% versus 55.8 ±3.0% _peak) in the hot environment (p<0.05). Data indicate that T_c thresholds for SkBF attenuation may exist. However, it is suggested that attenuation thresholds coincided with a reduced central blood volume, which may occur at a critical level of cutaneous blood pooling.     

Analysis of a tension/compression skeletal system: Possible strain-specific differences in the hierarchical organization of bone

Background: Examination of a simple skeletal cantilevered beam-like bone (artiodactyl calcaneus) suggests that regional differences in strain magnitude and mode (tension vs. compression) reflect regional adaptation in the structural/material organization of bone. The artiodactyl (e.g., sheep and deer) calcaneus has a predominant loading condition typified by the unambiguous presence of prevailing compressive and tensile strains on opposite cortices. Bone habitually loaded in bending may accommodate regional disparities in loading conditions through modifications of various aspects of its organization. These include overall bone build (gross size and shape), cross-sectional shape, cortical thickness, and mineral content. Methods & Results: Cross-sections taken along the calcaneal body exhibited cranial-caudal elongation with the compression (cranial) cortex thicker than the tension cortex (P < 0.01). Mineral content (ash fraction) was significantly greater in the compression cortex (P < 0.01), averaging 6.6% greater than in the tension cortex. Strong positive correlations were found between mineral content and section location in both the tension (r² = 0.955) and compression (r² = 0.812) cortices. These correlations may reflect functional adaptations to the linear increases in stress that are known to occur in the distal-to-proximal direction in simple, unidirectionally loaded cantilevered beams. According to engineering principles, the roughly triangular transverse cross-sectional geometries and thicker compression cortex are features consistent with a short cantilevered structure designed to resist unidirectional bending. Conclusions: Known differences in mechanical properties of bone in tension vs. compression suggest that these regional differences in cortical thickness and mineralization may be related to differences in strain mode. These structural/material dissimilarities, however, may be related to regional variations in strain magnitude, since bending and axially directed stresses in a simple cantilevered structure produce greater strain magnitudes in the compression domain. It is possible that the superimposed habitual strain magnitudes enhance strain-mode-specific adaptive responses. We hypothesize that these structural/material differences reflect the capacity of bone to process local information and produce a regionally heterogeneous organization that is appropriate for prevailing loading conditions. © 1994 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public dotmain in the United states of America

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Admission,recruitment, and retention

As the country strives to produce larger numbers of generalist physicians, considerable controversy has arisen over whether or not generalist applicants can be identified, recruited, and influenced to keep a generalist-oriented commitment throughout medical training. The authors present new and existing data to show that: 1) preadmission (BA/MD or post-baccalaureate) programs can help to identify generalist-oriented students; 2) characteristics determinedat admission to medical school are predictive of future generalist career choice; 3) current inpatient-oriented training programs strongly push students away from a primary care career; 4) women are more likely than men to choose generalist careers, primarily because of those careers’ interpersonal orientation; and 5) residency training programs are able to select applicants likely to become generalists. Therefore, to produce more generalists, attempts should be made to encourage generalist-oriented students to enter medical schools and to revise curricula to focus on outpatient settings in which students can establish effective and satisfying relationships with patients. These strategies are most likely to be successful if enacted within the context of governmental and medical school-based changes that allow for more reimbursement and respect for the generalist disciplines.     

Brain activation associated with visual motion studied by functional magnetic resonance imaging in humans

Localized brain activation in response to moving visual stimuli was studied by functional magnetic resonance imaging (fMRI). Stimuli were 100 small white dots randomly arranged on a visual display. During the Motion condition, the dots moved along random, noncoherent linear trajectories at different velocities. During the Blink condition, the dots remained stationary but blinked on and off every 500 ms. The Motion and Blink conditions continuously alternated with 10 cycles per run and 6–8 runs per experiment. In half of the runs, the starting stimulus condition was Motion, while in the remaining runs it was Blink. A series of 128 gradient echo echoplanar images were acquired from 5–7 slices during each run using a 1.5 T GE Signa with an Advanced NMR echoplanar subsystem. The time series for each voxel were analyzed in the frequency domain. Voxels which demonstrated a significant spectral peak at the alternation frequency and whose phase changed in response to stimulus order were considered activated. These activated voxels were displayed upon high resolution anatomical images to determine the sites of activation and were also transformed into the coordinates of Talairach and Tournoux ([1988] Co-planar Stereotaxic Atlas of the Human Brain, New York: Thieme) for comparison to prior neuroimaging studies. Seven of ten subjects showed clusters of activation bilaterally at the junction of the temporal and occipital lobes (area 37) in response to moving stimuli. Most activated voxels were located within or adjacent to a region designated the parietal-temporal-occipital fossa, or PTOF. Five subjects also showed activation to moving stimuli in midline occipital cortex. The activated voxels in midline cortex had a significantly shorter phase delay in their MR signal change relative to voxels in PTOF. © 1995 Wiley-Liss, Inc. 1

1 This article is a US Government work and, as such, is in the public domain in the United States of America

     

Is hypoxic pulmonary vasoconstriction important during single lung ventilation in the lateral decubitus position?

