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Biomedical subjects

R T Dorr

Publications and source records attributed to R T Dorr.

At least 145 records · Page 8Linked to original sources
PubMed1982

Evaluation of topically applied trans-retinoic acid in the treatment of cervical intraepithelial lesions.

The prevention and/or suppression of preneoplastic foci in animals has been convincingly demonstrated with the use of a variety of compounds, including retinoids. We report here a phase I/II trial of beta-trans-retinoic acid delivered via a collagen sponge/diaphragm insert for neoplasia of the cervix. Eighteen patients with biopsy-proved grades 2 and 3 cervical intraepithelial neoplasia underwent four consecutive daily applications of trans-retinoic aicd to the cervix. Conization of the cervix was performed 4 weeks later. Significant vaginal toxicity in 10 of 18 (55%) patients was unrelated to the concentration or carrying media of the drug. A reduction in size of the intraepithelial lesion was noted by colposcopy in six of 18 (33%) patients with complete resolution of disease at conization in two patients. A new delivery system designed to avoid vaginal toxicity while defining the optimal concentration and dosing schedule for these patients is currently under investigation.

Administration, Topical↗
PubMed1982

In vitro retinoid binding and release from a collagen sponge material in a simulated intravaginal environment.

Four in vitro preparations were constructed to simulate the intravaginal release of two retinoids, all-trans-retinoic acid (t-RA) and 13-cis-retinoic acid (c-RA), from a 0.7% collagen sponge diaphragm insert. Four t-RA concentrations, 0.019, 0.05, 0.1, and 0.15% in methanol were added to the sponge. The release into an artificial vaginal fluid was monitored serially over 72 h by serial analysis for t-RA and c-RA using high-pressure liquid chromatography. In each preparation, retinoid release was immediate and noncontinuous. At 37 degrees C, the retinoids were stable for at least 48 h. Trans-retinoic acid was the predominant retinoid recovered. Only trace amounts of the cis-isomer were released. Peak t-RA levels were 20 microM after 0.01%, 60-80 microM after 0.05%, 100-200 microM after 0.1%, and 320 microM after 0.15%. When the vaginal fluid bath was changed after 5 h, no further significant retinoid release occurred. There was significant loss of up to 70% of the applied t-RA into the collagen sponge. The retinoid binding was concentration dependent (higher binding with higher concentrations) and was maximal only after 24 h of co-incubation. The discontinuous release of t-RA and the high degree of binding to collagen would seem to preclude use of the diaphragm insert as a vaginal drug delivery system, at least for retinoids.

Biocompatible Materials↗
PubMed1982

Allopurinol kinetics and bioavailability. Intravenous, oral and rectal administration.

Six normal, healthy adult males received a single dose of allopurinol intravenously, orally in the form of a commercial tablet, and rectally in the form of an extemperaneously prepared suppository (either in a cocoa butter or in polyethylene glycol base). Plasma allopurinol and oxipurinol concentrations were measured over a period of at least 60 h. The following mean (+/- SD) values were obtained from the intravenous allopurinol experiment: clearance, 9.62 +/- 3.49 ml . kg-1 . min-1; Vd, 1.61 +/- 0.74 l/kg; t1/2, 1.62 h. Oxipurinol had a mean t1/2 of 16.90 h. The absolute systemic bioavailability of the oral tablet was 67% +/- 23%, while the allopurinol rectal suppositories produced no measurable plasma concentrations of allopurinol or oxipurinol in any of the subjects. Current use of rectal dosage forms as an adjunct in cancer chemotherapy should therefore be re-examined.

Administration, Oral↗
PubMed1982

Cimetidine enhancement of cyclophosphamide antitumour activity.

Male DBA2 mice were given 10(6) P-388 leukaemic cells i.p. and cimetidine (CMT) at 100 mg/kg 1 day for 10 days, or as a single 100 mg/kg injection 30 min before cyclophosphamide (CTX). CMT significantly prolonged the survival of groups of mice receiving 50, 100 and 200 mg/kg of CTX 3 days after tumour inoculation. Median survival increased by 5.5 days (P less than 0.05), 10 days (P less than 0.05) and 13 days (P less than 0.05) respectively. The addition of CMT had the effect of roughly doubling the CTX dose, without increasing the lethality. CMT produced the only long-term survival seen in the study (1-2/10) CMT alone had no apparent antitumour activity. CMT significantly prolonged mean pentobarbital sleep to 28.6-60 min vs only 10 min for phenobarbital treated mice. Both CMT regimens increased the plasma concentration time products for CTX-induced metabolites (NBP) by about 1.3 fold (in contrast to a 33% reduction with phenobarbital). On average the single-dose CMT regimen produced the greatest effect on survival, on pentobarbital sleep duration and on total NBP reactive species. Probable mechanisms for the CMT-CTX interaction include competitive microsomal enzyme inhibition and/or acutely depressed hepatic blood flow. Caution should be used in combining CMT with full doses of CTX and any other highly metabolized antineoplastic agents in man.

Animals↗
PubMed1982

Bleomycin compatibility with selected intravenous medications.

