Jupiter: an unidentified feature in the 5-micron spectrum of the north equatorial belt.

Grating spectra of the North Equatorial Belt of Jupiter 4.5 and 5.1 microns, obtained with a nominal resolving power of 180, are presented. An absorption feature centered at 4.73 microns and not due to a known constituent has been found. Its possible identification is discussed.

Preliminary infrared radiometry of venus from mariner 10.

The intensity of emission at 45 micrometers, measured with high spatial resolution along a single crossing of the Venus disk, is presented. On the average, the observed darkening toward the limb varies nearly linearly with the cosine of the emission angle. The brightness temperature, extrapolated to normal emission, is 255 degrees K. The limb darkening curve, interpreted in a linear approximation, implies that the atmosphere is quite opaque, with an absorption coefficient of 0.24 per kilometer. Changes in curvature present in the limb darkening curve suggest the existence of thermal inhomogeneities with scale comparable to that of the dark markings shown by ultraviolet images.

Preliminary infrared radiometry of the night side of mercury from mariner 10.

The infrared radiometer on Mariner 10 measured the thermal emission from the planet with a spatial resolution element as small as 40 kilometers in a broad wavelength band centered at 45 micrometers. The minimum brightness temperature (near local midnight) in these near-equatorial scans was 100 degrees K. Along the track observed, the temperature declined steadily from local sunset to near midnight, behaving as would be expected for a homogeneous, porous material with a thermal inertia of 0.0017 cal cm(-2) sec(-(1/2)) degrees K(-1), a value only slightly larger than that of the moon. From near midnight to dawn, however, the temperature fluctuated over a range of about 10 degrees K, implying the presence of regions having thermal inertia as high as 0.003 cal cm(-2) sec-(1/2) degrees K(-1).

Infrared radiometry experiment on mariner 9.

The brightness temperatures at 10 and 20 micrometers measured by the Mariner 9 infrared radiometer differ substantially from those predicted by the radiometer results of Mariners 6 and 7. The results indicate a significant latitude-dependent contribution of the atmospheric dust to the observed thermal emission.

Mariner 1969: preliminary results of the infrared radiometer experiment.

The thermal energy emitted by Mars was measured in the 8- to 12- and 18- to 25-micrometer bands. The minimum temperature derived for the southern polar cap is 150 degrees K, an indication that the cap is formed by frozen carbon dioxide. No significant temperature fluctuations were detected with a 100-kilometer scale.

Pioneer saturn infrared radiometer: preliminary results.

The effective temperature of Saturn, 94.4 + 3 K, implies a total emission greater than two times the absorbed sunlight. The infrared data alone give an atmospheric abundance of H(2) relative to H(2) + He of 0.85 +/- 0.15. Comparison of infrared and radio occultation data will give a more precise estimate. Temperature at the 1-bar level is 137 to 140 K, and 2.5 K differences exist between belts and zones up to the 0.06-bar level. Ring temperatures range from 60 to 70 K on the south (illuminated) side and from < 60 to 67 K in the planet's shadow. The average temperature of the north (unilluminated) side is approximately 55 K. Titan's 45-micrometer brightness temperature is 80 +/- 10 K.

Infrared thermal mapping of the martian surface and atmosphere: first results.

The Viking infrared thermal mapper measures the thermal emission of the martian surface and atmosphere and the total reflected sunlight. With the high resolution and dense coverage being achieved, planetwide thermal structure is apparent at large and small scales. The thermal behavior of the best-observed areas, the landing sites, cannot be explained by simple homogeneous models. The data contain clear indications for the relevance of additional factors such as detailed surface texture and the occurrence of clouds. Areas in the polar night have temperatures distinctly lower than the CO(2) condensation point at the surface pressure. This observation implies that the annual atmospheric condensation is less than previously assumed and that either thick CO(2) clouds exist at the 20-kilometer level or that the polar atmosphere is locally enriched by noncondensable gases.

Pioneer 10 infrared radiometer experiment: preliminary results.

