Effects of hyperthermia on blood flow and cis-diamminedichloroplatinum(II) pharmacokinetics in murine mammary adenocarcinomas.

The effect of localized hyperthermia on blood flow and cis-diamminedichloroplatinum(II) (CDDP) pharmacokinetics in 7,12-dimethylbenz[a]anthracene-induced mammary adenocarcinomas was studied. Blood flow was determined in rat tumors and normal tissue immediately and 1, 2, and 3 h after local hyperthermia treatment (43 degrees C, 1 h) as well as in unheated tumors of rats. The rate of blood flow in the tumor was increased 1.9 times at the end of treatment relative to control values and returned to the control values by 3 h after hyperthermia. Similarly, the rate of blood flow in the peripheral skin around the tumor immediately after hyperthermia was 2.2 times greater than that of unheated skin and returned to near normal values by 3 h after heating. Tumor-bearing rats received CDDP 1 h before, at the beginning of, at the end of, and 1 h after hyperthermia administration. The CDDP plasma concentration versus time profiles for rats did not vary statistically between treatment groups. Two h after CDDP administration, the mean tumor CDDP concentration of the rats which received drug at the beginning of hyperthermia was statistically greater (P less than 0.05) than tumor CDDP concentrations in rats which received drug at the end of heat treatment. The latter group was given CDDP when tumor blood flow was the greatest; however, mean tumor drug concentration was lowest of all the groups. The mean drug concentration in tumor tissues of rats which received drug 1 h after hyperthermia was comparable to rats which received drug at the beginning of hyperthermia. This suggests that drug delivery or uptake in tumors may be altered when local hyperthermia is administered concurrently or sequentially.

Effect of hyperthermia on normal tissue toxicity and on adriamycin pharmacokinetics in dogs.

This study examined the effects of Adriamycin (ADR) (30 mg/m2), whole-body hyperthermia (WBH) (42 degrees C for 1 h), and the combination of the two (ADR plus WBH) on gastrointestinal and hematopoietic toxicity and the effects of WBH on ADR pharmacokinetics in the normal dog (n = 5/treatment group). Duodenal biopsies were collected from animals in each group via endoscopy and were incubated in the presence of [3H]thymidine as an index of cell turnover. Additional duodenal biopsies were assayed for the enzymes gamma-glutamyltranspeptidase, N-acetyl-beta-D-glucosaminidase, and succinate dehydrogenase. Complete blood chemistry profiles and differential blood cell counts were done prior to and following treatment. Cell turnover was most depressed 3 days after ADR or ADR plus WBH; WBH alone had little effect on cell turnover. Neither gamma-glutamyltranspeptidase, N-acetyl-beta-D-glucosaminidase, nor succinate dehydrogenase activities were significantly altered by any of the treatment protocols. High performance liquid chromatography was used to quantify Adriamycin and adriamycinol in samples collected up to 6 h after drug administration. Duodenal biopsies were collected immediately and 1 h after drug administration for measurement of tissue concentrations of Adriamycin. A significant increase in the apparent volume of distribution and whole-body clearance and decrease in area under the plasma Adriamycin concentration versus time curve occurred when drug was administered concurrently with WBH. This differs from results reported in some other mammalian species.

Reduced adriamycin concentration in rat mammary tumors treated previously with hyperthermia.

The effect of prior hyperthermia on the concentrations of adriamycin in tumors was examined. Chemically induced (9,10-dimethyl-1,2-benzanthracene) rat mammary adenocarcinomas were not heated or were heated one or two times (43.5 degrees C, 1 h; 24 h apart when two times) using an Nd:YAG laser. Rats were administered adriamycin (5 mg/kg, iv) 3 h after hyperthermia treatment. The concentrations of adriamycin in plasma and tissue were determined using high-performance liquid chromatography. Although plasma pharmacokinetics was unchanged by prior local hyperthermia, the concentration of adriamycin was significantly lower in tumors that had been heated previously compared to that in unheated tumors. Tumor blood flow rate was determined after an identical heating protocol using a reference sample technique with 113Sn microspheres. Tumor blood flow rate increased slightly during hyperthermia and then rapidly returned to control levels after hyperthermia. Decreased concentrations of adriamycin in tumors may result from biochemical changes induced by hyperthermia in neoplastic cells and may explain the adriamycin resistance in thermotolerant cells reported previously.

Exponential intravenous infusions in toxicological studies: achieving identical serum drug concentration profiles in individuals with altered pharmacokinetic states.

