Assignment and analysis of fluorine nuclear magnetic resonance spectra of 4-fluorotryptophan myoglobins and hemoglobins.

We have obtained the 470 MHz 19F NMR spectra of wild type [4-F]Trp-labeled myoglobins (MbCO, MbO2, deoxyMb, metMb, and MbCN) and hemoglobins (HbCO, HbO2, and deoxyHb), as well as those of several mutants (W7F Mb, betaW15F Hb, betaW37S Hb, and betaY130F Hb, all as the carbonmonoxy adducts), prepared via site-directed mutagenesis. The maximum observed chemical shift range induced by folding is 6.4 ppm. Using a multipole shielding polarizability-local reaction field approach, we have computed the electrostatic field contributions to the fluorine shielding. For residues which do not have F atoms in contact with neighboring groups, we find an approximately 1 ppm mean square deviation in shift from experiment, with the R2-like structure of HbCOA being in very close accord with experiment.

Secondary and tertiary structural effects on protein NMR chemical shifts: an ab initio approach.

Recent theoretical developments permit the prediction of 1H, 13C, 15N, and 19F nuclear magnetic resonance chemical shifts in proteins and offer new ways of analyzing secondary and tertiary structure as well as for probing protein electrostatics. For 13C, phi, psi torsion angles dominate shielding for C alpha and C beta, but the addition of hydrogen bonding and electrostatics gives even better accord with experiment. For 15NH, side chain (chi 1) torsion angles are also important, as are nearest neighbor sequence effects, whereas for 1HN, hydrogen bonding is particularly significant. For 19F, weak or long-range electrostatic fields dominate 19F shielding nonequivalencies. The ability to predict chemical shifts in proteins from known or test structures opens new avenues to structure refinement or determination, especially for condensed systems.

Pharmacokinetic disposition of 14C-glyburide in patients with varying renal function.

The pharmacokinetics of 14C-labeled glyburide were studied in 13 men with varying degrees of renal impairment. Patients received a single, 5 mg oral dose of glyburide as a solution (10 microCi/ml/mg) after a high-carbohydrate breakfast. Serial plasma and breath samples were collected for 48 hours and urine and feces were collected for 5 to 7 days. Patients with normal to moderately impaired renal function (creatinine clearance [CLCR] of 29 to 131 ml/min/1.7 m2) had glyburide plasma t1/2 values of 2.0 to 5.0 hours, with no relationship between CLCR and glyburide clearance. One subject with severe renal impairment (CLCR = 5 ml/min/1.7 m2) had decreased glyburide clearance that resulted in a t1/2 of 11 hours. The elimination of metabolites was more dependent on renal status but was only significantly affected in the patient with severe renal impairment.

Pharmacokinetics of glyburide.

The pharmacokinetics of glyburide can be described by a two-compartment open model. Terminal-phase descriptions are formulation-dependent and are complicated by apparent food-associated mobilization of drug from the stomach. Some researchers indicate a possible third (or deep) compartment, but this appears to be an artifact of a nonspecific drug assay. Although no accumulation has been observed in short-term studies, further investigation of the possibility of drug accumulation with long-term therapy is needed. Distribution of glyburide is affected by high affinity for serum albumin (99 percent bound), and elimination of the drug appears to be evenly divided between biliary and renal routes. The biologic half-life of glyburide is not significantly correlated with renal function in subjects with creatinine clearances of 30 ml/minute/1.7 m2 or more. Gradations in disease state, multiple sites of sulfonylurea action, and inter-patient variability have made it difficult to relate biologic response to glyburide serum levels.

A pharmacokinetic comparison of cephalexin and cefadroxil using HPLC assay procedures.

The pharmacokinetics of cephalexin and cefadroxil were compared following single 500 mg oral doses to 12 healthy male volunteers. Doses were administered after an overnight fast according to a crossover design. Plasma and urinary levels of both compounds were determined by HPLC procedures. Cephalexin was absorbed rapidly, achieving a mean peak plasma level of 17.5 micrograms ml-1 at 1 h, compared to 16 micrograms ml-1 at 1.8 h for cefadroxil. Elimination half-lives of cephalexin and cefadroxil were 0.7 and 1.1 h, respectively. The area under the cefadroxil plasma curve was significantly larger than that for cephalexin. However, after allowing for differences in elimination rate constants and assuming equal distribution volumes, plasma data indicated the compounds were equally well absorbed. Only 70 per cent of cefadroxil was recovered in urine compared to 87 per cent of cephalexin during the 12 h following drug administration. The therapeutic significance of the different pharmacokinetic characteristics of cephalexin and cefadroxil, if any, may be a function also of their pharmacologic activity and/or the sensitivity of the target organism.

Combination v. sequential therapy with melphalan, 5-fluorouracil and methotrexate for advanced ovarian cancer.

The results of a national clinical trial to compare combination and sequential chemotherapy for stage III or IV ovarian cancer are reported. Of the 253 patients from 16 centres across Canada who were admitted to the trial 13 were excluded from the analysis. All the patients were observed for 2 to 5 years from entry into the trial. There were no differences in response to therapy or in survival between the patients treated with melphalan followed by 5-fluorouracil and then by methotrexate in high dosage and the patients treated with the same agents in combination. Patients with minimal residual disease after resection of stage III ovarian cancer had a good prognosis. Other favourable prognostic factors were age (less than 55 years), performance status (90% or 100% on the Karnofsky scale) and histologic grade of the tumour.

The present status and future potential of radiotherapy in the management of esophageal cancer.

The management of 2032 patients with squamous esophageal cancer seen in Edinburgh from 1931 to 1969 was studied. Since 1949 more radical surgical treatment has been offered and since 1956 more radical radiotherapy. From 1949 to 1969 there has been a swing over from mainly surgical to mainly radiation treatment associated with a rise in the overall one and five-year survival rates to 32% and 9% respectively. The main reason for failure is the prevalence of disseminated disease. The significant mortality of surgical treatment limits its usefulness. Too often, radiotherapy fails because of recurrence of tumor within the irradiated volume. In the upper 2/3 of the esophagus irradiation is preferable to surgery because of better sirvoval. In the lower 1/3 the two methods achieve similar long term survival but following irradiation the short term survival is better and the patient retains a normal stomach. Improvement could be achieved by prevention, earlier diagnosis, improved tumor delineation and a wide range of measures to improve the local effectiveness of irradiation.

Prednisolone and mustine in prevention of tumour swelling during pulmonary irradiation.

Ventilatory function declines during the early stages of irradiation for bronchial carcinoma. This decline is potentially dangerous if the tumour narrows the trachea or both main bronchi. The protective effect of preliminary treatment with prednisolone or mustine before irradiation was studied in 88 patients by serial estimations of forced expiratory volume and forced vital capacity. Twenty-three patients received prednisolone by mouth, 24 had mustine intravenously, and 41 had no preliminary treatment. Both prednisolone and mustine prevented a significant decline in ventilatory function due to tumour swelling, prednisolone being marginally superior. It is concluded that all patients at risk should be treated with oral prednisolone, 20 mg daily, for one day before and two days after the first fraction of irradiation.

The association of squamous oesophageal cancer and thyroid disease.

In 178 consecutive oesophageal squamous carcinoma cases, 5% (9 cases) had had thyrotoxicosis, hypothyroidism or thyroid carcinoma. The incidence in males was 1% (1 case) and in females 8% (8 cases). This incidence was in excess of other known associations of oesophageal cancer and in this series, it was exceeded only by previous gastric surgery for peptic ulceration.