Thermal maps of Jupiter at 20 and 40 micrometers show structure closely related to the visual appearance of the planet. Peak brightness temperatures of 126 degrees and 145 degrees K have been measured on the South Equatorial Belt, for the 20- and 40-micrometer channels, respectively. Corresponding values for the South Tropical Zone are 120 degrees and 138 degrees K. No asymmetries between the illuminated sunlit and nonilluminated parts of the disk were found. A preliminary discussion of the data, in terms of simple radiative equilibrium models, is presented. The net thermal energy of the planet as a whole is twice the solar energy input.

Pioneer 11 infrared radiometer experiment: the global heat balance of jupiter.

Data obtained by the infrared radiometers on the Pioneer 10 and Pioneer 11 spacecraft, over a large range of emission angles, have indicated an effective temperature for Jupiter of 125 degrees +/- 3 degrees K. The implied ratio of planetary thermal emission to solar energy absorbed is 1.9+/-0.2, a value not significantly different from the earth-based estimate of 2.5+/-0.5.

Early results from the infrared astronomical satellite.

For 10 months the Infrared Astronomical Satellite (IRAS) provided astronomers with what might be termed their first view of the infrared sky on a clear, dark night. Without IRAS, atmospheric absorption and the thermal emission from both the atmosphere and Earthbound telescopes make the task of the infrared astronomer comparable to what an optical astronomer would face if required to work only on cloudy afternoons. IRAS observations are serving astronomers in the same manner as the photographic plates of the Palomar Observatory Sky Survey; just as the optical survey has been used by all astronomers for over three decades, as a source of quantitative information about the sky and as a "roadmap" for future observations, the results of IRAS will be studied for years to come. IRAS has demonstrated the power of infrared astronomy from space. Already, from a brief look at a miniscule fraction of the data available, we have learned much about the solar system, about nearby stars, about the Galaxy as a whole and about distant extragalactic systems. Comets are much dustier than previously thought. Solid particles, presumably the remnants of the star-formation process, orbit around Vega and other stars and may provide the raw material for planetary systems. Emission from cool interstellar material has been traced throughout the Galaxy all the way to the galactic poles. Both the clumpiness and breadth of the distribution of this material were previously unsuspected. The far-infrared sky away from the galactic plane has been found to be dominated by spiral galaxies, some of which emit more than 50 percent and as much as 98 percent of their energy in the infrared-an exciting and surprising revelation. The IRAS mission is clearly the pathfinder for future missions that, to a large extent, will be devoted to the discoveries revealed by IRAS.

Viking first encounter of phobos: preliminary results.

During the last 2 weeks of February 1977, an intensive scientific investigation of the martian satellite Phobos was conducted by the Viking Orbiter-1 (VO-1) spacecraft. More than 125 television pictures were obtained during this period and infrared observations were made. About 80 percent of the illuminated hemisphere was imaged at a resolution of about 30 meters. Higher resolution images of limited areas were also obtained. Flyby distances within 80 kilometers of the surface were achieved. An estimate of the mass of Phobos (GM) was obtained by observing the effect of Phobos's gravity on the orbit of VO-1 as sensed by Earth-based radiometric tracking. Preliminary results indicate a value of GM of 0.00066 +/- 0.00012 cubic kilometer per second squared (standard deviation of 3) and a mean density of about 1.9 +/- 0.6 gram per cubic centimeter (standard deviation of 3). This low density, together with the low albedo and the recently determined spectral reflectance, suggest that Phobos is compositionally similar to type I carbonaceous chondrites. Thus, either this object formed in the outer part of the asteroid belt or Lewis's theory that such material cannot condense at 1.5 astronomical units is incorrect. The data on Phobos obtained during this first encounter period are comparable in quantity to all of the data on Mars returned by Mariner flights 4, 6, and 7.

Clinical pharmacologic investigations with carvedilol, a new beta-blocker with direct vasodilator activity.

