Prediction of student performance on the Comprehensive Osteopathic Medical Licensing Examination Level I based on admission data and course performance.

To predict student performance on the Comprehensive Osteopathic Medical Licensing Examination (COMLEX-USA) Level 1 examination based on academic performance during the first 2 years, stepwise regression analysis of COMLEX-USA Level 1 performance with preadmission grade point averages, Medical College Admission Test scores, and academic performance was performed on the class of 2000 to develop three formulae that were then used to predict performance on COMLEX-USA Level 1 for the class of 2001. Models ranged in accuracy of predicting the pass/fail status from 95.2% (all available data) to 96.8% (first-year grades and admissions data). A predictive model for student performance on COMLEX-USA Level 1 can be developed and has a high degree of accuracy. The model with the most variables available to choose from predicts the most failures.

Can an Internet-based system assist with administration and distance learning for third- and fourth-year rural clinical rotations?

This article describes the experience of the West Virginia School of Osteopathic Medicine during the past 5 years in using Internet technology to communicate with osteopathic medical students on remote, community-based clinical rotations. Federal funding initially supported creation of a new Internet-based system to connect students on their rural family medicine rotations. Accomplishments during and after federal funding include development of systems for remote submission and student access to feedback about clinical sites; on-line access to rotation objectives, policies, housing information, maps, and affiliated internship opportunities; access to medical journals and texts; secured access to rotation grades and rotation schedules; on-line reading lists for family medicine and pediatrics rotations; and Internet-based test administration. Remaining challenges include identification or development of interactive learning materials; development of test banks; flawless administration of Web-based examinations; and finding the right balance between patient care-based learning and didactics.

Relationship between academic achievement and COMLEX-USA Level 1 performance: a multisite study.

The purpose of this study was to examine the relationship of performance on the Comprehensive Osteopathic Medical Licensing Examination (COMLEX-USA) Level 1 with academic performance at colleges accredited by the American Osteopathic Association (AOA). Eighteen (95%) of 19 AOA-accredited colleges and 2146 students (91% of those taking the June 1999 examination) met criteria and participated. Students were classified by school representatives on the basis of academic performance in the first 2 years of the curriculum. The relationships of Level 1 performance with assigned classifications and grade point averages (GPAs) were studied. Of students classified in the highest 20% academically, the Level 1 pass rate was 100%, with a mean score of 599. Of students classified in the lowest 5%, the pass rate was 63.5%, with a mean of 416.3. For 16 schools that provided GPAs, the within-school correlations between Level 1 scores and GPAs ranged from r = 0.76 to r = 0.85, with a mean correlation of r = 0.79. School representatives were also asked to indicate, for each student, whether they expected the student to pass the examination. Pass rate for students in the "sure pass" category was 98.9%; "borderline," 82.5%; and "concerns," 61.5%. Academic performance in the first 2 years of osteopathic medical school was strongly associated with performance on COMPLEX-USA Level 1. The national pass rate for this examination was similar to those in previous years, and it remains unclear why school representatives overpredicted the number of failures. Further research is needed.

Relationship of preadmission variables and first- and second-year course performance to performance on the National Board of Osteopathic Medical Examiners' COMLEX-USA Level 1 examination.

The purpose of this study was to examine the relationship of performance on the Comprehensive Osteopathic Medical Licensing Examination (COMLEX-USA) Level 1 licensing examination to (1) academic performance during the first 2 years of the curriculum, and (2) preadmission grade point averages (GPAs) and Medical College Admission Test (MCAT) scores for one osteopathic medical school with the unique mission of providing osteopathic family physicians for West Virginia and rural Appalachia. Simple correlations were calculated for the 63 students at West Virginia School of Osteopathic Medicine who completed all requirements of the first 2 years of the curriculum in May 1998 and were first eligible for board exams in June 1998. These included 26 (41.3%) female students and 5 (7.9%) minority students. Students who had failed a year and/or a course but subsequently successfully completed the first 2 years of the curriculum in May 1998 were included in this study. Every student who qualified to take the June 1998 administration of COMLEX-USA Level 1 did so at that time. For the 55 academic or preadmissions variables of interest, correlation coefficients with COMLEX-USA Level 1 scores and significance levels were calculated using SPSS Base 9.0. The correlation of COMLEX-USA Level 1 performance with GPA for Phase I was 0.64; with GPA for Phase II, 0.67; and total GPA for the first 2 years, 0.70. Grades in most individual courses also correlated significantly with COMLEX-USA Level 1 performance. Given the special focus of this curriculum on the needs of the Appalachian region and use of clinical performance measures or participation measures in calculating academic GPAs, these correlations show a remarkable degree of agreement between these two sets of performance measures. Further research is needed to see if similar relationships exist for osteopathic medical schools with other missions and with other curriculum structures. Preadmissions GPAs and MCATs did not significantly relate to performance on COMLEX-USA Level 1.

