H.P. Drobeck

Histologic observation of soft tissue responses to implanted, multifaceted particles and discs of hydroxylapatite

The effects on soft tissue of short- and long-term implants of ceramic hydroxylapatite (durapatite) are reported. In rats, after one week and one, six, and 12 months of subcutaneous implantation of hydroxylapatite in multifaceted particle and disc form, neither particles nor discs had resulted in any microscopically remarkable inflammation. In beagle dogs, after subcutaneous implantation of hydroxylapatite as multifaceted particles and as discs for seven and 24 days, nine months, and two and six years, no implant migration was observed. Encapsulation of particles and discs of increasing thickness was seen throughout the six years of observation. Except for a few isolated macrophages seen within the connective tissue stroma at seven and 24 days, no evidence of inflammation was found. In tissue sections taken at six months from beagle dogs in which multifaceted particles had been placed subperiosteally beneath the gingiva, dense connective tissue was observed adjacent to and surrounding the individual particles. These results show that hydroxylapatite implanted subcutaneously in rats and dogs produces little or no inflammatory response and is compatible with tissue irrespective of the shape of the implant.

The biologic actions of a new series of bis(dichloroacetyl) diamines

Abstract Three members (Win 13,099, Win 17,416, Win 18,446) of a new series of bis(dichloroacetyl) diamines have been studied orally in rats, dogs, and/or monkeys. These data indicate the following points: 1. 1. These compounds proved to be relatively nontoxic substances which exert a specific effect upon the testes of the species studied. 2. 2. This biologic effect on the testes is characterized by arrest of spermatogenesis which is completely reversible within a few weeks after withdrawal of the drug. The Leydig, Sertoli, and spermatogonial cells appear to be normal even under the full influence of these drugs. 3. 3. The mechanism of the action of this phenomenon is not understood at present but should provide a fine tool in the study of the specific biochemical requirements for spermatogenesis.

Inhibition and recovery of spermatogenesis in rats monkeys and dogs medicated with bis(dichloroacetyl)diamines.

Abstract The antispermatogenic activity of three bis(dichloroacetyl)diamines, Win 13,099, Win 18,446, and Win 17,416, was studied in rats, monkeys and/or dogs. The drugs were administered orally and testicular tissue was obtained at various intervals by autopsy or biopsy. The data obtained from these experiments suggest the following conclusions: The three drugs, when given orally to adult male albino rats, monkeys, and dogs, resulted in arrest of spermatogenesis characterized by gradual depletion of the germinal cells of the testes. Full recovery occurred after withdrawal of medication even after antispermatogenic changes had had been in effect for long periods of time and the animals had become histologically azoospermic. The effect of these drugs upon the germinal epithelium was very specific; no other organs were affected. The histologic course of events observed resembled that seen with other agents except for this specificity. The formation of large multinucleated forms containing the nuclei of Golgi and cap-phase spermatids was a prominent characteristic of the inhibitory effects. The authors propose the term fusion bodies to describe these forms, and hope by this report to have resolved the confusion surrounding these forms. Although the antispermatogenic changes were basically similar in the rat, monkey, and dog there were marked differences in the minimal effective dose between the three compounds as well as with the same compound in different species of animals.

An 18-month study of the parasitologic and tumorigenic effects of hycanthone in Schistosoma mansoni-infected and noninfected mice.

A study was undertaken to determine whether single in injections of 12.5 or 50 mg/kg hycanthone (4 and 16 times the recommended human clinical dose) would induce or increase the development of neoplasms in normal mice or in mice infected with Schistosoma mansoni. During the 18-month study, infected mice, shamtreated or treated with hycanthone, developed hepatic granulomas which were distinguished from neoplasms and were characteristic of chronic S. mansoni infection. Fourteen different neoplasms were observed 43 times in 40 (10.3%) of 389 mice examined. The neoplasms were randomly distributed among the experimental groups; all were considered to be spontaneous. Hepatoma was diagnosed only once whereas lymphomas were observed in various organs of 13 mice and adenoma was observed in 12 mice (8 of the 12 cases were in the lungs). Other neoplasms, which in most cases occurred in a single mouse, included a metastatic adenocarcinoma of the stomach, an adenocarcinoma and a squamous cell carcinoma of the mammary gland, a hemangiosarcoma in a lymph node, a reticulosarcoma and a fibrosarcoma. The frequency of neoplasms in either infected or noninfected mice was not significantly altered by treatment with hycanthone. The incidence of S. mansoni granulomas was directly related to the dose of cercariae and inversely related to the relative efficacy of the dose of hycanthone administered. There was no indication that schistosome worms recovered from the effects of the drug to repopulate the mesenteric veins; the percent of dead worms found 21 days and 6, 12 and 18 months postmedication with 12.5 or 50 mg/kg were essentially the same. In ancillary experiments, there was no evidence that the offspring of worms that survived treatment were more resistant to hycanthone than the parent worms.