Carvedilol (BM 14.190) has been shown to have beta-adrenergic blocking and vasodilating activity. By means of digital plethysmography, the threshold for vasodilation was ascertained at a dose of 2.6 mg iv infused over 1 hour. The oral threshold dose was established at about 15 mg, with a linear increase in response (r = 0.78) up to 76.5 mg. This dose increased blood flow to the forearm by reduction of arterial resistance. Although venous capacity was not changed, postural symptoms in three subjects could also be indicative of venous involvement. Carvedilol, 50 mg, reduced exercise heart rate for about 10 hours.

The pharmacokinetic and pharmacodynamic profiles of the thromboxane A-2 receptor blocker BM 13.177.

The pharmacokinetics and pharmacodynamics of BM 13.177 were investigated in eight healthy men who received a single oral dose of 800 mg on the first day and seven equal doses in 8-hour intervals on the second to fourth days. Pharmacodynamic effects were measured ex vivo by the testing of platelet functions such as shape change, aggregation, and [3H]serotonin release. The maximum serum concentration of 6.6 or 6.7 mg/L was achieved within 1.6 hours after the first dose and within 1.5 hours after multiple doses, respectively. Afterwards, BM 13.177 was eliminated in urine with a terminal elimination t1/2 of 0.84 or 1.0 hours after single and multiple dosing, respectively. The inhibition of platelet function showed the same close correlation with the serum concentrations of BM 13.177 after single and after multiple doses. Apparently, BM 13.177 induces neither refractoriness to BM 13.177 nor desensitization of the platelet thromboxane receptor. Because BM 13.177 was also well tolerated without subjective or objective side effects, this drug appears to be useful in evaluating the clinical benefit of thromboxane receptor blockade.

Dose-effect and pharmacokinetic-pharmacodynamic relationships of the beta 1-adrenergic receptor blocking properties of various doses of carvedilol in healthy humans.

OBJECTIVE: To evaluate the pharmacodynamic properties of carvedilol across a broad range of doses in relation to its enantiospecific kinetics and adrenergic receptor occupancies, relative to placebo and propranolol. METHODS: Twelve healthy male subjects were investigated on six separate occasions at least 1 week apart when they received either a single peroral dose of 40 mg propranolol, 12.5, 25, 50, or 100 mg carvedilol, or placebo. The subjects were extensively profiled at supine rest, and they underwent supine bicycle ergometry before and at 2, 4, 6, 9, 12, and 22 hours after dosing. At these time points blood was drawn for the high performance liquid chromatographic determination of the enantiomers of carvedilol and for the radioreceptor assay determination of alpha 1- and beta 1-adrenergic receptor binding and related concentrations. RESULTS: Carvedilol was confirmed to bind to beta 1-adrenergic receptors and (albeit to a lesser extent) to alpha 1-adrenergic receptors. Carvedilol furthermore attenuated the ergometric increase in heart rate in a closely dose-related fashion, which exemplified its beta 1-adrenergic receptor blocking effects. However, the basal efferent adrenergic drive might have been too low to show consistent alpha 1-blocking properties. The radioreceptor and enantiomer kinetics were proportional with dose. There was no indication that the overall kinetic behavior of contributing active metabolites would differ from that of the S(-)-enantiomer. On average, there was a smooth linear relationship between the ergometric treatment responses and log-transformed dose, log-transformed concentrations of the S(-)-enantiomer, and the radioreceptor assay derived beta 1-adrenergic receptor occupancies. CONCLUSION: The relative complexity of the kinetics of carvedilol (enantiospecific kinetics and dynamics, protein binding, and involvement of active metabolites) does not preclude relatively simple and straight-forward dose-effect and kinetic-dynamic relationships.

Dose-ranging study of the novel recombinant plasminogen activator BM 06.022 in healthy volunteers.