Medical students' errors in pharmacotherapeutics.

OBJECTIVES: This study analysed the errors made by 16 final-year medical students in a classroom prescribing exercise. The aim was to gain greater understanding of the reasons for non-optimal prescribing and of how to improve basic training in pharmacotherapeutics. METHODS: The task was to adjust a patient's phenytoin sodium dosage to achieve better control of seizures. It was based on a real-life case, and was presented as a written exercise. Process-tracing and think-aloud techniques were used to study the students' performance. RESULTS: The results suggest that the root cause of the errors was lack of a knowledge base which integrated scientific knowledge with clinical know-how. Three different clinical reasoning strategies were observed. Students who followed an incremental strategy demonstrated superior scientific knowledge and this resulted in less hazardous errors. Those who followed gambling or backward-reasoning strategies appeared to possess inferior scientific knowledge and this resulted in more hazardous errors. CONCLUSIONS: The results support current trends towards integrating basic medical science into a foundation of clinical know-how, as in the problem-based curriculum. They also emphasize the importance of a thorough grounding in medical science as a means of minimizing error.

Effects of SCA40 on bovine trachealis muscle and on cyclic nucleotide phosphodiesterases.

While UK-93,928 (1-[[3-(6,9-dihydro-6-oxo-9-propyl-1H-purin-2-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine; 5 nM-5 microM) was devoid of relaxant activity, benzafentrine, isoprenaline, levcromakalim and SCA40 (6-bromo-8-methylaminoimidazo[1,2-a]pyrazine-2-carbonitrile) each relaxed histamine (460 microM)-precontracted bovine isolated trachealis. Each of these relaxants was antagonised by a K+-rich (80 mM) medium. Except in the case of levcromakalim, nifedipine (1 microM) offset this antagonism. Charybdotoxin (100 nM) antagonised isoprenaline in a nifedipine-sensitive manner but did not antagonise SCA40 or benzafentrine. Iberiotoxin (100 nM) did not antagonise SCA40. Acting on tissue precontracted with carbachol, SCA40 potentiated isoprenaline but did not potentiate sodium nitroprusside. While levcromakalim (1 and 10 microM) induced hyperpolarisation, SCA40 (1 and 10 microM) induced little change in the membrane potential of bovine trachealis. In trachealis preloaded with 86Rb+, levcromakalim (1 and 10 microM) promoted efflux of the radiotracer while SCA40 (1 and 10 microM) had no effect. Tested as an inhibitor of isoenzymes of cyclic nucleotide phosphodiesterase, SCA40 was most potent against the type III, less potent against the type IV and least potent against the type I isoenzyme. It is concluded that neither inhibition of phosphodiesterase type V nor the promotion of BKCa channel opening explains the tracheal smooth muscle relaxant activity of SCA40. This compound relaxes bovine tracheal smooth muscle mainly by inhibiting phosphodiesterase isoenzyme types III and IV.

Implementation of total quality management: conventional wisdom versus reality.

Hospitals nationwide are beginning to implement continuous quality improvement (CQI) (Barsness et al. 1993; Kosta 1992). In large part this is due to the belief that the implementation of CQI will lead to higher quality patient care, improved patient satisfaction, better employee morale, and lower cost service delivery. However, to date there have been few empirical studies of CQI implementation efforts in healthcare (Shortell et al. 1994).

Effects of some K(+)-channel inhibitors on the electrical behaviour of guinea-pig isolated trachealis and on its responses to spasmogenic drugs.

