Large Daily Doses Research Articles

Gonadotropin release as a function of mating and steroid feedback in the female rat

The aim of this investigation was to study possible relationships between mating-induced and steroid-induced luteinizing hormone (LH) release in spayed Long-Evans rats. Large amounts of LH were released approximately 7 hr following progesterone injection in rats primed with estradiol benzoate (EB). The amount of LH release varied widely depending on (1) the interval between the time of the progesterone injection and the EB priming; (2) the progesterone dose; and (3) the time of day when blood samples were collected. These findings provided confirmation of those of Caligaris, Astrada and Taleisnik (1971a). Females, prepared with estrogen-progesterone treatment in a variety of schedules in which the three above-mentioned variables were altered systematically, were allowed to mate with vigorous males. Mating under these various conditions did not significantly increase plasma LH levels even when the females showed high degrees of sexual receptivity. Sodium pentobarbital prevented the afternoon LH rise resulting from progesterone treatment 3 days after EB priming. Pituitary sensitivity to LRF was not enhanced in the afternoon and the mating did not significantly increase plasma LH in these barbiturate-blocked rats. Following administration of 5 large daily doses of EB without progesterone, however, significant increases in LH were produced by mating on the sixth day. Postcopulatory LH release in these circumstances was dependent on a diurnal factor since the effect of mating was greater in the afternoon than in the morning. Thus, although major LH release can be readily induced by mating in estrogen-treated spayed rats, this effect could not be obtained under conditions of progesterone administration to estrogen primed rats.

SINGLE DAILY DOSE OF ANTITHYROID MEDICATION IN ADOLESCENTS WITH HYPERTHYROIDISM

Many adolescent patients with hyperthyroidism fail to take antithyroid medication several times daily and, consequently, remain hyperthyroid. Greer, (NEJM,272:888,65) and Barnes, (JCEM,35:250,72) have reported successful therapy of hyperthyroid adults using a large single daily dose (SDD) of propylthiouracil (PTU) or methimazole (M). We have studied 9 adolescents with hyperthyroidism, 7 initially treated with a SDD of PTU (300mg/m2/24hr) and 2 with a SDD of M(30mg/m2/24hr). Over a 3 month follow-up period, we have monitored several parameters: symptoms of patient; opinion of physician re: thyroid status; weight change; goiter size; WBC, and serum thyroxine(CPB). After 3 months, 5 patients were asymptomatic and 4 patients experienced minimal symptoms. The physician considered 2 patients euthyroid and 7 definitely improved but slightly hyperthyroid. Gain in weight, expressed as mean ±S.E. was 3.0 ± 1.3kg (range:−2.5 to 10.9); P<0.035. Goiter size decreased in 7, remained the same in 1, and increased in 1 patient. At no time did the WBC fall below 4,000/cc in any of the 9 patients. Initial thyroxine level was 21.6 ± 1.7ug%, (range 18.1 to 31.0). Decrease in thyroxine was 10.0 ± 2.2 (range 2.0 to 24.8). Although follow-up has been relatively short, these results suggest that a SDD of antithyroid medication is successful and safe in inducing a remission in adolescents with hyperthyroidism and would enhance compliance.

Subacute and chronic toxicity studies of fluorocarbon propellants in mice, rats and dogs

Six subacute and chronic inhalation toxicity studies were conducted in rats, mice and dogs treated with fluorocarbon propellants. The studies varied in length from 2 weeks to 23 months and the dose of propellant varied from 164 mg/kg/day to 2240 mg/kg/day. The only signs of toxicity observed were sedation, ataxia and mild depression which occurred in the 2 studies in which the propellant doses were the highest. These effects, observed during and immediately after exposure, disappeared rapidly and were attributed to mild anesthetic properties of the fluorocarbon propellants. Abnormal values were not found in the hematologic, blood chemistry or urinalysis values in any of the 6 toxicity studies. Gross and microscopic examination of tissues of the respiratory tract, including lung, did not reveal any evidence of propellant toxicity, irritation or carcinogenicity. In the 3- and 12-month toxicity studies, EKG changes were not observed in dogs which had received large daily doses of the propellants.

Direct luteotropic action of estrogen in the hypophysectomized-hysterectomized rat.