The novel recombinant plasminogen activator BM 06.022 consists of the kringle 2 and protease domains of human tissue-type plasminogen activator and is unglycosylated because of its expression in Escherichia coli cells. Pharmacokinetics for activity and hemostatic effects of BM 06.022 were studied in 18 healthy male volunteers after an intravenous bolus injection over 2 minutes. BM 06.022 was administered successively at doses of 0.1125, 0.55, 2.2, 3.3, 4.4, and 5.5 MU to three volunteers. Plasma fibrinogen was unchanged; effects of BM 06.022 were observed on plasminogen only at higher doses, and dose-dependent effects were seen on alpha 2-antiplasmin and fibrin D-dimers. The concentration of plasminogen and alpha 2-antiplasmin was 87% +/- 3% and 79% +/- 3%, respectively, of baseline 2 hours after injection of 5.5 MU of BM 06.022. Fibrin D-dimers were highest with 1147 +/- 380 ng/ml at 5.5 MU of BM 06.022. The area under the activity concentration-time curve (AUC) increased dose-dependently and linearly. At 5.5 MU of BM 06.022, the AUC was 313 +/- 47 IU.hr.ml-1, the total plasma clearance was 306 +/- 40 ml/min, and the half-life was 14.4 +/- 1.1 minutes.

Association between pharmacokinetics of oral ibandronate and clinical response in bone mass and bone turnover in women with postmenopausal osteoporosis.

Data from the 1-year, phase II trial of oral ibandronate for treatment of postmenopausal osteoporosis are presented (n = 180). Participants were at least 10 years past menopause and had osteopenia defined as a forearm bone mineral density at least 1.5 SD below the premenopausal mean value. Doses were 0.25, 0.50, 1.0, 2.5, or 5.0 mg daily oral ibandronate or placebo. A total of 116 women treated with ibandronate completed the study. Blood samples for pharmacokinetic analyses were drawn 20 min, 40 min, 60 min, 2 h, 4 h, and 6 h after the first and last administration of the study drug. An enzyme-linked immunosorbent assay was used to determine the concentration of ibandronic acid (BM 21.0955) in serum (Enzymun-Test System ES 600). The assay is based on streptavidine technology to fix the capture antibody to the wall of the tube. Standards were prepared for each participant using individual drug-free serum. The serum concentration-time curves of ibandronate, expressed as the area under the curve over the sampling period (AUC(0-6h)), revealed a highly significant dose-response relationship, p < 0.0001, and linear pharmacokinetic behavior. An initial half-life (T(1/2lambda1)) in serum representing distribution and early elimination was 1.3 hours. Steady-state AUC (AUC(0-6h ss)) increased by a factor of 2.5, which is consistent with an apparent elimination half-life of 32.6 h and a dosing interval of 24 h. There was an exponential association between AUC(0-6h) (ss) and the change from baseline at month 12 in the bone markers (n = 116): r = -0.37 (serum total osteocalcin), r = -0.65 (urine C-telopeptides of type I collagen), and r = -0.65 (serum C-telopeptides of type I collagen), all p < 0.0001. All bone markers were maximally depressed at values of AUC(0-6h ss) of about 3 ng h/mL. AUC(0-6h ss) furthermore revealed a logarithmic association with change from baseline at month 12 in spine BMD, r = 0.39, p < 0.0001. In conclusion, the serum concentration of ibandronate was determined validly by the enzyme-linked immunosorbent assay. The data are the first to show highly significant associations between pharmacokinetic parameters of a bisphosphonate and the clinical response in bone mass and bone turnover.

Pharmacokinetic and hemostatic properties of the recombinant plasminogen activator bm 06.022 in healthy volunteers.

In a randomized, single-blind, placebo-controlled, cross-over Phase-I study pharmacokinetic and hemostatic properties of BM 06.022 were investigated in seven healthy, male human volunteers. The novel recombinant plasminogen activator BM 06.022 consists of the kringle 2 domain and the protease domain of human t-PA and is unglycosylated due to its expression in Escherichia coli cells. Vehicle or 6 MU (= 10.4 mg) BM 06.022 was administered as a single i.v. bolus injection of 10 ml over 2 min. BM 06.022 was well tolerated. Fibrinogen levels and clotting times remained unchanged at baseline levels after 6 MU BM 06.022; plasminogen and alpha 2-antiplasmin (collected on chloromethylketone) decreased maximally to 83 +/- 1% and 64 +/- 3%, respectively, of baseline. D-dimers and fibrinogen degradation products increased to 1,006 +/- 234 ng/ml and 555 +/- 155 ng/ml, respectively, after BM 06.022. Half-life of BM 06.022-activity was 11.2 +/- 0.4 min and of antigen was 13.9 +/- 0.7 min, followed by a terminal half-life only for antigen of 173 +/- 33 min. Plasma clearance of BM 06.022 was 371 +/- 13 ml/min for activity and 183 +/- 15 ml/min for antigen. Thus, BM 06.022 is not fibrinogenolytic at 6 MU and is a fibrinolytic agent with a longer half-life than t-PA.