It is common practice in the clinical setting to adjust the dosage of a drug administered to a patient with altered pharmacokinetic characteristics, e.g., renal impairment, in such a way that the steady-state level of the drug is the same as that which would be observed in normal patients. This may also be done in experimental studies of the interaction of drug toxicity and a disease state. Dosage adjustment does alter average steady-state serum concentrations but the resulting concentration-time profiles of the normal and the diseased groups will be of entirely different shapes due to differences in elimination. In a toxicological study, this would lead to a confounding of the disease state and the difference in exposure. In this paper, model-independent deconvolution analysis is applied to derive the infusion schedule needed to achieve a constant serum concentration followed by a predetermined monoexponential decline in concentration. The resulting exponential infusion is applied to attain identical serum gentamicin concentration-time profiles in five pairs of subtotally nephrectomized and normal dogs during a 12-h infusion.

Naturally occurring tumors in dogs as comparative models for cancer therapy research.

The United States pet population has been a vastly underutilized resource for cancer therapy studies. Naturally occurring tumors in dogs develop twice as frequently as in man, have histopathologic features and a biologic behavior similar to tumors in man, and progress at a more rapid rate than in man. Cancer is one of the leading causes of death in man and dogs. The canine malignancies that are of practical use for comparative therapeutic studies include lymphoma, mammary tumors, oral melanoma, lung tumors, nasal tumors, soft tissue sarcomas, and osteosarcoma. This report will discuss the comparative nature of these malignancies and the current trends in clinical cancer research, namely dose intensification and biomodulation, using naturally occurring tumors in client-owned dogs.

Effect of intravenous lidocaine on halothane minimum alveolar concentration in ponies.

This study investigated the effect of lidocaine i.v. on halothane minimum alveolar concentration (MAC) in ponies. Six ponies were anaesthetised with thiopentone and succinylcholine, intubated and anaesthesia maintained with halothane. Ventilation was controlled and blood pressure maintained within clinically acceptable limits. Following a 2 h equilibration period, baseline halothane MAC was determined. The ponies were then given a loading dose of lidocaine (2.5 or 5 mg/kg bwt) or saline over 5 min, followed by a constant infusion of lidocaine (50 or 100 microg/kg/min, or saline, respectively). The halothane MAC was redetermined after a 60 min infusion of lidocaine or saline. The baseline halothane MAC for the control group was mean +/- s.d. 0.94 +/- 0.03%, and no significant decrease occurred following saline infusion. Lidocaine decreased halothane MAC in a dose-dependent fashion (r = 0.86; P < 0.0003). The results indicate that i.v. lidocaine may have a role in equine anaesthesia.

Acetaminophen as a marker of gastric emptying in ponies.

Gastric emptying was evaluated in ponies using the acetaminophen (AP) method. Fifteen minutes after i.v. administration of metoclopramide, erythromycin, yohimbine, atropine or saline, the ponies were given AP by stomach tube. Blood samples for AP analysis were collected at baseline and 15, 30, 45, 60, 75, 90, 105 and 120 min after AP administration. Time to reach peak serum concentration (Tmax), maximum serum concentration (Cmax) and area under the AP serum concentration vs. time curve (AUC) were determined for each treatment group. In the control group, Tmax was 31 min and this decreased significantly (P < 0.05) following the administration of metoclopramide. Atropine significantly increased Tmax and decreased Cmax and AUC. Yohimbine significantly increased AUC. Erythromycin did not significantly change any parameter. This study indicates that acetaminophen can be used to evaluate gastric emptying in ponies. The method is easy to perform and is minimally invasive. Metoclopramide stimulated gastric emptying of liquid in healthy, fasting ponies. Atropine significantly delayed, while erythromycin had little effect on, gastric emptying. Yohimbine increased the cumulative absorption of AP.

Effect of cisapride on gastric emptying in horses following endotoxin treatment.

The effect of cisapride pretreatment on gastric emptying in horses was determined by measuring serum concentrations of acetaminophen, a drug known to be readily absorbed in the small intestine but not in the stomach. The time to reach maximum serum acetaminophen concentrations (Tmax), the maximum serum concentrations (Cmax) and the area under the serum acetaminophen concentration vs. time curves (AUC) were compared among treatment groups. In the first part of the study, the effect of orally administered cisapride (0.1, 0.2 and 0.4 mg/kg bwt) on gastric emptying was examined in 6 normal fasted horses. In the second part of the study, gastric emptying in horses given endotoxin i.v. (n = 6) was compared to those that received cisapride per os prior to administration of endotoxin (n = 6) and those that received neither compound (n = 6). Cisapride did not alter gastric emptying in normal horses. Endotoxin caused a profound delay in gastric emptying and pretreatment with cisapride significantly attenuated this effect. It is concluded that cisapride may be useful as a prophylactic measure when administered prior to the development of endotoxaemia.

