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Biomedical subjects

G H Hottendorf

Publications and source records attributed to G H Hottendorf.

At least 37 records · Page 2Linked to original sources
PubMed1985

Carcinogenicity testing of antitumor agents.

Carcinogenicity testing of antitumor agents in animal bioassays has been proposed because of the potential for carcinogenicity of this class of agents and the expectation that such testing may indicate prospectively the target organs of any related human oncogenesis. The literature reveals the anticipated confirmations in animals of the carcinogenicity of many antitumor agents. Furthermore, these agents have been associated with human tumors in numerous case reports. Review of the literature also indicates the inability of animal studies to predict the sites of carcinogen-induced tumors in man. The carcinogenic risk assessment of antitumor agents should begin with the determination of the ability of the agent to interact with DNA. Those agents which are capable of alkylating or binding DNA should be tested for mutagenic and teratogenic potential. The presumption of carcinogenicity should be made for DNA-reactive, mutagenic/teratogenic antitumor agents without requiring confirmation in long-term carcinogenicity bioassays in large numbers of animals. The inability of carcinogenicity studies in animals to accurately predict potential human tumor sites must also be recognized.

Abnormalities, Drug-Induced↗
PubMed1985

Effect of cephalosporins on organic ion transport in renal membrane vesicles from rat and rabbit kidney cortex.

The effects of cephaloridine and cephalothin on prototypical organic anion (p-aminohippurate, PAH) and cation (N-methylnicotinamide, NMN) transport were observed in brush border and basolateral membrane vesicles prepared from rat and rabbit renal cortex. The cephalosporins interacted with both the cationic and anionic transport systems. Cephalothin inhibited PAH transport in basolateral and brush border membrane in both rats and rabbits. Cephaloridine on the other hand inhibited PAH and NMN transport across rabbit basolateral membranes while it showed a lack of interaction with transport systems in rat basolateral membranes. Conversely, cephaloridine inhibited brush border transport of PAH and NMN in the rat but not in the rabbit. These results provide indirect evidence that cephalothin may be secreted across the renal tubule cell in rats and rabbits while cephaloridine may not accumulate in the rat kidney and becomes trapped in rabbit renal tubule cells. The differences in transport effects observed may explain intra- and interspecies differences in susceptibility to cephalosporin nephrotoxicity.

Alkaline Phosphatase↗
PubMed1985

Inhibition of renal membrane binding and nephrotoxicity of gentamicin by polyasparagine and polyaspartic acid in the rat.

The effect of the polyamino acids, polylysine, polyasparagine and polyaspartic acid, on 3H-gentamicin binding to rat renal brush border membranes was observed. All three polyamino acids showed inhibition of 3H-gentamicin binding at 1X and 0.1X the molar amount of gentamicin. Polylysine, polyasparagine and polyaspartic acid were subsequently tested in vivo for potential nephroprotective activity vs. gentamicin in a 14-day subacute nephrotoxicity model at 3X, 0.5X and 0.3X the molar dose of gentamicin, respectively. While polylysine did not produce significant nephroprotection, polyasparagine and polyaspartic acid completely eliminated gentamicin-induced nephrotoxicity.

Animals↗
PubMed1985

Toxic factors limiting the use of anticancer agents.

Anticancer agents are administered at toxic doses to achieve maximum tumor cell kill. In addition to rapidly proliferating tissues such as bone marrow, the subsequent toxicities may involve the heart, liver, lungs, kidneys and other organs. Exploration of noncytotoxic mechanisms of anticancer activity may provide safer cancer chemotherapy.

Antineoplastic Agents↗
PubMed1984

Evaluation of the bioavailability of sarpicillin, the methoxymethyl ester of hetacillin, in humans.

The relative bioavailability of sarpicillin (the methoxymethyl ester of hetacillin) from three different oral dosage forms was compared in humans employing a three-way crossover study design. Each unit dose contained 250 mg of sarpicillin in terms of anhydrous ampicillin activity. The comparative bioavailability of a tablet containing added buffer, a liquid-filled capsule, and a standard powder-filled capsule was determined. The bioavailability parameters were Cmax, tmax, and AUC of intact plasma sarpicillin levels and saliva ampicillin levels. Significant correlation was found between plasma sarpicillin levels and saliva ampicillin levels following the administration of sarpicillin. All three formulations yielded statistically similar Cmax and AUC values with respect to plasma sarpicillin and saliva ampicillin levels. However, a more rapid absorption of intact sarpicillin was observed with the buffered tablet formulation, as reflected by significantly smaller tmax for both plasma sarpicillin and saliva ampicillin levels. The faster absorption from the tablet formulation gave more precise absorption among subjects.