1. A study has been made of the effects of inhibitors selective among plasmalemmal K(+)-channels on the sensitivity and responsiveness of guinea-pig trachealis muscle to carbachol, histamine and KCl. The effects of the K(+)-channel inhibitors on the resting membrane potential and spontaneous electrical activity of the trachealis cells have also been examined. 2. In indomethacin (2.8 microM)-treated trachealis muscle, dofetilide (1 microM) and glibenclamide (10 microM) were each devoid of spasmogenic activity. In contrast, 4-aminopyridine (4-AP, 62.5 microM--8 mM), charybdotoxin (ChTX, 100 nM) and iberiotoxin (IbTX, 100 nM) were each spasmogenic. Spasm evoked by 4-AP, IbTX or ChTX was reduced, though not abolished, by atropine (1 microM). Spasm evoked by 4-AP (1 mM), ChTX (100 nM) or IbTX (100 nM) was unaffected by tetrodotoxin (TTX; 3.1 microM) or by tissue pretreatment with capsaicin (1 microM for 30 min). Spasm evoked by IbTX or ChTX was abolished by nifedipine (1 microM). 3. Dofetilide (1 microM) and glibenclamide (10 microM) were each without effect on the tracheal sensitivity or responsiveness to carbachol, histamine or KCl. 4-AP (1 mM) antagonized carbachol, potentiated histamine but did not affect tissue sensitivity to KCl. When the effects of 4-AP were examined in the presence of atropine (1 microM), it potentiated all the spasmogens including carbachol. IbTX and ChTX (each 100 nM) potentiated all three spasmogens. Potentiation of histamine induced by 4-AP (1 mM) or IbTX (100 nM) was also observed in tissues treated with a combination of atropine (1 microM) and TTX (3.1 microM). 4. Dofetilide (1 and 10 microM) was without effect on the resting membrane potential or spontaneous electrical activity of the trachealis cells. 4-AP (1 mM) evoked depolarization and caused a small increase in the frequency of slow wave discharge. The depolarization evoked by 4-AP was abolished by atropine (1 microM). IbTX (100 nM) and ChTX (100 nM) each evoked little or no change in resting membrane potential but converted the spontaneous slow waves into spike-like, regenerative action potentials. These electrophysiological effects of IbTX and ChTX were unaffected by atropine (1 microM). 5. It is concluded that the dofetilide-sensitive, cardiac, delayed rectifier K(+)-channel is either not expressed in trachealis muscle or is of no functional importance in that tissue. The ATP-sensitive K(+)-channel (KATP) does not moderate tracheal sensitivity to spasmogens such as carbachol, histamine and KCl. The 4-AP-sensitive delayed rectifier K(+)-channel (Kdr) and the large Ca(2+)-dependent K(+)-channel (BKCa) each moderate trachealis muscle sensitivity to spasmogens. Neither Kdr nor BKCa plays an important role in determining the resting membrane potential of guinea-pig trachealis cells. However, the BKCa channel is responsible for limiting the effects of the increase in membrane Ca2+ conductance associated with the depolarizing phase of slow waves. It is BKCa channel opening that prevents the development of a slow wave into a spike-like regenerative action potential.

Keys for successful implementation of total quality management in hospitals.

This article reports the findings of an analysis of the implementation of continuous quality improvement (CQI) or total quality management (TQM) programs in 10 hospitals. This analysis is the result of a 2-year study designed to identify and assess the ingredients that lead to the successful implementation of CQI programs in acute care hospitals.

Assessing the impact of continuous quality improvement/total quality management: concept versus implementation.