Use of body surface area (BSA)-based dosages to calculate chemotherapeutic drug dose in dogs: I. Potential problems with current BSA formulae.

The dose of most cancer chemotherapeutic drugs administered to dogs is calculated on the basis of estimated body surface area (BSA); however results of some chemotherapy trials have revealed that this dosing method increases toxicosis in small dogs. The current formula used to estimate BSA in dogs may be inaccurate or the assumption that BSA correlates with chemotherapeutic drug exposure may be unfounded. Results presented in this review suggest that canine BSA estimates may be inaccurate because the values for the constant (K) and exponent (a) in the formulae (BSA = K.Wa) are incorrect or because a linear parameter such as body length is lacking from the formulae. Results that suggest the relationship between BSA and the physiologic/pharmacologic factors that influence drug exposure may not be closely correlated are also presented. Studies are warranted to determine whether there are dosing methods that normalize chemotherapeutic drug toxicity in dogs.

Use of body surface area to calculate chemotherapeutic drug dose in dogs: II. Limitations imposed by pharmacokinetic factors.

Anticancer drug dosages that specify the maximum dose and minimum dosing interval that are tolerated in a population of dogs are commonly recommended. Because the differences between the effective and toxic doses of most cancer chemotherapeutics is slight, it is important to achieve therapeutic concentrations in tumor tissues at the same time that concentrations in nontarget tissues are minimized. In order to determine the dosage regimen that will most likely accomplish these goals, similar drug concentrations must be achieved in all patients dosed according to a specific regimen. Dosing based on body surface area (BSA) is generally used in an effort to normalize drug concentrations. This is because it is well recognized that measures of many physiologic parameters that are responsible for drug disposition, including renal function and energy expenditure, can be normalized by use of BSA. However, there is substantial evidence that drug disposition is not always proportional to BSA. Differences in distribution, metabolism, and excretion pathways may preclude dose extrapolation among species or among individuals within a species based on BSA. Moreover, genetic differences in drug metabolism are well recognized in humans and in laboratory animals, and it is likely that similar differences exist among breeds of dogs. A review of the pharmacokinetic disposition of several cancer chemotherapeutics suggests that studies are needed to determine the most effective method to achieve equivalent anticancer drug concentrations in diverse veterinary patients.

Metoclopramide ameliorates the effects of endotoxin on gastric emptying of acetaminophen in horses.

The effect of metoclopramide on gastric emptying of a liquid marker in horses was evaluated by measuring serum concentrations of acetaminophen. Gastric emptying was determined in normal, fasted horses (n = 7), horses given endotoxin intravenously (n = 7), and horses given intravenous metoclopramide plus endotoxin (n = 6). The mean time to reach maximum serum acetaminophen concentration (Tmax), the maximum serum concentration (Cmax), and the area under the serum acetaminophen concentration vs time curve (AUC) were compared among treatment groups. Endotoxin caused a profound delay in gastric emptying, and pretreatment with metoclopramide significantly (P < 0.05) ameliorated this effect.

Phenylbutazone prevents the endotoxin-induced delay in gastric emptying in horses.

The effect of phenylbutazone on gastric emptying in horses was determined by measuring serum concentrations of acetaminophen. Gastric emptying was determined in normal fasted horses (n = 6), horses given endotoxin intravenously (n = 6), horses given intravenous phenylbutazone (n = 6), and horses given intravenous phenylbutazone plus endotoxin (n = 6). The mean time to reach maximum serum acetaminophen concentration (Tmax), the maximum serum concentration (Cmax), and the area under the serum acetaminophen concentration versus time curve (AUC) were compared among treatment groups. Phenylbutazone did not alter gastric emptying in normal horses. Endotoxin caused a profound delay in gastric emptying, and pretreatment with phenylbutazone abolished this effect.

Yohimbine ameliorates the effects of endotoxin on gastric emptying of the liquid marker acetaminophen in horses.

The effect of yohimbine pretreatment on gastric emptying of a liquid marker in horses was evaluated by measuring serum concentrations of acetaminophen. Gastric emptying was determined in normal, fasted horses, in horses given endotoxin (E. coli 055 B5; 0.2 microg/kg) intravenously, and in horses given yohimbine (0.25 mg/kg, IV, over 30 minutes) plus endotoxin. Acetaminophen (20 mg/kg) was given by stomach tube 15 minutes after the endotoxin infusion. Blood samples for acetaminophen analysis were collected, and time to reach the peak serum concentration (Tmax), the maximum serum concentration (Cmax) and the area under the acetaminophen serum concentration versus time curve (AUC) were determined for each treatment group. Endotoxin significantly increased Tmax, indicating a profound delay in gastric emptying and yohimbine pretreatment significantly (P < or = 0.05) prevented this effect.

