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Biomedical subjects

C M Metzler

Publications and source records attributed to C M Metzler.

At least 37 records · Page 2Linked to original sources
PubMed1989

The effects of cefmetazole and latamoxef on platelet function in healthy human volunteers.

This study has compared the effects of normal saline (placebo), cefmetazole, and latamoxef (moxalactam) on platelet function in healthy human volunteers. Twenty-nine volunteers were randomized to receive placebo (n = 10), cefmetazole 2 g (n = 9) or latamoxef 2 g (n = 10) intravenously every 6 h for six days. Under double-blind conditions template bleeding time and ex-vivo adenosine diphosphate (ADP) induced platelet aggregation were measured before drug dosing, after the first, ninth, and last drug doses and one and three days after the last drug dose. Latamoxef caused progressive impairment of platelet function with statistically significant increases in the mean bleeding time to 7.4 +/- 3.7 min (P = 0.02) and the amount of ADP (0.2 mM) required to induce 50% platelet aggregation to 77.3 +/- 91.1 microliters (P = 0.03) on day 6 of treatment compared with values before drug administration (4.2 +/- 0.7 min; 3.7 +/- 22 microliters, respectively). These changes were reversible following discontinuation of drug dosing. Cefmetazole and placebo had no significant effects on either measure of platelet function at any time during the study.

Adenosine Diphosphate↗
PubMed1989

Clinical experience with cefmetazole sodium in the United States: an overview.

The clinical development programme for cefmetazole sodium included over 4000 patients treated by 78 investigators. Cefmetazole therapy was compared with that of cefoxitin sodium (cefoxitin) for the treatment of urinary tract, skin and soft tissue, lower respiratory, abdominal, and gynaecological infections (with cefoxitin-sensitive pathogens) and for the prevention of postoperative wound infection in patients undergoing surgical procedures. Both cefmetazole and cefoxitin were administered intravenously in all studies. Cefmetazole was as effective as cefoxitin in the treatment of the infections studied. In the surgical wound infection prophylaxis studies, multiple-dose cefmetazole therapy was more effective than multiple-dose cefoxitin therapy in patients undergoing lower gastrointestinal surgery; this difference approached statistical significance. Both multiple-dose and single-dose cefmetazole therapy were as effective as multiple-dose cefoxitin treatment in the other types of surgery studied. Clinical laboratory findings and adverse medical events reported among cefmetazole patients were similar to those observed in patients treated with cefoxitin.

Bacterial Infections↗
PubMed1988

Correlation of polarized absorption spectroscopic and X-ray diffraction studies of crystalline cytosolic aspartate aminotransferase of pig hearts.

Absorption spectra of large, well-formed crystals of cytosolic aspartate aminotransferase have been recorded using plane polarized light. Making use of measurements of crystal thickness we have calculated extinction coefficients with the electric vector of the light parallel to both the a and c axes of the crystals of the enzyme in space group P2(1)2(1)2(1). The spectra have been resolved into components with lognormal distribution curves and the resulting integrated intensities have been used to calculate the c/a polarization ratios for the absorption bands of the bound co-enzyme pyridoxal 5'-phosphate. From the polarization ratio and the co-ordinates of the co-enzyme ring atoms, provided by X-ray crystallography, we have assigned principal molecular directions of the transition dipole moment within the plane of the co-enzyme ring. Of two possible orientations, only one predicts the correct crystal extinction coefficients for the 436 nm band. In this orientation, when viewed from the B face of the ring (i.e. looking into the active site of the enzyme), the transition moment is related to the N-1-C-4 axis of the ring by counterclockwise rotation by 27 degrees. A tentative assignment of the principal molecular directions of the transition moment has also been made for the 368 nm band of the high pH form of the enzyme. In each case, the plane of the co-enzyme ring was located from the atomic co-ordinates of the ring atoms and of those atoms attached directly to the ring. The projection of the N-1 to C-4 axis on to this plane was used to evaluate the orientation of the transition moment, which was presumed to lie precisely within the plane of the ring. We have tilted this plane systematically to evaluate the error in transition moment direction resulting from uncertainties in the atomic co-ordinates. When 2-methylaspartate is diffused into the crystals if forms a Schiff base with the co-enzyme in which the ring has tilted about 32 degrees from its original position and the polarization ratio of the 436 nm band drops from 1.6 in the free enzyme to about 0.38. On the assumption that the orientation of the transition moment within the co-enzyme does not change during this rotation, this value of the polarization ratio is within experimental error of that predicted from X-ray structures on the two forms. The 2-methylaspartate binds only to subunit 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Spectroscopic studies of quinonoid species from pyridoxal 5'-phosphate.