Current clinical use of reteplase for thrombolysis. A pharmacokinetic-pharmacodynamic perspective.

Clinical evaluation of a new thrombolytic agent should start with a dose that provides adequate efficacy and has an acceptably low bleeding risk; this results in a narrow therapeutic window at the upper end of the dose-response curve. Angiographic patency of the infarct-related artery is still the clinical surrogate end-point for mortality in phase II dose-ranging studies. There is experimental and clinical evidence that the area under the concentration-time curve (AUC) for plasminogenolytic activity of a thrombolytic agent is positively correlated with patency of the infarct-related artery. Dose-ranging studies of the novel recombinant plasminogen activator reteplase in healthy volunteers enabled computation of a linear regression curve by which a clinical starting dose could be calculated for an adapted target AUC that would be clinically effective. Pharmacokinetic analysis also revealed that the half-life of reteplase is 4 times longer than that of the reference thrombolytic alteplase, thus allowing bolus injection. The suggested single bolus starting dose of 10U was supported by results from studies in a canine model of coronary thrombolysis. The feedback of insufficiently high patency rates compared with the increased efficacy of front-loaded and accelerated alteplase demanded optimisation strategies for reteplase. Animal experiments suggested that a double bolus regimen of reteplase would be preferable to doubling the single bolus dose. Pharmacokinetic modelling suggested a time interval of 30 min between the 2 bolus injections. Selection of the tested double bolus regimens was conservative and empirical. First, the previously tested single bolus of 15U was divided to 10 + 5U; secondly, the second bolus dose was increased to 10U. This strategy proved to be successful. The current dosage recommendation for reteplase is a double bolus intravenous injection of 10 + 10U, each over 2 min, 30 min apart. This produces a reduction in mortality in patients with acute myocardial infarction that is equivalent to that produced by front-loaded and accelerated infusion of alteplase.

Systematic screening for pharmacokinetic interactions during drug development.

The possible involvement of a new chemical entity in pharmacokinetic drug interactions is an important safety issue. Not all relevant drug combinations for evaluation of the interactive potential of a new drug can be examined. Therefore, experiments should be selected to provide information which is valid not only for the interaction investigated, but which can be extrapolated to other comedications. In this respect the typical approaches currently used, including interaction studies with high risk drugs and compounds frequently given as comedication, or studies involving standard inhibitors and standard substrates are unsatisfactory. A better approach is to characterize drugs according to their effects on the underlying pharmacokinetic processes. Indeed, recent progress in understanding drug interaction mechanisms and in the development and refinement of in vitro test systems enables in many cases experiments to be designed which predict the occurrence of drug interactions. This paper illustrates systematic investigational procedures based on mechanism of interaction. Interaction mechanisms involving drug absorption, distribution, metabolism, and/or excretion are briefly summarized. Detailed proposals are derived which allow identification of the possible role of a new drug in interaction mechanisms for which valid test systems are available. Emphasis is placed on the rational selection of experiments with optimal cost-effectiveness. In vitro methods are integrated in the schemes wherever possible. In addition, it is proposed that pharmacoepidemiological screening, starting in phase II of drug development, be used to identify those relevant drug interactions missed by the mechanism-based approach. As exemplified by several recently discovered interactions it should be possible, by implementation of the proposed procedure, to avoid most serious unexpected adverse effects due to pharmacokinetic drug interactions.