Head and neck nodal station images: guidance for three-dimensional radiation therapy treatment planning.

When we use radiation to treat cancer patients, the irradiated volume usually encloses the detectable tumor and any metastatic areas that are thought to be at risk. Usually, in three-dimensional (3D) radiation therapy, we need to define the clinical target volume (CTV), which identifies the areas suspected of containing microscopic metastasis. We can use a set of computed tomographic (CT) images to define these suspected areas, which we relate to nodal station distributions. The traditional method uses special anatomic landmarks for such definition. This lymph node image guidance method uses a set of CT images to show the relevant nodal stations and find the correlation between the suspected areas and the lymphatic pathways. First, we used CT images from head and neck cancer patients. Then, we designed a program to delineate the regional lymphatic areas in order to distinguish the position of all the major lymph nodes in the head and neck region. These lymph nodes were then used to assist the oncologist in developing treatment references. Finally, we established a database management system to determine the relationships between different lesions and lymph nodes, as well as correlations, with metastatic pathways. Defining these relationships on the CT images provided oncologists specific information that could be used to define the CTV more precisely for 3D radiation therapy.

Population pharmacokinetic/pharmacodynamic methodology and applications: a bibliography.

This bibliography lists all published methodological works (statistical methodology, implementation methodology, review papers, descriptions of software) in the area of population pharmacokinetics/pharmacodynamics up to 1993 and all published works describing applications of population pharmacokinetics/pharmacodynamics up to 1992.

Pharmacokinetics of vigabatrin following single and multiple oral doses in normal volunteers.

The pharmacokinetics of vigabatrin were investigated after single and multiple oral doses in two groups of 24 healthy male volunteers. Vigabatrin was well tolerated by the volunteers; headache was the most frequently reported adverse event. There were no clinically remarkable changes in serum chemistry, urinalysis, or hematology attributable to vigabatrin. For the single-dose study, a stepwise linear contrast method was used to assess dose proportionality. The results showed that vigabatrin exhibited dose linear pharmacokinetics after single oral doses ranging from 0.5 to 4.0 g. Slight changes in the terminal phase half-life and renal clearance were evident in the higher dosage groups. These changes with increasing dose of vigabatrin were relatively minor and not considered to be clinically important. Evaluation of the multiple-dose pharmacokinetics indicated that vigabatrin exhibited dose linearity over the range of 0.5 to 2.0 g administered every 12 hours. The terminal phase half-life and renal clearance of vigabatrin during multiple dosing were consistent with that after single doses. During multiple dosing, steady-state concentrations of vigabatrin were reached on the second day of dosing, and drug accumulation was minimal.

Pharmacokinetics of teicoplanin upon multiple dose intravenous administration to normal healthy male volunteers.

Teicoplanin pharmacokinetics were investigated upon multiple dose intravenous administration of 6 and 12 mg kg-1 in 10 normal, healthy, male volunteers, using a two-period, randomized, crossover design; six subjects completed both periods. On day 1, 6 or 12 mg kg-1 was administered every 12 h as a 30-min constant rate intravenous infusion (two doses). Starting on day 2, the same dose (6 or 12 mg kg-1) was administered every 24 h for an additional 13 days. Blood and urine samples were collected over 21 days. Serum and urine were analyzed using a microbiological assay. Following a minimum of 3 weeks after completion of the first period, subjects were crossed over to the other dose. Following multiple dose intravenous administration of 6 and 12 mg kg-1, median pharmacokinetic parameters included: steady-state volume of distribution of 1.4 and 1.2 l kg-1; total clearance of 12.2 and 14.0 ml h-1 kg-1; renal clearance of 11.1 and 10.3 ml h-1 kg-1; and terminal disposition half-life of 159 and 155 h, respectively. No statistically significant dose-related difference was observed. In addition, a cross-study comparison further supports dose proportionality of teicoplanin upon multiple dose intravenous administration of 3 to 12 mg kg-1.

Absence of food effects on the pharmacokinetics of terfenadine.

Administration of terfenadine (Seldane) immediately after a high fat breakfast slightly affects the rate but not the extent of absorption relative to fasting administration. Mean peak levels of the active metabolite were increased by 13 per cent but delayed by 0.9 h while AUC was virtually the same as when terfenadine was administered while fasting. Changes in rate of absorption may be due to delayed gastric emptying and more rapid terfenadine solubilization. In any case, these rate differences are unlikely to be clinically important in the absence of differences in extent of absorption.

