M2 Profile Research Articles

Stereoselective pharmacokinetics of moguisteine metabolites in healthy subjects.

We studied the pharmacokinetics of moguisteine, a racemic non-narcotic peripheral antitussive drug, in 12 healthy male subjects after a single oral administration of 200 mg. The unchanged drug was absent in plasma and urine of all subjects. Moguisteine was immediately and completely hydrolyzed to its main active metabolite, the free carboxylic acid M1. Therefore, we evaluated the kinetic profiles of M1, of its enantiomers R(+)-M1 and S(-)-M1, and of M1 sulfoxide optical isomers M2/I and M2/II by conventional and stereospecific HPLC. Maximum plasma concentrations for M1 (2.83 mg/l), M2/I (0.26 mg/l) and M2/II (0.40 mg/l), were respectively reached at 1.3, 1.6 and 1.5 h after moguisteine administration. Plasma concentrations declined after the peak with mean apparent terminal half-lives of 0.65 h (M1), 0.88 h (M2/I) and 0.84 h (M2/II). Most of the administered dose was recovered in urine within 6 h from moguisteine treatment. The systemic and renal clearance values indicated high renal extraction ratio for all moguisteine metabolites, and particularly for M1 sulfoxide optical isomers. Plasma concentration-time profiles and urinary excretion patterns for M1 enantiomers R(+)-M1 and S(-)-M1 were quite similar. Thus, for later moguisteine pharmacokinetic evaluations the investigation of the plasma concentration-time curve and the urinary excretion of the sole racemic M1 through non-stereospecific analytical methods may suffice in most cases.

Characterization of muscarinic receptor subtypes in pig airways: radioligand binding and northern blotting studies.

This study was undertaken to characterize the muscarinic receptor subtypes present in adult pig peripheral lung and airway smooth muscle. The binding of the nonselective muscarinic antagonist [N-methyl-3H]scopolamine ([3H]NMS) to pig airways showed a single class of binding sites with a maximum density of 172 and 450 fmol/mg protein in peripheral lung and airway smooth muscle, respectively. Unlike [3H]NMS, the M1-selective antagonist, [3H]telenzepine, recognized two populations of binding sites in peripheral lung. Approximately 14% of total [3H]telenzepine binding sites displayed high affinity [dissociation constant (Kd) = 0.95 nM], whereas the remaining sites showed low affinity (Kd = 14.2 nM). The high- and the low-affinity [3H]telenzepine binding sites displayed the pharmacological profile of M1 and M2 receptors, respectively. Heterogeneity of pig airways muscarinic receptor was also revealed by competitive binding experiments against [3H]NMS with the M2-selective antagonist methoctramine. This compound recognized 70 and 90% of total receptors with high affinity in airway smooth muscle (Ki = 4.44 nM) and peripheral lung (Ki = 9.82 nM), respectively. This result suggests that the dominant muscarinic receptor in pig airways is of the M2 subtype. Northern blot analysis demonstrated the presence of m1 and m2 mRNAs transcripts in peripheral lung and m2 and m3 mRNAs in airway smooth muscle with no evidence for m4 mRNA.

Muscarinic receptor subtypes in bovine adrenal medulla.

Catecholamine secretion in the bovine adrenal medulla is evoked largely by nicotinic receptor activation. However, bovine adrenal medulla also contain muscarinic receptors that mediate several cell responses. To understand the physiological role of muscarinic receptors in the bovine adrenal medulla it is important to identify the pharmacological subtypes present in this tissue. For this, we analyzed the abilities of different selective muscarinic antagonists in displacing the binding of the non-selective antagonist [3H] quinuclidinyl benzylate to an enriched plasma membrane fraction prepared from bovine adrenal medulla. All the selective antagonists bind at least two bindings sites with different affinities. The binding profile of the sites with high proportion is similar to the M2 subtype and those present in low proportion have a M1 profile. However, some variation in the proportion of the sites for the different ligands suggest the presence of the third pharmacological subtype (M3). We conclude that the sites in high proportion (60-80%) correspond to M2 muscarinic subtypes, and the rest is constituted by M1 plus M3 subtypes. The presence of multiplicity of subtypes in the adrenal medulla membranes suggests a diversity of functions of muscarinic receptors in the adrenal gland.

Conformational and thermodynamic consequences of the introduction of a nick in duplexed DNA fragments: an NMR study augmented by biochemical experiments.