Long-term study of hydroxylapatite implants in canine alveolar bone

Routine light and fluorescence microscopic examination of hydroxylapatite root implants showed that, in general, bone formed above the original superior surface of the ceramic implant on the lingual crest. In the 40 experimental specimens recovered, 30% also showed new bone completely covering the implant, proceeding from the buccal to the lingual area. Sixty per cent of the specimens that exhibited complete osseous covering were the more posteriorly placed implants from the fourth premolar and the first molar areas. Thirty-three per cent of the specimens exhibited bone formation at or over the superior buccal margin of the implant.

Tissue response in dogs to dense hydroxylapatite implantation in the femur

Six and eight years after the implantation of both granular and solid ceramic hydroxylapatite forms in the femurs of beagle dogs, histologic examination demonstrated that the implants were totally encased in dense mature bone. The endosteal and periosteal surfaces appeared normal, and no resorption of the solid implants was observed. However, at six years, a few granules located at the periosteal surface showed interdigitation of connective tissue stalks, with large multinucleated cells at the interface with the implant. This phenomenon may represent some limited resorptive activity on the surfaces of these few isolated granules. Initially, radiographs showed exaggerated degrees of bone deposition on the endosteal surface under the solid implants (discs), as opposed to a less pronounced endosteal response to the implants of particulate material. In some cases, particularly with the disc implants, cracks were found in the ceramic material six years after implantation. These cracks, on staining, were found to be filled with amorphous material, suggesting an osseous matrix. The results of these long-term studies indicate that such hydroxylapatite implants in bone are highly biocompatible. Bone deposition and maturation on the implant surface resulted in a homogeneous bone/implant interface in which the host tissues appeared to respond to the implant as if it were normal bone.

The pharmacology and toxicology of mepivacaine, a new local anesthetic.

Abstract The local anesthetic activity, toxicity, and irritancy of mepivacaine HCl 1 (1-methyl-2′,6′-pipecoloxylidide hydrochloride) and a solution (solution B) containing 2.0% mepivacaine HCl and 1:20,000 levo-nordefrin (levo-2,4-dihydroxyphenyl-3-hydroxy-2-isopropylamine 2 ) have been studied by various methods. By the intracutaneous wheal test in guinea pigs mepivacaine HCl is 2.5 times more active than procaine HCl. The addition of levo-nordefrin produced a slight increase in the local anesthetic activity of the solution. Solution B was found as active as a solution of 2.0% lidocaine + epinephrine 1:100,000 by the same route of administration ( dilution test ). At the 2.0% concentration level in solutions containing epinephrine 1:100,000 the duration of mepivacaine intradermal anesthesia was approximately 25% longer than that produced by lidocaine. Mepivacaine HCl was found to be as active as cocaine HCl by topical application to the rabbit eye. The topical TAC 5 was 0.18%. At 2, 3, 4, and 8% concentrations, mepivacaine HCl injected intraspinally in rabbits produced anesthesia lasting from 17 to 115 minutes (urethral anesthesia). The degree of intraspinal irritancy appears to be somewhat lower than that of lidocaine. By intravenous injection the following LD 50 values for mepivacaine HCl in mice, rabbits, and guinea pigs were obtained: 32±2, 22±2, and 20±1.4 mg/kg, respectively. Mepivacaine is approximately twice as toxic as procaine HCl and 40% less toxic than lidocaine HCl in mice. The subcutaneous LD 50 values were: 260±22, 110±11, and 94±10 mg/kg for mice, rabbits, and guinea pigs, respectively. Solution B and a 3% solution of mepivacaine HCl without levo-nordefrin (solution A) were well tolerated by monkeys and rats when injected intramuscularly or intravenously in single daily doses eighteen times in 21 days. No significant changes were observed in the body weights, blood counts, urinalyses, or blood pressures of the medicated animals at the end of the medication period. No changes attributable to medication with mepivacaine were observed at the autopsies of the medicated animals. By the trypan blue test the threshold irritant concentration 4 of mepivacaine HCl was 3.3%. That of lidocaine HCl, which was tested in parallel, was 1.9%. Lidocaine HCl is therefore approximately 70% more irritant than mepivacaine HCl. Applied topically on the rabbit eye, mepivacaine HCl and lidocaine HCl were well tolerated in concentrations up to 20%. Solution A and solution B produced a slight, transient inflammatory reaction when injected intramuscularly into rabbits in 1.0-cc doses. No lesions at the injection sites were observed at 7 days after the injection. In summary, mepivacaine HCl, which is 2.5 times more active than procaine HCl is only 25% more irritating and is well tolerated locally as well as systemically on repeated subcutaneous or intramuscular administration.