OBJECTIVE: This study examines the relationships among organizational culture, quality improvement processes and selected outcomes for a sample of up to 61 U. S. hospitals. DATA SOURCES AND STUDY SETTING: Primary data were collected from 61 U. S. hospitals (located primarily in the midwest and the west) on measures related to continuous quality improvement/total quality management (CQI/TQM), organizational culture, implementation approaches, and degree of quality improvement implementation based on the Baldrige Award criteria. These data were combined with independently collected data on perceived impact and objective measures of clinical efficiency (i.e., charges and length of stay) for six clinical conditions. STUDY DESIGN: The study involved cross-sectional examination of the named relationships. DATA COLLECTION/EXTRACTION METHODS: Reliable and valid scales for the organizational culture and quality improvement implementation measures were developed based on responses from over 7,000 individuals across the 61 hospitals with an overall completion rate of 72 percent. Independent data on perceived impact were collected from a national survey and independent data on clinical efficiency from a companion study of managed care. PRINCIPAL FINDINGS: A participative, flexible, risk-taking organizational culture was significantly related to quality improvement implementation. Quality improvement implementation, in turn, was positively associated with greater perceived patient outcomes and human resource development. Larger-size hospitals experienced lower clinical efficiency with regard to higher charges and higher length of stay, due in part to having more bureaucratic and hierarchical cultures that serve as a barrier to quality improvement implementation. CONCLUSIONS: What really matters is whether or not a hospital has a culture that supports quality improvement work and an approach that encourages flexible implementation. Larger-size hospitals face more difficult challenges in this regard.

Further analysis of the mechanisms underlying the tracheal relaxant action of SCA40.

1. SCA40 (1nM-10 microM), isoprenaline (1-300 nM) and levcromakalim (100 nM-10 microM) each produced concentration-dependent suppression of the spontaneous tone of guinea-pig isolated trachea. Propranolol (1 microM) markedly (approximately 150 fold) antagonized isoprenaline but did not antagonize SCA40. The tracheal relaxant action of SCA40 was unaffected by suramin (100 microM) or 8-(p)-sulphophenyltheophylline (8-SPT; 140 microM). 2. An isosmolar, K(+)-rich (80 mM) Krebs solution increased tracheal tone, antagonized SCA40 (approximately 60 fold), antagonized isoprenaline (approximately 20 fold) and very profoundly depressed the log concentration-effect curve for levcromakalim. Nifedipine (1 microM) did not itself modify the relaxant actions of SCA40, isoprenaline or levcromakalim. However, nifedipine prevented the rise in tissue tone and the antagonism of SCA40 and isoprenaline induced by the K(+)-rich medium. In contrast, nifedipine did not prevent the equivalent antagonism of levcromakalim. 3. Charybdotoxin (100 nM) increased tracheal tone, antagonized SCA40 (approximately 4 fold) and antagonized isoprenaline (approximately 3 fold). Nifedipine (1 microM) prevented the rise in tissue tone and the antagonism of SCA40 and isoprenaline induced by charybdotoxin. 4. Quinine (30 microM) caused little or no change in tissue tone and did not modify the relaxant action of isoprenaline. However, quinine antagonized SCA40 (approximately 2 fold). Nifedipine (1 microM) prevented the antagonism of SCA40 induced by quinine. 5. Tested on spontaneously-beating guinea-pig isolated atria SCA40 (1 nM-10 microM) increased the rate of beating in a concentration-dependent manner. Over the concentration-range 1 microM-10 microM, SCA40 also caused an increase in the force of atrial contraction. 6. Intracellular electrophysiological recording from guinea-pig isolated trachealis showed that the relaxant effects of SCA40 (1 micro M) were often accompanied by the suppression of spontaneous electrical slow waves but no change in resting membrane potential. When the concentration of SCA40 was raised to 10 micro M, its relaxant activity was accompanied both by slow wave suppression and by plasmalemmal hyperpolarization.7. SCA40 (10 nM- 100 micro M) more potently inhibited the activity of cyclic AMP phosphodiesterase (PDE)than that of cyclic GMP PDE derived from homogenates of guinea-pig trachealis. Theophylline(1 micro M- 1O mM) also inhibited these enzymes but was less potent than SCA40 in each case and did not exhibit selectivity for inhibition of cyclic AMP hydrolysis.8. Tested against the activity of the isoenzymes of cyclic nucleotide PDE derived from human blood cells and lung tissue, SCA40 proved highly potent against the type III isoenzyme. It was markedly less potent against the type IV and type V isoenzymes and even less potent against the isoenzymes types I and II.9. It is concluded that the tracheal relaxant action of SCA40 (1 nM- 1 micro M) does not involve the activation of beta-adrenoceptors or P1 or P2 purinoceptors. Furthermore, this action is unlikely to depend upon the opening of BKca channels with consequent cellular hyperpolarization and voltage-dependent inhibition of Ca2+ influx. The tracheal relaxant action of SCA40 (up to 1 micro M) is more likely to depend upon its selective inhibition of the type III isoenzyme of cyclic nucleotide PDE. At concentrations above 1 micro M, SCA40 exerts more general inhibition of the isoenzymes of cyclic nucleotide PDE and may then promote the opening of BKca channels.