Three separate in vitro admixture experiments were accomplished with bleomycin and other common parenteral medications. Bleomycin was assayed by a radioimmunoassay procedure. Bleomycin was found to be compatible with a majority of drugs including the aminoglycoside antibiotics, the vinca alkaloid antineoplastics, the antimetabolite fluorouracil, several phosphate salt corticosteroids, diphenhydramine and the anticoagulant heparin sulfate. Incompatible admixtures include the acidic cephalosporin and penicillin-derived antibiotics, the antineoplastics, methotrexate, and mitomycin C, the sodium succinate salt of hydrocortisone as well as ascorbic acid (vitamin C).

Aminophylline↗
PubMed1981

Poor rectal absorption of trimethoprim/sulphamethoxazole in treating Pneumocystis carinii pneumonia.

A 24-year-old female with Hodgkin's disease and Pneumocystis carinii pneumonia was tested with trimethoprim/sulphamethoxazole (TMP/SMX) tablets. Because treatment failure was feared owing to chronic emesis potentially resulting in incomplete drug absorption, the same TMP/SMX dose was administered by rectal suppositories after the 5th day of oral dosing. The relative fractions (rectal/oral) or the suppository dose absorbed for TMP and SMX were 3.0% and 19.5% respectively. When TMP/SMX treatment is required and the oral route is not practical, the investigational i.v. preparation should be obtained.

Administration, Oral↗
PubMed1981

Modulation of experimental doxorubicin skin toxicity by beta-adrenergic compounds.

Doxorubicin [Adriamycin (ADM), a potent intercalating antineoplastic agent, occasionally causes severe local skin toxicity if extravasated during administration. Previous experiments using intradermal (i.d.) ADM in BALB/c mice have shown limited antidotal activity for local i.d. corticosteroids in preventing ADM-induced ulceration and no effect for a number of other compounds except beta-adrenergic agonists and antagonists. Three sequences of i.d. administration of beta-adrenergics were evaluated in this study: a single dose immediately after 0.05 or 0.5 mg ADM; 8 daily doses of isoproterenol (ISO) or 0.9% NaCl solution, 0.05 ml after ADM; and 5 days of pre-ADM to ostensibly "up" or "down"-regulate beta-receptor number (with propranolol and ISO, respectively). The results demonstrate consistent antidotal activity for ISO and propranolol as single antidotal injections. Terbutaline, a beta 2-specific agonist, was not effective as an antidote. Continuous daily ISO did not improve results, whereas continuous i.d. NaCl solution significantly increased skin lesion size and duration. ISO pretreatment significantly decreased subsequent ADM-induced ulceration, while propranolol pretreatment was not different from control. The results confirm a role for beta-adrenergics in the management of experimental ADM skin ulceration and suggest that local toxicity is mediated through specific beta-receptors (possibly beta 1) in the mouse skin.

Animals↗
PubMed1981

Escalating costs for cancer chemotherapy.

The annual costs of chemotherapeutic agents from 1975 to 1980 were determined, and the impact on a hospital's budget of new chemotherapeutic agents marketed during this period was evaluated. Pharmacy purchasing records for the antineoplastics were reviewed retrospectively to determine fiscal year (FY) costs. Statistics from the Consumer Price Index report and hospital patient load were used to project an adjusted annual cost for cancer chemotherapy. The annual expenditures for seven agents marketed in the past five years were expressed as a percentage of the pharmacy's budget. In addition, the oncology clinic records for the past four years were reviewed to assess trends in the number of visits and quantity of drugs prescribed. Analysis indicated that the costs of antineoplastic drugs have risen from $10,156 for FY 1973-1974 to $296,914 for FY 1979-1980. Antineoplastic drug costs have risen from 5.74 to 16.74% of the total drug budget during the same period. Only a portion of the increase in costs could be attributed to increased patient load and inflation. The percentage of patients receiving chemotherapy has reached a plateau, and the quantity of agents being prescribed was not found to be increasing. It was concluded that the rise in cost tends to follow the recent commercial availability of several new antineoplastics, especially doxorubicin. Cancer drug costs will continue to represent a large portion of the total hospital budget in the future and budgets must be planned accordingly.

Ambulatory Care↗
PubMed1980

The limited role of corticosteroids in ameliorating experimental doxorubicin skin toxicity in the mouse.

Local skin necrosis is a serious complication of doxorubicin (Adriamycin) infiltration in man. Intradermal (ID) doxorubicin infection was used in the mouse to create skin lesions, after which a number of local corticosteroid interventions were studied. The most effective local antidote was low-dose (2.5 mg) hydrocortisone (HC), but only against the low-dose doxorubicin challenge (0.05 mg). Other andidotes with lesser effectiveness included dexamethasone-sodium bicarbonate and an intermediate dose of HC (6.25 mg). Larger doses of ID HC did not prevent local doxorubicin toxicity and were inherently toxic to the skin. Systemic corticosteroids were similarly ineffective. The superiority of the low ID HC dose, the ineffectiveness of additions (sodium bicarbonate, topical HC cream), and the resistance of the high-dose doxorubicin ID challenge (0.5 mg) suggests a limited role for corticosteroids in the management of experimental doxorubicin skin toxicity.