Adult↗
PubMed1984

The toxicological evaluation of tallysomycin s10b--biosynthetic tallysomycin derivative.

Tallysomycin S10b, a biosynthetic derivative of tallysomycin B, was subjected to intravenous toxicologic studies in mice and dogs. LD50 and LD10 values from lethality studies in mice were utilized to establish dose levels for single and five daily dose toxicity studies in mice and dogs. Nephrotoxicity was the most consistent and prominent drug-related alteration in single and multiple dose studies in both species and was considered the dose limiting toxicity. Other toxicities included pulmonary toxicity, lymphopenia and necrosis of extremities in mice and dogs and testicular degeneration and focal vacuolation of adrenal cortical cells in the dog. Bleomycin was administered to dogs as a reference control agent at a single dose of 270 mg/m2 which was approximately equivalent to the highest tallysomycin S10b dose of 240 mg/m2. Tallysomycin S10b showed a greater nephrotoxic potential than bleomycin at earlier time periods. However, at termination there was no meaningful difference in the degree of chronic nephrotoxicity. The pulmonary toxicity of both drugs was comparable.

Animals↗
PubMed1983

The toxicologic evaluation of marcellomycin--an antineoplastic anthracycline antibiotic.

Dose-related toxicologic effects of marcellomycin, an antineoplastic anthracycline antibiotic, were observed in single-dose studies in mice iv (43.05-67.65 mg/m2) and dogs iv (41.0-90.2 mg/m2), and in multiple-dose studies in dogs iv (9.8-29.6 mg/m2 2X/week for 6 weeks) and rats sc (9 weekly doses at 26.2-72.2 mg/m2). Toxicity was primarily manifested by suppression of myeloid tissue, especially the erythrocytic and thrombocytic series, and lymphoid tissues. Initially a neutrophilic leukocytosis was observed in dogs and rats, which was considered possibly to be due to mobilization of the marginal and bone marrow neutrophil pools. In dogs, this was followed by a marked, dose-related neutropenia; and, in rats that died, there was marked depletion of bone marrow cells. Other toxicities observed included enteropathy, severe subcutaneous serofibrinous inflammatory edema and necrosis at injection sites, prostate and seminal vesicle atrophy, uterine hypoplasia, testicular and pancreatic degeneration, thyroid follicular proliferation and hemorrhage in various organs. In general, these toxicities were reversible in surviving animals during recovery periods. Significant cardiotoxicity was not demonstrated.

Animals↗
PubMed1981

Human pharmacokinetics and disposition of sarmoxicillin, a lipophilic amoxicillin prodrug.

Sarmoxicillin, an amoxicillin prodrug, is the methoxymethyl ester of hetamoxicillin. Esterification converted amoxicillin from an amphoteric to a cationic compound and resulted in a 30- to 600-fold increase in lipid partitioning. Oral absorption studies in normal subjects demonstrated that sarmoxicillin was only partially hydrolyzed by nonenzymatic and gut or hepatic first-pass metabolism and that significant quantities of intact ester appeared in the systemic circulation. Sarmoxicillin was converted to amoxicillin in plasma by hydrolysis of the acetone penicinate and the methoxymethyl ester bonds. Significant amoxicillin levels were demonstrated in saliva after administration of sarmoxicillin, but not amoxicillin, over a 250- to 1,000-mg dose range. Differences in the absorption, distribution, or metabolism of amoxicillin were also evident in the lower plasma amoxicillin maximum concentration and area under the curve and longer half-life after sarmoxicillin administration. Differences in the distribution of this lipophilic ester could result in a significant increase in tissue penetration and subsequent therapeutic efficacy of amoxicillin when administered as sarmoxicillin.