NMR studies were carried out on various equimolar mixtures consisting of a combination of oligomers: d(ACGGCT) (I). d(pACGGCT) (Ia), d(TGCAGT) (II), d(AGCCGTACTGCA) (III), d(TGCAGTACGGCT) (IV). It is shown that I + II + III (MI) and Ia + II + III (M2) form stable duplexes with nicks in the centre of the respective double helices. A close analysis of the NOESY experiments of M1 and M2 revealed that these fragments form B-DNA type duplex structures. A comparison of the chemical-shift data of the nicked duplexes with those of the intact duplex of III + IV (M3) demonstrated that only small local distortions occur when a nick is introduced. The chemical-shift profiles of M1 and M3 were used to obtain the thermodynamic data for the duplex/coil transitions. The profiles of M1 were analysed by means of a new thermodynamic model (TRIDUP). From the calculated thermodynamic data of M1 and M3 it is concluded that the melting behaviour of M1 occurs cooperatively. A ligation experiment demonstrated that the relatively small substrate (M2) was almost completely joined after an overnight incubation at 14 degrees C.

Simultaneous observations of reflection echoes and refractive index gradient in the troposphere and lower stratosphere

We have studied some characteristics of clear air echoes in the lower stratosphere and troposphere from simultaneous observations of vertical echo power and temperature profiles. The vertical echo power has been oversampled every 75 m with a height resolution of 150 m by the middle and upper atmosphere (MU) radar (35°N, 136°E). During the radar observations a radiosonde was launched at the MU radar site in order to measure temperature, humidity, and pressure with a height resolution of a few tens of meters, from which the mean gradient of generalized potential refractive index, M, was determined. In the lower troposphere (below 10 km altitude), M is enhanced owing to humidity by about 10–20 dB, and its fine structure is mainly determined by the vertical gradient of humidity. The relatively large time‐height variation of tropospheric echo power seems to be attributed to rapid changes in the humidity profile. On the other hand, in the upper troposphere (above 10 km altitude) and stratosphere the vertical structure of M is mainly determined by the Brunt‐Väisälä frequency and air density, where the former determines fine vertical structure of M and the latter the gradual decrease in M with a scale height of about 7 km. The measured M2 profile agrees well with the vertical echo power profile down to the radar height resolution of 150 m. That is, the vertical structure of the reflection coefficient is mainly determined by M2, and therefore the energy density of 3‐m scale fluctuations E(2k) seems to be distributed uniformly with height. The vertical spacing of intense reflection layers usually ranges from 500 m to a few kilometers, which corresponds to the dominant vertical scale of fluctuations in the Brunt‐Väisälä frequency profile. The vertical distribution of intense reflection layers seems to be explained by a predominance of a saturated vertical wave number spectrum of gravity waves with a slope of −3 and a dominant vertical scale of a few kilometers.

"Friction Slope Models for M2 Profiles,"2

"Friction Slope Models for M2 Profiles,"²

FRICTION SLOPE MODELS FOR M2 PROFILES1

ABSTRACT: Results of studies which have considered the relative merit of various friction slope averaging equations previously used in water surface profile computations are described. Limitations of the most accurate equation known for the M2 profile have indicated that a new equation which gives more emphasis to the upstream energy gradient is desirable. Based upon friction slope curves developed for M2 water surface profiles two new equations, one a parabolic and the other an elliptical approximation, are presented. The behavior of the new equations and of the previously most recommended equation is described by test calculations. The elliptical equation performed more satisfactorily than the harmonic method commonly recommended for M2 profile computations. Insertion of an additional cross‐section about 50 feet upstream from a critical depth section was found to reduce computational errors for any energy gradient averaging method.

Characteristics on M1 Backwater Curves

An analysis of M1 profiles with Froude number as a reference parameter is made. A total of 182 M1 profiles in rectangular, trapezoidal, triangular, and parabolic channels are studied. Ranges of variables considered are: Bread-depth ratio, 1 to 20; side slope, 0 to 3; top width-depth ratio in parabolic channels, 2 to 20; roughness coefficient n, 0.012 to 0.045; and bed slope, 4 × 10\U-3\N to 4 × 10\U-4\N. A relationship between uniform flow Froude number and the length of the profile is developed. It is shown that the nondimensional length of the profile varies as the square of the uniform flow Froude number. The effects of channel shape, slope, and roughness on the profile characteristics are examined.