Comparison of body surface area-based and weight-based dosage protocols for doxorubicin administration in dogs.

Pharmacokinetics and toxicity of a single dose of doxorubicin, at dosages of 30 mg/m2 of body surface area and 1 mg/kg of body weight, were compared in 17 dogs. Effects of doxorubicin on complete blood cell count, platelet count, and the dogs' clinical condition were evaluated for 14 days. Cluster analysis, on the basis of clinical signs of doxorubicin toxicosis at the 30-mg/m2 dosage, revealed that 6 of 7 small dogs (< or = 10 kg) became ill, whereas 7 of 10 large dogs (> 10 kg) remained clinically normal. Small dogs that received doxorubicin at a dosage of 30 mg/m2 had higher peak plasma concentrations, greater area under the curve for plasma drug concentration vs time, longer drug elimination half-lives, greater volumes of distribution, and more clinical signs of toxicosis than had large dogs (P < or = 0.05). Five of 9 small dogs that received doxorubicin at a dosage of 30 mg/m2 developed severe myelosuppression (< 1 x 10(3) granulocytes/microliters). In contrast to the toxicoses with body surface area-based dosing, myelosuppression was not induced in small dogs that received doxorubicin at a dosage of 1 mg/kg. In small and large dogs given doxorubicin at a dosage of 1 mg/kg, pharmacokinetic characteristics and clinical signs of toxicosis were similar. Mean WBC counts and granulocyte counts for all dogs were lower on day 7 with 30 mg of doxorubicin/m2 (n = 17), compared with that for 1 mg of doxorubicin/kg (n = 14; P < or = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Gentamicin pharmacokinetics and nephrotoxicity in naturally acquired and experimentally induced disease in dogs.

Pharmacokinetic disposition of gentamicin was studied in 69 dogs--12 control and 33 subtotally nephrectomized dogs representing combined data from previous experimental studies, and 24 dogs with a variety of diseases and degrees of renal dysfunction. Drug disposition varied considerably within and between diseases, and dosages had to be altered to achieve therapeutic drug concentrations and to minimize drug toxicosis. Decreased drug clearance when serum creatinine and urea nitrogen concentrations are normal may be indicative of subclinical renal disease and therefore may indicate a predisposition for development of nephrotoxicosis. Results of the study indicated the need to individualize aminoglycoside dosage regimens on the basis of pharmacokinetic disposition of drug, especially in dogs with preexisting subclinical renal dysfunction. Because of the large variability normally encountered in dogs with various diseases, monitoring of renal function alone is not sufficient to accurately predict gentamicin clearance, volume of distribution, or half-life.

Gentamicin dosing strategies for dogs with subclinical renal dysfunction.

Twenty-six subtotally nephrectomized dogs were used as a model for subclinical renal dysfunction to evaluate the nephrotoxic potential of gentamicin administered according to four different dosage regimens. Dosages were individualized based on the pharmacokinetic disposition of drug in each dog. Gentamicin at 3.75 +/- 0.15 mg/kg (mean +/- standard error of the mean, total daily dose) was given for 12 days in two or three divided daily doses (BID and TID, respectively) or in a 2-h or 4-h once-daily variable-rate infusion (2HI and 4HI, respectively) with loading dose. Analyses of serum chemistries and pharmacokinetic data were performed on the ratio of pretreatment versus posttreatment parameters in individual animals. While serum chemistries and histopathology revealed no significant differences in toxicity between treatment groups, pharmacokinetic analysis revealed a significant difference in the ratio of pretreatment versus posttreatment gentamicin clearance (1.35 +/- 0.22, BID; 2.44 +/- 0.52, TID; 0.91 +/- 0.08, 2HI; 0.91 +/- 0.07, 4HI). By using mean population pharmacokinetic parameters (all dogs), predicted times for each treatment group administered 3.75 mg/kg per day to achieve concentrations in serum above the MICs of 2, 4, 6, and 8 micrograms/ml, respectively, were 7.8, 4.2, 2.0, and 0.6 (BID); 6.1, 3.0, 0.5, and 0.2 (TID); 7.1, 5.3, 4.2, and 3.5 (2HI); and 7.4, 5.8, 4.8, and 4.0 (4HI) h daily. This study suggests that decreasing the total daily dosage of drug may decrease the incidence of gentamicin-induced nephrotoxicity. Regardless of the dosage regimen, however, regimens may differ significantly in predicted therapeutic efficacy. Predicted 30-min postdosing concentrations in serum were lowest in dogs administered drug TID, and gentamicin clearance decreased in this group with treatment, suggesting that this regimen may be the least efficacious as well as the most prone to causing future nephrotoxicity.