EFFECTS OF THALIDOMIDE ON FETAL DEVELOPMENT IN RABBITS AND ON ESTABLISHMENT OF PREGNANCY IN MONKEYS.

Abstract Medication with thalidomide (150.0 mg/kg) in pregnant New Zealand white rabbits resulted in a wide range of teratogenic changes in the kits. The most predominant effects were seen in the limbs (arthrogryposis, micromelia, absence of digits). When rhesus monkeys ( Macaca mulatta ) were fed thalidomide in the diet (150.0 mg/kg), interference with establishment of pregnancy occurred. No pregnancies were observed in the five medicated females while two unmedicated controls delivered normal young.

Activity of quinfamide against natural infections of Entamoeba criceti in hamsters: a new potent agent for intestinal amoebiasis

A novel tetrahydroquinolinyl ester, quinfamide, administered orally in multiple doses for 3 days had an ED50 of 0.25 mg/kg/day (total dose 0.75 mg/kg) for eradicating Entamoeba criceti in hamsters in several tests. It was significantly more active by direct comparison than 3 commercially available amoebicides and at least as active as 2 other esters of the parent compound, 1-(dichloroacety)-1,2,3,4-tetrahydro-6-quinolinol. After administration of a single dose, ED50 calculations for quinfamide averaged 0.9 mg/kg. Quinfamide was considerably more active than the other tetrahydroquinolinols, diloxanide furoate and teclozan, and it was approximately 1.5 times more active than etofamide; a statistical significance between the latter 2 drugs could be demonstrated in one of 4 tests. Administered prophylactically, quinfamide was shown to protect hamsters from re-infection with E. criceti. It also inhibited propagation of E. histolytica in vitro at a concentration of 20 microgram/ml. No adverse effects were noted in rodents after a single dose as high as 10 g/kg. Daily administration to monkeys of doses up to 500 mg/kg for as long as 37 days produced no pharmacological aberrations during or after medication; haematological studies and urine analyses were normal and no gross or microscopical tissue changes attributable to quinfamide were observed. No toxicity was revealed following acute (2 g/kg) and chronic (500 mg/kg/day x 31 days) administration of the drug to dogs and rats, respectively.

Inhibition of experimental inflammation by oral toxic agents.

Abstract The effects of oral administration of carbon tetrachloride and mercuric chloride on experimental inflammation were determined in order to define the role of toxicity on inflammation. Cotton granuloma and carrageenin edema in rats were chosen as the procedures for experimental inflammation. Sublethal doses of CCl4 and HgCl2 inhibited experimental inflammation in proportion to the doses administered in both procedures. The degree of inhibition of carrageenin edema by CCl4 nad HgCl2 was similar in adrenalectomized and in intact rats. The results indicate (1) the presence of extraadrenal anti-inflammatory mechanisms following oral administration of toxic agents, and (2) the necessity of obtaining concurrent parameters of toxicity in the assessment of new anti-inflammatory compounds.