An integrative model for organization-wide quality improvement: lessons from the field.

This article describes a model of CQI that is designed to characterize the elements necessary for successfully improving quality at an organization-wide level; describe and understand the organizational dynamics in implementing an organization-wide effort; and aid in diagnosing and solving common implementation challenges. Three cases illustrate the model and how it can be used.

Airway response to inhaled methacholine in normal human subjects.

The individual airway responsiveness to inhaled, nebulized methacholine (MeCh) was estimated in normal volunteers, measuring specific airway conductance (sGAW). The dose of MeCh was increased logarithmically until a 60-65% reduction from baseline sGAW or an asymptotic approach to a maximal response was attained. The concentration of MeCh that caused a 35% reduction in sGAW (PC35), the dose that caused a 62.5% reduction in sGAW, the slope of the straight, central part of the log-dose-response curve (LDRC), the slope of the straight, initial part of the dose-response curve, the maximal response attainable (Emax) and the dose causing a half-maximal response (ED50) were derived. These parameters were transformed as necessary to attain normality of distribution. Relationships between them were examined by measuring the correlations between their transformed values. The ED50 was taken to represent the least biased estimate of the sensitivity to MeCh. The PC35 was the best practical estimate of sensitivity. The Emax was taken to represent the least biased estimate of the reactivity to MeCh. The slope of the LDRC was the best practical estimate of reactivity. The sensitivity and reactivity varied independently in these normal subjects. Each was also independent of the baseline sGAW.

Beta-adrenoceptor subtypes and the opening of plasmalemmal K(+)-channels in trachealis muscle: electrophysiological and mechanical studies in guinea-pig tissue.

1. Mechanical and electrophysiological studies of guinea-pig isolated trachealis have been made with the objectives of: (a) identifying which of the beta-adrenoceptor subtypes mediates the opening of plasmalemmal K(+)-channels, (b) gaining further insight into the properties of the novel, long-acting beta-adrenoceptor agonist, salmeterol and (c) clarifying the role of K(+)-channel opening in mediating the relaxant actions of agonists at beta-adrenoceptors. 2. Noradrenaline (10 nM-100 microM) caused a concentration-dependent increase in the rate of beating of guinea-pig isolated atria. The selective beta 1-adrenoceptor blocking drug, CGP 20712A (100 nM-10 microM) caused concentration-dependent antagonism of noradrenaline. The selective beta 2-adrenoceptor blocking drug, ICI 118551, also produced concentration-dependent antagonism of noradrenaline, but only when used in concentrations greater than 300 nM. 3. Cromakalim (100 nM-10 microM), isoprenaline (1-100 nM), procaterol (0.1-30 nM), salbutamol (1 nM-1 microM), salmeterol (1-100 nM) and theophylline (1 microM-1 mM) each caused concentration-dependent suppression of the spontaneous tone of guinea-pig isolated trachealis. 4. ICI 118551 (10 nM-1 microM) antagonized isoprenaline, procaterol and salmeterol in suppressing the spontaneous tone of the isolated trachea. The antagonism was concentration-dependent. In contrast, ICI 118551 (1 microM) antagonized neither cromakalim nor theophylline. CGP 20712A (up to 1 microM) failed to antagonize cromakalim, isoprenaline, procaterol, salmeterol or theophylline. In trachea treated with indomethacin (2.8 microM) and carbachol (10 microM), salmeterol (1 microM) antagonized the effects of isoprenaline but not aminophylline. 5. Intracellular electrophysiological recording from guinea-pig isolated trachealis showed that the relaxant effects of cromakalim (10 microM), isoprenaline (100 nM), procaterol (10 nM) and salbutamol(10 nM- 1 microM) were accompanied by the suppression of spontaneous electrical slow waves and by cellular hyperpolarization. In contrast, the relaxant effects of salmeterol (10 nM- 1 microM) were not accompanied by significant cellular hyperpolarization.6. CGP 20712A (1 microM) inhibited the hyperpolarization but not the relaxation induced by isoprenaline(100 nM). In contrast ICI 118551 (100 nM) inhibited both the hyperpolarization and the relaxation induced by isoprenaline (100 nM). Neither CGP 20712A (1 microM) nor ICI 118551 (100 nM) inhibited the hyperpolarization induced by cromakalim (10 microM). Salmeterol (1 microM) inhibited the hyperpolarization induced by isoprenaline (100 nM) but not that induced by cromakalim (10 microM).7. It is concluded that activation of either beta l- or beta 2-adrenoceptors can promote the opening of K+-channels in the trachealis plasmalemma. The poor ability of salmeterol to hyperpolarize trachealis muscle reflects neither its selectivity in activating beta 2-adrenoceptors as opposed to beta 1-adrenoceptors nor a non-specific action in stabilizing the cell membrane. Instead, it may reflect low intrinsic efficacy of the drug at beta 2-adrenoceptors. The opening of plasmalemmal K+-channels plays a supportive rather than a crucial role in mediating the tracheal relaxant actions of agonists at beta-adrenoceptors.