Rats hypophysectomized (Hx) on day 12 of pregnancy had plasma and luteal levels of. progesterone on days 16 and 20 comparable to intact controls. Progesterone levels were also unaffected by fetectomy at day 16 (with placentae left in situ). However, hysterectomy (Hs) at day 12 led to a precipitous decline in progesterone by day 16 and low plateau values were maintained through day 20. The combined effects of Hx and Hs at day 12 were even more drastic in curtailing progesterone synthesis by day 20. Thus, the corpora lutea of the second half of pregnancy were not autonomous, requiring continuous hormonal support for the maintenance of progesterone levels. The effects of Hx and Hs at day 12 were not reversible by prolactin (PRL) or FSH or LH or the combination of these hormones. However, large daily doses of estrone (10 μg) or single or daily doses of estradiol cyclopentylpropionate (25 μg) restored luteal and plasma levels of progesterone to values of intact day 16 pregnant rats. These results in hypophysec...

Luteal maintenance in the hypophysectomized pseudopregnant rabbit: effect of ovine luteinizing hormone and follicle-stimulating hormone.

SUMMARY Ovine luteinizing hormone (LH) (300 μg/day in divided subcutaneous doses) had a luteotrophic effect of limited duration in intact and hypophysectomized 10-day pseudopregnant rabbits (6–10 days in intact animals; 3–6 days in hypophysectomized animals). Higher dose levels caused reovulation in which case luteolysis occurred. Suppression of reovulation with anti-ovine follicle-stimulating hormone (FSH) serum permitted the daily dose of LH to be raised to 750 μg without causing luteolysis or reovulation. Anti-LH serum was luteolytic in the intact animals. A combination of ovine FSH (200 μg) and LH (300 μg) was indistinguishable from LH alone in terms of its luteotrophic effect in hypophysectomized 10-day pseudopregnant rabbits. Ovine FSH at large daily dose levels (1000 μg) was more effectively luteotrophic than LH alone in a significant number of animals for 10 days after hypophysectomy: endometrial changes in these animals resembled those only seen in normal pregnancy. The luteotrophic effect of 1000 μg FSH was believed to be dependent on a small but significant content of LH, estimated to be about 10 μg. Ovine FSH and anti-FSH serum in intact pseudopregnant rabbits had no detectable effect on luteal function. Animals hypophysectomized at the 7th day and treated with 300 or 500 μg LH/day showed no luteal maintenance for 6 days nor was reovulation induced. Sensitivity to the luteotrophic effect of LH was deemed, therefore, to be greater at 10 than at 7 days of pseudopregnancy. Endometrial criteria were found to be reliable indicators of luteal function. The appearance of ciliated cells was correlated with the decline of the corpora lutea. When reovulation occurred, a new progestational cycle was rapidly superimposed on the existing one.

Short-term toxicity of propoxyphene salts in rats and dogs

Two salts of d-propoxyphene, the hydrochloride and the 2-naphthalene sulfonate (napsylate), were compared in short-term toxicity studies. In rats and dogs the effects produced by daily administration of equimolar doses of these salts were indistinguishable. Large daily doses of propoxyphene, representing between 40 and 110 times the maximum human clinical dose, resulted in liver enlargement, slight fatty change in the liver, and reduced growth rate in rats. Signs of developing toxicity in dogs were observed during 90 days of treatment with oral doses of 30–40 mg/kg of propoxyphene HCl or equivalent doses of propoxyphene napsylate. The following effects were dose-related in incidence or degree: loss of body weight, increased serum alkaline phosphatase values, increased liver weight, and slight fatty change in the liver. Lower doses were tolerated by dogs without significant toxicity.

Disturbed patterns of behaviour in morphine tolerant and abstinent rats.

1. Eating, drinking and spontaneous motor activity were studied in rats receiving large daily doses of morphine. These forms of behaviour were largely suppressed when the rats were made abstinent and were restored when morphine was given again.2. Compensation for depressions of behaviour during abstinence did not seem sufficient to account for all the stimulant effects of morphine in tolerant rats. Morphine also had slight stimulant actions in non-tolerant rats.3. In tolerant rats, the repeated pairing of the effects of morphine with the re-emergence of behaviour such as eating and drinking may intensify the rewarding value of the drug.