To establish the state of protonation of quinonoid species formed nonenzymically from pyridoxal phosphate (PLP) and diethyl aminomalonate, we have studied absorption spectra of the rapidly established steady-state mixture of species. We have evaluated the formation constant and the spectrum of the mixture of Schiff base and quinonoid species. For N-methyl-PLP a singly protonated species with a peak at 464 nm is formed from the unprotonated aldehyde and the conjugate acid of diethyl aminomalonate with a formation constant Kf of 240 M-1. The very intense absorption band with characteristic vibrational structure (most evident as a shoulder at 435 nm) is accompanied by a weaker, structured band at about 380 nm and a weak, broad band at 330 nm. We suggest that the 380-nm band may represent a tautomeric form of the quinonoid compound. Protonation of the phosphate group appears to affect the spectrum only slightly. The corresponding mixture of Schiff base and quinonoid species formed from PLP has a very similar spectrum at pH 6-7. It has a formation constant Kf of 230 M-1 and a pKa of 7.8, which must be attributed to the ring nitrogen atom. The dissociated species, which may be largely carbanionic, has a strong structured absorption band at 430 nm and a weaker one, again possibly a tautomer, in the 330-nm region. The analysis establishes that in all species a proton remains on either the phenolic oxygen or the imine nitrogen. Proton NMR spectroscopy, under some conditions, reveals only two components: free PLP and what appears to be Schiff base. However, we suggest that the latter may, in fact, be a quinonoid form, either alone or in rapid equilibrium with the Schiff base. Absorption spectra of quinonoid species formed in enzymes are analyzed and compared with the spectra of the nonenzymic species.

Chemical Phenomena↗
PubMed1988

Effects of a fish oil concentrate in patients with hypercholesterolemia.

The effects of a fish oil supplement on lipid and lipoprotein levels, platelet function, and vital signs were investigated in 31 hypercholesterolemic patients. Thirteen patients took 5 g of encapsulated fish oil per day and 18 patients took 5 g of encapsulated safflower oil "placebo" per day for 28 days. Diet and exercise patterns were kept as constant as possible during the study. The fish oil group had significant increases in several lipid/lipoprotein values at the end of the treatment, including an increase of total cholesterol of 14% (P = 0.0001), LDL of 16% (P = 0.003), HDL of 13% (P = 0.015) and HDL2 of 36% (P = 0.009). The triglyceride level fell 24%, a nonsignificant change (P = 0.217). The ratios of total cholesterol/HDL and LDL/HDL were increased at the end of fish oil treatment, and returned to baseline 30 days after fish oil was stopped. The placebo group had no significant changes in any of the lipid/lipoprotein values. Neither the fish oil nor the placebo group had significant changes in vital signs or platelet function tests (bleeding time, thromboxane B2, platelet factor 4 and beta-thromboglobulin) during the study. These results suggest that fish oil supplements may have an adverse effect on lipid/lipoprotein values in hypercholesterolemic patients.

Adolescent↗
PubMed1988

Ciprostene in patients with peripheral vascular disease (PVD). An open-label, tolerance trial.

Epoprostenol (Prostacyclin) has been studied with various success in patients with peripheral vascular disease (PVD). We investigated the tolerance of a new, stable prostacyclin derivative ciprostene (9-beta-methyl carbacyclin) in 9 PVD patients. The drug was infused intravenously for 8 hours a day, once a week for 4 consecutive weeks, at a dose of 120 ng/kg/min. There were 6 men and 3 women with a mean age of 63 years (42-78). The PVD was verified by arteriography (9 patients) and by clinical findings. Patient #9 was lost to follow up after the first infusion and, consequently, was excluded from further evaluation. In patient #5 with a history of arrhythmias, the last ciprostene infusion had to be discontinued at 4.5 hours due to arrhythmias but his data were included into the evaluation. The cardiac disturbances were not judged to be ciprostene-related. Patients were followed monthly for 3 months after last infusion. Ciprostene was well tolerated although it produced adverse medical events (AMEs); most of them were rated as mild. The most frequent were those typical of prostacyclin: headache, facial flushing and warmth, body warmth, jaw pain and sleepiness. No consistent changes in blood pressure and heart rate were observed. One patient who initially had 9 ischemic ulcers underwent transmetatarsal amputation at month 4. The absolute and relative claudication time was measured by treadmill. As compared to baseline, the absolute claudication time increased significantly at week 2 and 4 of the infusion period and also at the end of month 3, but not at the end of month 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Nasal airway response to infused phenylephrine in normals and in patients with allergic and non-allergic rhinitis.