Beta-adrenoceptor subtypes and the opening of plasmalemmal K(+)-channels in bovine trachealis muscle: studies of mechanical activity and ion fluxes.

1. Studies of mechanical activity and 86Rb+ efflux have been made in bovine isolated trachealis with the objectives of: (a) identifying which of the beta-adrenoceptor subtypes mediates the opening of plasmalemmal K(+)-channels, (b) gaining further insight into the properties of the novel, long-acting beta 2-adrenoceptor agonist, salmeterol and (c) clarifying the role of K(+)-channel opening in mediating the mechano-inhibitory actions of agonists at beta-adrenoceptors. 2. In bovine trachealis muscle strips precontracted with histamine (460 microM), isoprenaline (0.1 nM-1 microM), procaterol (0.1-10 nM) and salmeterol (0.1-10 nM) each caused concentration-dependent relaxation. 3. ICI 118551 (10 nM-1 microM) antagonized isoprenaline, procaterol and salmeterol in suppressing histamine-induced tone of the isolated trachealis muscle. The antagonism was concentration-dependent. In contrast, CGP 20712A (10 nM-1 microM) failed to antagonize isoprenaline, procaterol or salmeterol. 4. Salmeterol (1-10 microM) antagonized isoprenaline in relaxing strips of bovine trachea which had been precontracted with carbachol (1 microM). 5. Cromakalim (10 microM), isoprenaline (100 nM-10 microM), procaterol (10 nM-1 microM) and salbutamol (100 nM-10 microM) each promoted the efflux of 86Rb+ from strips of bovine trachealis muscle preloaded with the radiotracer. In contrast, salmeterol (100 nM-10 microM) failed to promote 86Rb+ efflux. 6. CGP 201712A (1 microM), ICI 118551 (100 nM) and salmeterol (1 microM) did not themselves modify 86Rb+ efflux from trachealis muscle strips, nor did they affect the promotion of 86Rb+ efflux induced by cromakalim (10 microM). In contrast, CGP 20712A (1 microM) and ICI 118551 (100nM) were each able to inhibit the promotion of 86Rb+ efflux induced by isoprenaline (1 microM) or procaterol (100 nM). Furthermore,salmeterol (10 microM) inhibited isoprenaline (1 microM)-induced promotion of 86Rb+ efflux.7. It is concluded that, in bovine trachealis, activation of either beta l- or beta 2-adrenoceptors can promote the opening of 86Rb+-permeable K+-channels in the plasmalemma. The failure of salmeterol to promote plasmalemmal K+-channel opening may reflect, not its selectivity in activating beta 2- as opposed to beta 1-adrenoceptors, but rather its low intrinsic efficacy at beta 2-adrenoceptors. The opening of plasmalemmal K+-channels plays a supportive rather than a crucial role in mediating the mechano-inhibitory effects of agonists at beta-adrenoceptors acting on trachealis muscle.