Amoxicillin↗
PubMed1981

Nonparallel nephrotoxicity dose-response curves of aminoglycosides.

Nephrotoxicity comparisons of aminoglycosides in rats, utilizing large multiples of human doses, have indicated an advantage for netilmicin. However, no nephrotoxicity advantage of netilmicin has been demonstrated at the lower doses used in clinics. Some high-dose studies in rats have also suggested that the slope of the nephrotoxicity dose-response curve of netilmicin was less steep than the slopes of other aminoglycosides. Therefore, the slopes of the nephrotoxicity dose-response curves of gentamicin, amikacin, and netilmicin were compared in 200 rats at low multiples (one to five times) of human clinical doses. Histopathological evaluations of both kidneys from each rat revealed that netilmicin produced equivalent or greater nephrotoxicity as compared with gentamicin and amikacin and that the slope of the nephrotoxicity dose-response curve of netilmicin was approximately one-half as steep as the slopes of amikacin and gentamicin, which were parallel. The distribution of casts excreted in the urine after 2 weeks of dosing and the terminal gross observations corroborated the flatter dose-response slope of netilmicin. Nephrotoxicity advantages predicted by high-dose comparisons with netilmicin in rats are apparently a function of its less steep dose-response slope and therefore may have no relevance to lower doses.

Amikacin↗
PubMed1981

Preliminary studies of the pharmacokinetics of talisomycin in the rhesus monkey.

The single dose intravenous pharmacokinetics of talisomycin (3 mg/M2) and bleomycin (18 U/M2) were determined in the rhesus monkey at non-nephrotoxic doses. Serum concentrations were analyzed by radioimmunoassay procedures. The tissue distribution of talisomycin was significantly higher and the elimination slower than bleomycin. The volume of distribution (Vdss) was 2.3 and 22.6 L/M2 for bleomycin and talisomycin, respectively. The volume of the peripheral tissue compartment (V2) of talisomycin was 17 times greater than bleomycin. The slower elimination of talisomycin was reflected by a half-life (t1/2) of 10.6 hr versus 1.6 hr for bleomycin. The slower elimination from the peripheral tissue compartments was also evidenced by a five-fold difference in the tissue transfer ratio (k12/k21) for these compounds. Similar differences, of lesser magnitude, have also been reported in the dog. The potential for higher tissue distribution and slower elimination of talisomycin could be related to the differences in in vivo antitumor activity and toxicity, and should be considered in design of the dose schedule in clinical studies.

Animals↗
PubMed1980

Comparative pharmacokinetics of ceforanide (BL-S786R) and cefazolin in laboratory animals and humans.

Ceforanide (BL-S786R) is a new, broad-spectrum, parenteral cephalosporin. Pharmacokinetic properties were determined in rats (100 mg/kg), rabbits (30 mg/kg), dogs (25 mg/kg), and humans (2 g or 30 mg/kg) and compared with equivalent single doses of cefazolin. Plasma half-lives for ceforanide and cefazolin were 1.1 and 0.5 h in the rat, 5 and 0.3 h in the rabbit, 1 and 0.8 h in the dog, and 2.6 and 2 h in humans, respectively. The slower elimination of ceforanide, as reflected by longer plasma half-life, larger area under the curve, and peak plasma concentrations, was due to slower body and renal clearances. The apparent volumes of distribution of ceforanide and cefazolin were comparable. Rats, dogs, and humans excreted 80 to 100% of the ceforanide dose in the 0- to 24-h urine; rabbits excreted only 50%. Tubular secretion constituted 50% of ceforanide renal excretion in rabbits, dogs, and humans and 90% in rats; the remainder was excreted by glomerular filtration. There was no apparent correlation between the extent of tubular secretion and degree of plasma protein binding in different species. There was no significant pharmacokinetic interaction between ceforanide and amikacin in the rat. The slower elimination kinetics of ceforanide are indicative of the potential for a longer dosing interval and more effective antibiotic therapy as compared with available cephalosporins.

Adult↗
PubMed1980

Comparative low-dose nephrotoxicities of gentamicin, tobramycin, and amikacin.