To find whether patients with chronic rhinitis might be congested because of hyporesponsiveness to adrenergic vasoconstrictive influences, we measured nasal airway resistance (NAR) in normals and allergic and non-allergic rhinitics during intravenous infusion of graded doses of phenylephrine. All responded with decreases in NAR and first evidences of NAR fall appeared no later in those with rhinitis than in normals. Nasal congestion and response were asymmetrical; absolute NAR in the low resistance side was similar in all groups and there was little response to phenylephrine. In the high resistance side, NAR reached its minimum by the time the total infused dose was 1400 mcg, indicating maximum response to drug was achieved within the dose range studied. Minimum NAR achieved on the high resistance side was higher in rhinitics suggesting residual vascular engorgement resistant to phenylephrine or non-vascular mucosal swelling. Resistance to adrenergic vasoconstriction does not appear to be the primary contributor to mucosal swelling in chronic rhinitis.

Airway Resistance↗
PubMed1987

Quantitative description of absorption spectra of a pyridoxal phosphate-dependent enzyme using lognormal distribution curves.

Ultraviolet-visible absorption spectra of cytosolic aspartate aminotransferase of pig hearts have been analyzed by resolution with lognormal distribution curves. These have been compared with spectra of reference Schiff bases of pyridoxal 5'-phosphate. Spectra of the free enzyme in two different states of protonation and of complexes with monoanions, dicarboxylates, the substrates L-glutamate, L-aspartate, and L-erythro-3-hydroxyaspartate, and the quasi-substrate 2-methylaspartate have been analyzed. Relative amounts of three tautomeric species have been estimated, as have amounts of various enzyme-substrate intermediates. Bandshape parameters which can be used as a guide to analysis of spectra of other pyridoxal phosphate-dependent enzymes are tabulated. Some formation constants and pKa values, which were evaluated at the same time as the spectra of the complexes, are also reported.

Animals↗
PubMed1987

The effect of itazigrel and aspirin on the mucosa of the esophagus, stomach, and duodenum of normal subjects.

The effects of aspirin, itazigrel (U-53,059; a new antiplatelet drug), and placebo on the mucosa of the esophagus, stomach, and duodenum were evaluated in this double-blind, randomized, placebo-controlled study. Six normal male subjects were included in each of five treatment groups: aspirin (325 mg each morning for five doses), aspirin (325 mg tid for 12 doses), itazigrel (25 mg each morning for five doses), itazigrel (50 mg tid for 12 doses), and placebo. Aspirin and itazigrel, at all doses investigated, significantly inhibited ex vivo, ionophore (A23187)-stimulated thromboxane B2 synthesis. Collagen-induced platelet aggregation was significantly inhibited on day 3 (P = .021) and day 5 (P = .002) in both aspirin and itazigrel groups as compared with placebo. Upper gastrointestinal endoscopy was performed before the first dose of drug (day 1) and two hours after the last dose (day 5) for each subject. A rating scale was used to score the amount of mucosal damage. The baseline (day 1) endoscopic scores revealed no significant differences between groups. On day 5, neither placebo nor itazigrel treatment groups showed any significant change compared with baseline. On day 5, both aspirin groups had significantly (P less than .001) more mucosal damage than the placebo group and either itazigrel group. It is concluded that in this relatively acute study, at doses that produce comparable inhibition of platelet aggregation and platelet cyclo-oxygenase, itazigrel was superior to aspirin in terms of toxicity to the upper gastrointestinal tract.

Adolescent↗
PubMed1987

Extended least squares (ELS) for pharmacokinetic models.

An important part of pharmacokinetic research is fitting models to observed data and estimating the parameters in the model. In general, parameter estimation in pharmacokinetics is a subset of the general problem of nonlinear regression or parameter estimation in nonlinear regression models. The same criteria, algorithms, and software used in other areas of science have been used in pharmacokinetics. Nonlinear modeling is a difficult mathematical and statistical task, often presenting problems. Any proposed new tool is of interest, and extended least squares (ELS) has been suggested as being better than the methods usually used. This suggestion and the evidence supporting it are examined; additional simulations are reported. With the evidence presently available, ELS does not seem to be superior to traditional least squares methods.

Biometry↗
PubMed1985

Resonance Raman spectra of the pyridoxal coenzyme in aspartate aminotransferase. Evidence for pyridine protonation and a novel photochemical H/D exchange at the imine carbon atom.