The oral 100-day LD50 index of phenacetin in guinea pigs

The oral LD50 (100 days) of phenacetin in young, male guinea pigs (the daily intragastric dose which killed 50% of animals over a period of 100 days of administration) was 0.228 ± 0.081 g/kg/day. The oral 100-day LD50 index, or oral LD50 (100 days) expressed as a percentage of the acute, oral LD50 (1 dose), was 8.6 ± 3.1. At the oral LD50 (100 days) there occurred growth inhibition, increase in food and water intake and urinary volume, slowing of the respiratory rate, ataxia, dacryorrhea, loss of weight, some hydration of body tissues, extensive capillary-venous congestion, degenerative changes and infection of certain body organs. Part of the toxicity syndrome at the LD50 (100 days) was similar to that reported for several other chemical agents. Higher daily doses produced signs which approached those at the oral LD50 (1 dose). Compared with corresponding published data on other drugs, the results indicate that the oral 100-day LD50 index could be a useful single relative index of the effects of giving repeated large daily doses of drugs. Since the oral 100-day LD50 index of phenacetin in guinea pigs was lower than that in albino rats, species of animal would appear to be a factor in evaluating the significance of the index.

Skeletal abnormalities in the hindlimbs of young cats as a result of hypervitaminosis A.

HYPERVITAMINOSIS A causes extensive confluent exostosis formation of the cervical spine in adult cats. It was initially reported that no juvenile osteodystrophy occurred in this disease, but an abnormal hindquarter gait was described later in a group of young cats receiving large daily doses of vitamin A (ref. 2). No explanation of this abnormal gait was given and the condition was therefore studied further.

The attenuation by reserpine or guanethidine of the cutaneous vasoconstriction caused by tobacco smoking

The effect of reserpine and guanethidine on the vasoconstriction in the foot induced by smoking 2 cigarettes was studied in normal subjects. Large daily clinical doses of guanethidine or reserpine were given for 2 and 3 weeks, respectively. Blood flow in the foot was measured by venous-occlusion water plethysmography. A pre-drug (control) study was performed on each subject; cigarette smoking produced a significant decrease in blood flow and an increase in vascular resistance in the foot. A statistically significant attenuation of the vasoconstrictor response in the foot to cigarette smoking was found with both drugs, compared to the pre-drug studies. Subjects evidenced a depletion of catecholamines during administration of the agent, by a significant decrease in pulse rate, by postural hypotension, by hypotension after exercise, and by blockade or attenuation of the Valsalva “overshoot.” Since reserpine and guanethidine produced a marked attenuation of the cutaneous vasoconstrictor response to smoking, the conclusion is that cigarette smoking exerts its effects on the circulation in the skin via the sympathetic nerves, and that the release of catecholamines from the adrenal medulla is not important. Patients with peripheral vascular disease who refuse to stop smoking may benefit from the use of catecholamine-depleting agents.

Eradication of Eperythrozoon coccoides with Oxophenarsine in Normal and Drug-Resistant Lines of Plasmodium berghei in Mice