Most investigations of the comparative nephrotoxicities of aminoglycosides in animals have utilized large multiples of the human dose. Furthermore, many of these assessments have used only one or two dose levels and have not described a dose-response comparison among antibiotics. Because of this lack of comparative dose-response data over a range of low multiples of the human dose, the nephrotoxicities of gentamicin, tobramycin, and amikacin were investigated in 180 rats, utilizing doses ranging from one to seven times the equivalent human clinical doses. Histopathological evaluations of both kidneys from each rat were scored without knowledge of the treatment, and statistical analyses of the results indicated that a linear and parallel dose-response relationship existed for each drug, the relative nephrotoxicity over the range of doses analyzed was gentamicin > tobramycin > amikacin (P = 0.0001), and, unlike amikacin, the human dose equivalents (milligrams per kilogram) of gentamicin and tobramycin were significantly nephrotoxic in rats (P < 0.05).

Amikacin↗
PubMed1980

Bioavailability and metabolism of potassium phosphanilate in laboratory animals and humans.

Phosphanilic acid is an antibacterial agent with a mode of action and antibacterial spectrum similar to those of sulfamethoxazole, with the exception that it has potent antipseudomonal activity. Bioavailability studies in rats (50, 300, and 600 mg/kg, oral and subcutaneous), dogs (50, 150, and 450 mg/kg, oral and intravenous infusion), and humans (400 and 800 mg, oral) showed that the extent of oral absorption of potassium phosphanilate was low. The bioavailability, calculated by comparing the oral values for area under the plasma concentration curve with those for the respective parenteral doses, was 10% for rats and 45 (50 and 150 mg/kg) and 19% (450 mg/kg) for dogs. The 24-h urinary recovery also confirmed the low oral bioavailability, i.e., rat, 13 (oral) and 75% (subcutaneous); dog, 15 to 29 (oral) and 87% (intravenous) of the dose. Plasma levels and urinary recovery (4%, oral) were low and variable in humans. The poor absorption of oral doses may be due to drug precipitation in the stomach, low permeability of the soluble species due to extensive in situ ionization (pK(a), 1.8 to 2) in the intestine, or first-pass metabolism to N-acetylphosphanilic acid. The plasma t((1/2)) values after parenteral administration were 0.3 h in rats and 1.3 h in dogs. Although the lack of adequate blood levels of phosphanilic acid after oral administration in humans precludes the use of this compound for treatment of systemic infections, the sustained urinary concentration at levels severalfold higher than the minimal inhibitory concentration (1 mug/ml) for at least 10 h postdose was indicative of the therapeutic usefulness in urinary tract infections.

Adolescent↗
PubMed1979

Clinical pharmacokinetics and safety of high doses of ceforanide (BL-S786R) and cefazolin.

The pharmacokinetics and safety of ceforanide and cefazolin were compared in normal subjects after 30-min intravenous infusions of 2-, 3-, and 4-g single doses and 4-g twice-daily doses for 10 days. No significant differences were observed in plasma-renal pharmacokinetic parameters between single and multiple doses of ceforanide. Half-life (t((1/2)), 2.8 h), plasma clearance (Cl(p), 48 ml/min per 1.73 m(2)), and renal clearance (Cl(0-12h) (r), 47 ml/min per 1.73 m(2); tubular secretion, 44%, and glomerular filtration, 56%) did not change with increased dose or on multiple dosing. No significant change was observed in t((1/2)) (1.9 h), area under the plasma concentration-time curve, Cl(r) (60 ml/min per 1.73 m(2); tubular secretion, 80%, and glomerular filtration, 20%), or Cl(p) (75 ml/min per 1.73 m(2)) for 4-g single doses compared with twice-daily administration of cefazolin. A small increase in cefazolin clearance was observed when plasma concentrations were greater than 100 mug/ml, when the single dose was increased from 2 to 4 g; this was a result of the decrease in percentage of plasma protein binding and increased renal clearance due to increased glomerular filtration. The increase in renal clearance resulted in a lack of linear proportionality of the plasma area under the curve with dose over a range of 2 to 4 for both cephalosporins, although this effect was much less marked with ceforanide. Both compounds were well tolerated both locally and systemically. There was no evidence of any change in renal function based on clearances of drug, p-aminohippuric acid, or creatinine, and other standard clinical parameters.

Adult↗