The properties of voltage-operated Ca(2+)-channels in bovine isolated trachealis cells.

Freshly-dispersed bovine trachealis cells were used for recording by the patch clamp technique of whole-cell and unitary currents through Ca(2+)-channels. Whole-cell Ca(2+)-current (ICa) activated at -40 mV and appeared to be carried by a single type of Ca(2+)-channel. Inactivation of ICa was increased by increasing the concentration of free Ca2+ within the recording pipette but reduced by using Ba2- as the charge carrier. Steady-state inactivation studies showed that the Ca(2+)-channels were half-maximally available following a conditioning depolarization to -35 mV. A two-pulse protocol showed that ICa induced by the step to a test potential was inversely related to ICa induced by the step to the conditioning potential. Unitary Ba(2+)-currents were activated at a threshold of -30 mV and had a reversal potential of +41 mV. The channel carrying the unitary Ba(2+)-currents had a slope conductance of 23 pS. Steady-state inactivation studies showed that the unitary Ba(2+)-currents were half-maximally available at a holding potential of -28 mV. ICa and unitary Ba(2+)-currents were inhibited by nifedipine (10 nM-1 microM) but augmented by Bay K 8644 (10 microM). It is concluded that the plasmalemma of bovine trachealis muscle contains a single population of voltage-dependent Ca(2+)-channels of the L-type. These channels may be subject to inactivation primarily by an increase in the concentration of free Ca2+ on the cytosolic side of the plasmalemma and secondarily by a voltage-dependent mechanism. Overlap of the inactivation and activation curves of ICa may allow the passage of 'window current' through the Ca(2+)-channels during sustained depolarization.

Trials of the bronchodilator activity of the xanthine analogue SDZ MKS 492 in healthy volunteers during a methacholine challenge test.

An approximately steady-state reduction of specific airway conductance was induced in healthy human subjects by means of an individualized inhaled methacholine loading dose followed by a maintenance dose regime. Tested against this background bronchoconstriction, the xanthine analogue SDZ MKS 492, when administered as a single oral dose of 40 mg, showed a significant bronchodilator action, which lasted for up to 5.5 h. Bronchodilatation was not seen after administration of 10 or 20 mg doses. SDZ MKS 492 inhaled as a dry powder had a bronchodilator action that was small, most evident with the 12 mg dose and transient. The peak relief of imposed bronchoconstriction was 29% and the apparent half-time of removal of SDZ MKS 492 from its site of action was 5-6 min. Inhaled SDZ 492 had a bitter taste that was not masked by inclusion of menthol and aspartame in the formulation. The bronchodilatation seen in laboratory animals can also be produced by SDZ MKS 492 in man when administered orally or by inhalation. Its magnitude correlates better with the plasma concentration of parent drug than with that of either of the identified metabolites. Dispositional processes in the lung abbreviate its action after administration by inhalation.

Trials of the bronchodilator activity of the isoenzyme-selective phosphodiesterase inhibitor AH 21-132 in healthy volunteers during a methacholine challenge test.

1. An approximately steady-state reduction of specific airway conductance was induced in normal human subjects by means of a methacholine individualized loading+maintenance dose regime. Tested against this background bronchoconstriction, the mixed type III/IV phosphodiesterase inhibitor AH 21-132, ingested in doses up to 90 mg, had no detectable bronchodilator activity. 2. AH 21-132, infused intravenously over 15 min, evoked short-lived bronchodilatation at doses of 20 and 40 mg, without affecting blood pressure or heart rate. 3. AH 21-132, mixed 1:18.5 by weight with sucrose, dissolved in saline, nebulized and inhaled in doses between 2 and 24 mg of AH 21-132, produced dose-dependent bronchodilation. The ED50 was estimated as 9.2 mg AH 21-132. The peak relief of imposed bronchoconstriction was 80% and the apparent half-time of removal of AH 21-132 from its site of action was 25 min. 4. Inhaled, nebulized, hypertonic sucrose had a minor bronchodilator action. 5. AH 21-132, by intravenous and inhaled routes of administration, provides relief of methacholine-induced bronchoconstriction.