Resonance Raman (RR) spectra are reported for aspartate aminotransferase from pig heart cytosol, and for inhibitor complexes. They are interpreted with reference to the previously analyzed spectra of pyridoxal phosphate (PLP) Schiff base adducts. This comparison shows that, as expected, the pyridine N atom is protonated in the native enzyme at pH 5, and in the glutarate complexes at pH 8.5, and that it is also protonated in the alpha-methylaspartate complex; the stabilization of the pyridine proton at high pH must be due to the interaction with aspartate 222 seen in the x-ray crystal structure. RR spectra of the erythro-beta-hydroxy-DL-aspartate complex, representing the p-quinoid enzyme intermediate, as well as of AlIII complexes of PLP Schiff bases with phenylalanine and tyrosine ethyl ester have been obtained via the coherent anti-Stokes Raman scattering technique, and partially assigned. A novel H/D exchange at the coenzyme C4' atom has been observed for the native enzyme in D2O, and has been determined, by a combination of NMR and RR measurements, to be due to the Raman laser irradiation. This photoprocess, which is not observed for PLP Schiff bases in aqueous solution, is attributed to a photoexcited p-quinoid intermediate, similar to that implicated in the enzyme mechanism. It is suggested that this intermediate is stabilized by protein interactions which localize charge on the phenolate O atom, plausibly a hydrogen bond from the nearby tyrosine 225. H/D exchange would then follow via the aldimine-ketimine interconversion known to take place in the enzyme reaction.

Animals↗
PubMed1984

Effect of dog food containing 460 ppm fluoride on rat reproduction.

A one-generation, two-litter rat reproduction study was done in a kennel in Allegan County, Michigan, as part of an investigation of reproductive problems in Shetland sheepdogs (shelties). Since 1970, at least 115 sheltie litters at this kennel have been grossly deformed and/or have died, generally within 3 d of birth. The causative factor(s) appears to be associated with the environment, as the shelties have had successful pregnancies elsewhere. There was some concern that a potential threat to human reproduction also might exist in this area. After it was discovered that fluoride in the dog food had apparently caused mottled teeth and bony exostoses in dogs at this and at least two other kennels, dog-food fluoride content and local well water were investigated as possible causes of the reproductive problems. A two-way factorial statistical design allowed assessment of dietary fluoride content and water source and interaction between the two. UPj:TUC(SD)spf rats, 9 males and 18 females in each group, were assigned to treatment with high-fluoride dog food (460 ppm) and well water; high-fluoride dog food and distilled water; low-fluoride dog food (56 ppm) and well water; and low-fluoride dog food and distilled water. After 60 d in the kennel, the rats were mated. Even after two litters, the only adverse effect was dental fluorosis in the high-fluoride groups. The results indicated that rats cannot be used in the search for the cause(s) of reproductive problems in dogs in this kennel.

Abnormalities, Drug-Induced↗
PubMed1983

On some stochastic formulations and related statistical moments of pharmacokinetic models.

This paper presents the deterministic and stochastic model for a linear compartment system with constant coefficients, and it develops expressions for the mean residence times (MRT) and the variances of the residence times (VRT) for the stochastic model. The expressions are relatively simple computationally, involving primarily matrix inversion, and they are elegant mathematically, in avoiding eigenvalue analysis and the complex domain. The MRT and VRT provide a set of new meaningful response measures for pharmacokinetic analysis and they give added insight into the system kinetics. The new analysis is illustrated with an example involving the cholesterol turnover in rats.

Animals↗
PubMed1983

Percutaneous absorption of clindamycin in the pig and the rat.

Clindamycin HCl in a 3% formulation was applied twice daily to the back skin of three white (Yorkshire) and three black (Hampshire) pigs for 22 days. Partial thickness samples of skin were obtained by use of a dermatome on shaved opposite sides at 4 hours and 5 days posttreatment. More than twice the antibiotic activity (P less than or equal to .001) was found in thinner (254 micrometers epidermis) samples than in thicker (1016 micrometers epidermis and dermis, 1 to 3) samples. A significantly higher content of antibiotic (P = 0.015) was retained in the skin of black pigs at five days posttreatment. Groups of ten Upjohn Sprague-Dawley rats were treated similarly with clindamycin phosphate in a 3% formulation three times daily for 22 days. At termination of treatment antibiotic activity was widely distributed, whereas at five days posttreatment residual activity was confined largely to samples of treated skin. No cutaneous irritation due to treatment was observed in either study.

Animals↗