A parent line of Plasmodium berghei and three drug-resistant derivatives inadvertently became mixed with Eperythrozoon coccoides. Oxophenarsine hydrochloride (Mapharsen?) was used to eradicate E. coccoides. The parent line was cleared by repeated passage through mice maintained on 0.05% or 0.1% drug diets or given 10 mg/kg doses of the drug daily by parenteral administration. Examinations several months after 0.05% drug-diet treatment indicated that the plasmodia were not resistant to oxophenarsine. The 0.1% drug-diet treatment also was used in clearing a line highly resistant to cycloguanil hydrochloride. P. berghei lines that were highly resistant to 4,4'-diaminodiphenylsulfone or to chloroquine were cleared by the repeated parenteral administration of 5 mg/kg doses daily. The maintenance of disease agents in mice by serially transferring blood or tissues provides repeated opportunities for the agents to be mixed with such natural organisms of mice as Eperythrozoon coccoides. The type of disease then induced may differ markedly from that produced by the experimental agent alone. Stansly (1965) has reviewed instances of synergism with the agents of mouse hepatitis, lymphocytic choriomeningitis, and lactic dehydrogenase. He also reviewed the independent induction of splenomegaly by E. coccoides, which has greatly complicated studies of neoplastic diseases in mice. A competitive action by E. coccoides has been described with Plasmodium berghei by Kretschmar (1963) and Peters (1965) and with Babesia rodhaini by Peters (1965). E. coccoides was detected recently in several of our P. berghei lines. Both theoretical considerations and practical difficulties emphasized the importance of freeing these parasites of the contaminant. Neoarsphenamine has been used to cure mice of E. coccoides (Bruynoghe and Vassiliadis, 1929; Thurston, 1953). Kretschmar (1963) has described the elimination of E. coccoides from a line of P. berghei in mice by sequential treatment with neoarsphenamine and oxytetracycline. Inasmuch as neoarsphenamine is not readily available in this country, we elected to try the related trivalent arsenical oxophenarsine hydrochloride. This report deReceived for publication 14 March 1966. 674 scribes the successful use of this drug with a parent line and three drug-resistant lines of P. berghei. MATERIALS AND METHODS The 12A strain of Plasmodium berghei and three drug-resistant derivatives used in this work were maintained in female CF-1 mice. All mice were sprayed with a disinfectant (1:300 Kreso Dip?) upon arrival and no lice were ever seen on any of the animals. Infections were passed weekly by inoculating parasitized blood intraperitoneally. In some instances a known inoculum (15 X 106 parasitized cells) was injected but usually from 0.1 to 0.3 ml of whole blood was used, roughly in accordance with the parasite density. The drug-resistant parasites included lines that had been induced, by long periods of partially effective treatment, to grow in mice given large daily doses of the drugs subcutaneously (Thompson et al., 1965a, b). The drugs and maintenance doses were as follows: 4,6diamino1( p-chlorophenyl ) -1,2-dihydro-2,2-dimethyl-s-triazine hydrochloride (cycloguanil HC1), 25 mg/kg; 4,4'-diaminodiphenylsulfone (DDS), 25 mg/kg; and chloroquine diphosphate, 30 mg/kg. Each line was more than 30-fold more resistant to the homologous drug than the parent line. The resistant lines were maintained by serial passage through treated mice (usually five to ten), on a schedule designed to provide daily exposure of the parasites to the drugs. Each passage also included the infection of a side group of five to ten untreated mice. Oxophenarsine hydrochloride (3-amino-4-hydroxyphenyl arsineoxide hydrochloride, Mapharsen?) was given either in a powdered diet ad lib. or parenterally. The first parenteral dose was given subcutaneously, to avoid local effects on the parasites injected during the same day into the periThis content downloaded from 157.55.39.220 on Fri, 02 Sep 2016 05:18:44 UTC All use subject to http://about.jstor.org/terms THOMPSON AND BAYLES-ERADICATION OF EPERYTHROZOON FROM P. BERGHEI MICE 675 toneal cavity; all subsequent doses were given intraperitoneally, to avoid skin lesions at the injection site by high doses. All drug dosages and diet concentrations were expressed in terms of the free base. Parenteral doses were given as aqueous preparations in volumes of 5 to 10 ml/kg of body weight. The effects of treatment were assessed by examining Giemsa-stained blood films. Smears made on the 5th day were used mostly in examining the E. coccoides, and 7th-day smears were routinely used for P. berghei studies.

Further Studies on Inhibitory Effect of Excess Iodide on Thyroidal Hormone Release in the Rat

To determine whether a decrease of thyroidal radioiodine release produced by excess iodide in animals receiving small daily doses of PTU reflects a change in the secretion rate of thyroid hormone, several mechanisms were investigated in the rat. In agreement with the previous study (Yaraada et al., Endocrinology 72: 83, 1963), the present data indicated that thyroidal radioiodine release was inhibited by 50 or 200 μg KI in animals receiving small daily doses of PTU. Excess iodide apparently does inhibit the secretion of thyroid hormone. Furthermore, a decrease of plasma PBI in KI-treated animals was suggested by the measurements of muscle and resin sponge uptake of labeled thyroxine, processes which indicate indirectly the concentration of stable hormone in the blood. The inhibitory effect of excess iodide on thyroid hormone release was completely abolished by prior administration of KC1O4. The blocked thyroid failed to respond to exogenous TSH. In animals receiving large daily doses of PTU or in animals ...

Subacute toxicity of cephaloridine to various species

Cephaloridine, an antibiotic derived from cephalosporin C, was administered parenterally for 5 days to rats (1100 mg/kg/day), for 8 weeks to rats and cats, for 12 weeks to dogs (15, 50, or 150 mg/kg/day) and for 8 weeks to rabbits (15, 30, or 45 mg/kg/day). Large daily doses damaged the kidneys of rats, but less than might have been expected from previous studies of single-dose effects. The nephrotoxic effect of cephaloridine also appeared to be noncumulative in rabbits. The kidneys of rabbits and cats were enlarged, but histologic examination did not present evidence of changes attributable to the antibiotic. Liver weights were increased in rats and cats, but without histologic abnormality. Leukocytopenia occurred in rats and, temporarily, in dogs. Cephaloridine was not toxic to the rabbit fetus, and toxic doses did not impair the fertility or mating ability of buck rabbits.

Relation of the testis to adrenal enzyme activity and adrenal corticosterone production in the rat.