Pharmacokinetic estimation for therapeutic dosage regimens (PETDR)--a software program designed to determine intravenous drug dosage regimens for veterinary applications.

Pharmacokinetic estimation for therapeutic dosage regimens (PETDR) is a soft-ware program used to design individualized intravenous dosage regimens, determine concentration-time profiles, predict serum concentrations at a specific time after intravenous dosing and predict the time after the last dose to achieve a specified concentration of drug. The reference pharmacokinetic parameters may be based on an individual animal's pharmacokinetic disposition of drug or on FARAD (Food Animal Residue Avoidance Databank) mean population kinetic parameters. An individual animal's kinetic parameters may be input for predetermined analysis or the program can calculate these values by input of raw serum concentration-time data. The program allows the user to specify certain parameters of the dosage regimen, then calculates the other parameters (given desired maximum and minimum serum concentrations, dose and interval are calculated; given desired maximum serum concentration and interval, dose is calculated, etc.). Given the kinetic parameters, the dose and dosing interval, the program calculates and plots the serum concentration-time profile of the drug for that animal. The time and the number of doses to reach steady state can be calculated as well as the determination of loading dose. The percentage of the time of a dosing interval at steady state that the serum concentration is above a specific minimum inhibitory concentration (MIC) allows evaluation of efficacy of an antimicrobial regimen. Similarly, the time to reach a specific concentration (e.g. residue tolerance) or the MIC of a drug can be calculated. Legal tissue tolerances can be accessed from FARAD to aid in predicting for what period of time illegal residues will remain in the animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor cell-enhanced sensitivity of vascular endothelial cells to photodynamic therapy.

Effective antitumor photodynamic therapy (PDT) may be related to damage of vasculature within the tumor. The purpose of this study was to determine if tumor cells secrete factors that stimulate proliferation of human umbilical vein endothelial cells (HUVEC) and result in enhanced sensitivity of HUVEC to aluminum-sulfonated phthalocyanine (AlSPc)-PDT. Three human tumor cell lines--pharyngeal squamous carcinoma, colonic carcinoma, and mammary carcinoma--were used in this study. Co-culture of HUVEC and either squamous carcinoma or colonic carcinoma, but not mammary carcinoma, significantly increased HUVEC proliferation and AlSPc-PDT mediated cell damage. In addition, supernatant from squamous carcinoma and colonic carcinoma cultures also stimulated HUVEC proliferation and sensitivity to AlSPc-PDT. Both supernatant and cell lysate from squamous carcinoma cells contained angiogenic factors consistent with basic and acidic fibroblast growth factors, as evidenced by Western blot analysis and BALB/c 3T3 fibroblast cell proliferation assays. Collectively, these results suggest that selected tumor cell lines produce angiogenic factors that induce HUVEC proliferation and subsequently enhance sensitivity to AlSPc-PDT.

Nd:YAG laser hyperthermia treatment of rat mammary adenocarcinoma in conjunction with surface cooling.

Electromagnetic radiation ranging from radiofrequency to microwave has classically been used to induce hyperthermia for treatment of cancer. This paper presents a new technique using near infrared radiation from an Nd:YAG laser in conjunction with surface cooling to induce hyperthermia in a rat tumor model. A CW Nd:YAG laser hyperthermia system was used to induce hyperthermic temperatures in chemically (DMBA) induced rat mammary adenocarcinomas. The laser was interfaced to a computer and a thermometry unit that provided feedback to control the tumor temperature between 43.2-43.5 degrees C. A thermocouple was placed at the base of the tumor and its temperature was used to control laser exposure. All tumors were 10 to 20 mm in diameter. Surface cooling methods investigated included forced air flow from a fan, forced oxygen flow plus an IV drip, and forced moist oxygen flow from a nebulizer. Twelve rat mammary adenocarcinomas have been treated with Nd:YAG laser hyperthermia. In 4 treatments, no surface cooling was employed. In one treatment the surface was cooled using oxygen flow plus IV drip. In 7 treatments the skin was cooled using the nebulizer technique. The nebulization provided the most effective and reproducible surface cooling. Nd:YAG laser hyperthermia delivered in conjunction with nebulizer surface cooling produced efficient heating of rat mammary adenocarcinomas. A mean temperature of 42.1 degrees C was obtained at the base of the tumors while the mean surface temperature was 37.0 degrees C.