Pharmacokinetics and bioavailability of a new formulation of teicoplanin following intravenous and intramuscular administration to humans.

Pharmacokinetics, bioavailability, and local tolerance (at the site of intramuscular administration) of a new formulation of teicoplanin (400 mg/3 mL) were investigated in 24 normal, healthy, male volunteers. A single dose of 6 mg/kg was administered intravenously and intramuscularly using a randomized crossover design. Volunteers and investigator were blinded as to the route of administration; placebo was administered by the other route. Blood and urine samples were collected for 21 days and were analyzed for microbiological activity. The median (range) pharmacokinetic parameters of teicoplanin following single-dose iv administration were as follows: steady-state volume of distribution of 1.6 (1.2-2.8) L/kg; total clearance of 10.2 (8.6-15.1) mL/h/kg; renal clearance of 10.0 (7.9-13.8) mL/h/kg; and terminal disposition half-life of 168 (111-278) h. Following single-dose im administration, significantly more subjects complained of pain following administration of teicoplanin (58%) compared with placebo (4%). Teicoplanin was completely absorbed with a median (range) peak serum concentration of 12.3 (6.6-37.5) micrograms/mL occurring at a median (range) time of 4.1 (0.7-6.1) h. Since the 90% confidence interval for the ratio of areas under the serum concentration-time curve falls within the range of 80 to 120%, the extent of systemic absorption of teicoplanin following im administration is equivalent to that following iv administration.

Teicoplanin pharmacokinetics in intravenous drug abusers being treated for bacterial endocarditis.

The pharmacokinetics of teicoplanin were determined after multiple 30-min intravenous infusions of 10 to 15 mg/kg every 12 to 24 h in 11 intravenous drug abuse (IVDA) patients being treated for bacterial endocarditis. Multiple serum samples were obtained over 7 to 14 days. Twenty-four-hour urine collections were obtained on days 1 and 5. Serum concentration-time data were analyzed by using multiple-dose pharmacokinetic analysis (NONLIN84). Results were compared with pharmacokinetic parameters derived from previous studies in normal healthy volunteers following multiple intravenous infusions of teicoplanin (3 to 6 mg/kg/day). Total and renal clearances of teicoplanin in IVDA patients were found to be significantly greater and more highly variable than those observed previously in normal healthy volunteers. As a result, predicted steady-state trough concentrations in serum may vary up to fivefold. The mechanism responsible for this variation appears to be related to the glomerular filtration rate. In IVDA patients, individualized teicoplanin dosage may be required in the treatment of bacterial endocarditis.

Induction of uterine leiomyomas in mice by medroxalol and prevention by propranolol.

Medroxalol hydrochloride is an antihypertensive agent with beta 1 adrenergic cardiac blocking properties, and beta 2 and some alpha 1 vasodilating activity. In previous carcinogenicity studies medroxalol was shown to induce leiomyomas of the uterus in CD-1 mice but not in Long Evans rats. In addition, there was a significant increase in endometrial stromal sarcomas in mice receiving the lowest dose of medroxalol; however, the lack of a dose response made the relationship to treatment questionable. Because of these findings, additional 18-month drug diet studies were conducted in 3 parallel segments using female CD-1 mice to determine the effects of: 1) an expanded range of doses, 2) various durations of dosing, and 3) the effect of the beta-blocker, propranolol, on leiomyoma induction. These studies confirmed the fact that chronic dietary treatment with medroxalol can lead to an increased incidence of leiomyomas in the mouse uterus, but failed to demonstrate any relationship between endometrial stromal sarcomas and medroxalol administration. A linear trend occurred in the incidence of leiomyomas and of smooth muscle hypertrophy/hyperplasia, a possible precursor to leiomyoma. Both findings were notably increased at 250 mg/kg/day or more. Doses of 50 mg/kg/day or less were considered no effect levels. At 500 mg/kg/day a treatment period of 12 months or more was required before a noticeable increase in leiomyomas occurred in mice examined after 18 months. The beta-blocker, propranolol, prevented this increase in leiomyomas, and led to the conclusion that the beta 2 agonist activity of medroxalol was involved in their induction. Propranolol did not block the spontaneous occurrence of these tumors.