Administration, Topical↗
PubMed1980

Experimental model of doxorubicin extravasation in the mouse.

Doxorubicin (Adriamycin), a widely used antitumor agent, can occasionally cause severe and protracted local tissue damage if inadvertently extravasated during intravenous injection. An animal model was developed in adult BALB/c mice to experimentally duplicate such human skin toxicity, Intradermal (ID) doxorubicin injections of 0.5, 0.05 and 0.005 mg (per 0.05 ml) provided reproducible, dose-related skin lesions, quantitated with daily measurement of perpendicular diameters of induration, erythema, and ulceration. Maximal lesions developed rapidly (within 3-5 days) and slowly resolved over 30-40 days. There were dose-related increments in peak toxicity levels, total toxicity, and the duration of damage for each parameter (0.5 > 0.05 > 0.005 mg). Subcutaneous (ie, subpannicular) injections, and ID saline control injections did not cause local skin toxicity. A local intervention with ID hydrocortisone (2.5 mg) substantially reduced erythema and induration, and eliminated ulceration only in animals receiving the lower dose (0.05 mg) doxorubicin challenge (p < 0.05). This direct skin toxicity method is compared to reported animal skin toxicity models, and the intervention results are discussed in reference to current toxicity observations in man.

Animals↗
PubMed1979

Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy.

Two double-blind, crossover trials comparing the antiemetic effectiveness of nabilone, a new synthetic cannabinoid, with that of prochlorperazine were conducted in patients with severe nausea and vomiting associated with anticancer chemotherapy. Of 113 patients evaluated, 90 (80 per cent) responded to nabilone therapy, whereas only 36 (32 per cent) responded to prochlorperazine (P less than 0.001). Complete relief of symptoms was infrequent, occurring only in nine patients (8 per cent) given nabilone. When both drugs were compared, both nausea (P less than 0.01) and vomiting episodes (P less than 0.001) were significantly lower in patients given nabilone. Moreover, patients clearly favored nabilone for continued use (P less than 0.001). Predominant side effects noted by patients were similar for both agents and included somnolence, dry mouth and dizziness but were about twice as frequent and more often severe in patients receiving nabilone. In addition, four patients (3 per cent) taking nabilone had side effects (hallucinations in three, hypotension in one) that required medical attention. Euphoria associated with nabilone was infrequent (16 per cent) and mild.

Adolescent↗
PubMed1979

Inapparent infiltrations associated with vindesine administration.

Vindesine is des-acetyl vinblastine amide sulfate (Eldisine, Eli Lilly and Co), an investigational derivative of the vinca alkaloid, vinblastine. Initial phase I results with vindesine have determined that myelotoxicity is dose-limiting and that, contrary to preclinical studies in animals [1], a neurotoxic potential is indeed present [2]. Another phase I study also observed a rather high incidence of phlebitis (16%) and of cellulitis (10%), however, myelosuppression remained the dose-limiting toxicity [3]. Because good clinical responses have been noted in lymphomas, leukemias [4] and some solid tumors including breast cancer [5], the drug has a potential for wide utility. However, while we have noted several clinical responses with vindesine, injections of the drug have been complicated by serious infiltration with atypically delayed presentation. The purpose of this communication is to briefly describe the incidence and course of these infiltrations.

Adult↗
PubMed1979

Limitations of a portable infusion pump in ambulatory patients receiving continuous infusions of anticancer drugs.

The delivery of continuous iv bleomycin and 5-fluorouracil to nine ambulatory cancer patients was studied using a novel disposable portable infusion pump, the Ar/Med Infusor. Although the chemotherapy was satisfactorily delivered, there were significant mechanical problems, including variable flow rates and substantial drug cartridge failure. Most therapy courses were finished within 10% of the projected termination time. Serious venous complications did not occur. While further exploration of various devices for outpatient continuous iv therapy is recommended, we believe that technical improvements are needed for the Ar/Med Infusor.

Ambulatory Care↗
PubMed1978

The current status of laetrile.

Amygdalin at various concentrations and with numerous impurities is the most common cyanogenic glycoside found in laetrile samples. Its chemical properties were first described in 1837, and pharmacologic studies have shown that ultimately it is broken down to HCN, benzaldehyde, and glucose by enzymes found in gut bacteria but not intracellularly in humans. Fatal and nonfatal toxicities to orally ingested cyanogenic glycosides have been reported worldwide. We review here the signs and symptoms of acute cyanide toxicity and its treatment. Substantial in-vitro and in-vivo testing in animal tumor systems has shown that amygdalin is entirely devoid of significant anticancer activity. Control animals often have lived longer than those treated with various doses and schedules of amygdalin. Acceptable clinical studies in humans are lacking, but such ventures would appear to be contraindicated from animal studies and observed human toxicities. We also discuss current legal-judicial aspects of laetrile therapy for cancer.

Amygdalin↗