Hypoxic pulmonary vasoconstriction (HPV) has not been demonstrated in human single lung anaesthesia in the lateral decubitus position (LDP). The purpose of this study was to determine whether (1) HPV occurs in the non-dependent, nonventilated lung, and (2) if the infusion of sodium nitroprusside (SNP) inhibits HPV During intravenous anaesthesia the tracheas of seven patients were intubated with double lumen endotracheal tubes. Standard monitors plus radial and pulmonary arterial catheters were placed. Patients were positioned in the LDP and haemodynamic and gas exchange data were recorded for each of three stages; I: two-lung ventilation, II: single, dependent lung ventilation (1LV) and III: 1LV with infusion of SNP. In stage II the PaO₂ decreased from 531 ± 42 mmHg to 285 ± 42 mmHg (P < 0.05) and Qs/Qt increased from 12.3 ± 2.7 to 29.0 ± 6.3% (P < 0.05). With SNP infusion there was a 30% increase in cardiac index (CI) (P < 0.05). The SNP infusion was not associated with changes in Qs/ Qt or PaO₂. This model demonstrates changes in Qs/ Qt and PaO₂ associated with single-lung ventilation in ASA I and II patients in the LDP but we were unable to demonstrate inhibition of HPV by SNP.     

Rest and treadmill exercise first-pass radionuclide ventriculography: Validation of left ventricular ejection fraction measurements

Background

To assess the accuracy of rest and treadmill exercise first-pass radionuclide ventriculographic measurements of left ventricular ejection fraction (LVEF), 40 patients underwent treadmill exercise first-pass and bicycle exercise equilibrium radionuclide ventriculography. To determine the frequency of technically adequate treadmill exercise first-pass studies, an additional 128 consecutive patients undergoing treadmill exercise first-pass procedures during stress^99mTc-labeled sestamibi myocardial perfusion studies were assessed.

Methods and Results

The treadmill exercise first-pass procedure used a multicrystal camera and an²⁴¹Am point source to allow for correction of patient motion. Excellent correlations were observed between resting first-pass and resting equilibrium LVEF (r=0.91; standard error of the estimate=5.6). A high correlation was also observed between treadmill exercise first-pass and bicycle equilibrium exercise LVEF measurements (r=0.85, standard error of the estimate=7.6). Treadmill first-pass LVEF systematically underestimated the bicycle equilibrium LVEF. Intraobserver agreement for rest and exercise first-pass LVEF was high (r values of 0.98 and 0.94, respectively). Of the 168 consecutive treadmill exercise first-pass studies evaluated for technical adequacy, 21 (12.5%) were deemed technically inadequate, with most of the sources of error being avoidable. The frequency of technically adequate studies was as high (87%) in high levels of exercise (Bruce stages 3 and 4) as in lower levels (88%). The findings of this study validate the first-pass treadmill exercise LVEF measurement.

Conclusion

This procedure now provides the option for combining the information of peak treadmill exercise LVEF with measurements of exercise myocardial perfusion from the same injection of radioactivity.     

Assessment of retinol-binding protein excretion in normal children

Retinol-binding protein (RBP) is a low molecular weight protein freely filtered at the glomerulus. The fractional tubular reabsorption of RBP is 99.97% and increased excretion is therefore a sensitive marker of tubular dysfunction. We obtained early-morning urine specimens from 151 well children, from newborn to 16 years of age. RBP was measured using an enzyme-linked immunosorbent assay, albumin by a radioimmunoassay and creatinine by a modified Jaffé reaction. Protein excretion was assessed by calculating the protein: creatinine ratio for early-morning urine samples. We found a fall in both RBP and albumin excretion with increasing age, particularly in the 1st year of life, with a much wider variation in values from the infants studied. The mean excretion of RBP for children aged 0–6 months [51.4 (0.6–4,719) g/mmol] was significantly higher (P<0.001) than the mean for children aged 6 months to 16-years [15.0 (3.8–60) g/mmol]. It has been shown that measurement of tubular proteinuria using the RBP: creatinine ratio is useful in the assessment of children with renal disease and we propose a value two standard deviations above the geometric mean for the age of the patient as an upper limit of normal.     

An audit of occupational medicine consultation records

There is a need to develop and test methods of audit of theconsultation process in occupational medicine and to draw conclusionsfrom the findings. An external audit was carried out on 313randomly selected consultation records from the occupationalhealth services of three health boards over a 26-month period.Additionally, nine months after the date of the first externallyaudited sample, a prospective internal audit was commenced withinone board. In 58 of the consultations selected (19 per cent),audit was not possible mainly because records could not be found.In an appreciable proportion of the rest, there were shortcomingsin the referral record or in the consultation record. The consultationrecords of ‘career’ occupational physicians werebetter than those of ‘non-career’ physicians, especiallyin recording specific diagnoses (91 per cent vs. 67 per cent;P<0.0001) and in conclusions regarding occupational implications(86 per cent vs. 74 per cent; P<0.0001). Multivariate regressionsshowed a highly significant improvement associated with prospectiveinternal audit in one item, namely the record of occupationalimplications. However, the magnitude of this difference beforeand after audit was smaller than the independent differencearising from the career status of the physicians. The valueof medical audit in improving quality of care and educationin occupational medicine is discussed.     

Outsourcing therapy services. A strategy for professional autonomy

Explores the problems and opportunities for professions allied to medicine (PAMS) in the new NHS internal market. Uses a mechanism from IT, namely outsourcing, to provide a new organizational model for the effective delivery of care by this group of professionals who are marginalized by the new role of the doctor as manager.