Castration of male rats after puberty results in decreased production of corticosterone by adrenal slices. Replacement with small doses of a depot preparation of testosterone phenylacetate increases adrenal corticosterone production. Large daily doses of testosterone propionate do not change corticosterone production by adrenal glands from castrated rats and decrease production in intact rats. Castration increases adi-enal cholesterol but lowers adrenal glycogen and phosphorylase, phosphodiesterase and 5′-nucleotidase activities. Testosterone replacement restores the activities of these enzymes. Adrenal glucose-6-phosphate dehydrogenase and malic dehydrogenase activities are increased by castration. No changes are obtained in glucose-6- phosphatase, hexokinase, phosphoglucoisomerase, ATP-ase, isocitric dehydrogenase and lactic dehydrogenase. Corticosterone production in vitro by adrenal homogenates from castrated rats is decreased compared to that by homogenates from intact or testosterone-treated castrat...

TOXICITY AND ANTITUMOR EFFECT OF DIVIDED DOSES OF METHOTREXATE.

IT IS generally agreed that single daily doses of folic acid antagonists given by mouth for prolonged periods are usually ineffective in the treatment of solid tumors. 1-5 Since the successful treatment of women with choriocarcinoma by Li et al and Hertz et al 6-9 with large daily oral, intravenous or intramuscular doses of methotrexate, there has been renewed interest in dosage schedules and routes of administration. 10-12 Repeated courses in large oral doses (up to 25 mg for five days), 13 single intravenous injections (2.5-15 mg/kg), 14 or continuous intra-arterial infusions (50 mg/24 hours) 10 produced objective responses in solid tumors more frequently than previously noted. In addition to these clinical observations there has been considerable advance in knowledge of the pharmacology of methotrexate recently. It has been reviewed in detail by several authors. 15-18 It seemed appropriate to us to attempt to apply this new pharmacologic knowledge to

EFFECTS OF PROLACTIN, GROWTH HORMONE AND ACTH, ALONE AND IN COMBINATION, UPON ORGAN WEIGHTS AND ADRENAL FUNCTION IN NORMAL RATS.

Groups of normal rats were injected for 10 days with large daily doses of prolactin (10 mg), growth hormone (10 mg) or ACTH (80 IU), or all 3 combined. Body weight and length were increased by prolactin as well as by growth hormone. The combination of all 3 hormones produced large milkfilled mammary glands and splanchnomegaly of the liver, kidney, heart and spleen. Kidney and heart weights were increased mainly by ACTH injection. ACTH alone increased adrenal weight and the blood corticosterone level 10-fold and reduced the adrenal ascorbic acid level to 100 mg/100 g. Relative to the effects of ACTH given alone, growth hormone and prolactin decreased the effect of ACTH on adrenal weight by 40%, and on blood corticosterone level by 50%. The adrenal ascorbic acid level was reduced to only 200 mg/100 g of adrenal weight in the rats receiving the 3 hormones. Depot fat was greatly reduced by all 3 hormones, while brown fat was increased by ACTH. Thymus weight was reduced by ACTH or combined hormone treatment. P...

The Serum Cholesterol Level and Mucosal Mast Cell Count in the Gastrointestinal Tract of Rats in Dexamethasone‐shock

AbstractRats were injected with large daily doses of dexamethasone for 5 and 8 days, during which they and the control rats which were not given dexainethasone were kept on a fat‐rich and fat‐poor diet. The serum cholesterol was determined and the mast cells in the mucosa of the stomach, duodenum and colon were counted at the end of the test period. The serum cholesterol level rose distinctly in the rats given fat and it was raised significantly further by dexamethasone administration. The elevation of the serum cholesterol level was small in the rats kept on a fat‐poor dirt despite the dexamethasone administered. The mast cells in the mucosa of the glandular stomach, duodenum and colon were degranulated during dexamethasone treatment, most rapidly in the mucosa of the glandular stomach. The diet had no effect on the mucosal mast cells. It is suggested that a fartor activating the clearing factor is mobilised into the organism from the mucosal mast celly in the gastrointestinal tract and that this activating factor is absent after mast cell degranulation. resulting in alimentary cholesterolemia.

IS PREGNANCY DIABETOGENIC?

It has been shown that pregnancy often worsens known increases the insulin requirement in juvenile type and may produce a state of temporary diabetes in women who were previously considered normal. That in these apparently normal women pregnancy has uncovered a latent or prediabetic state is illustrated in a case history. This patient developed a severe diabetic ketosis during her 1st pregnancy. Between pregnancies her glucose tolerance curve was normal but the added stress of 50 mg of cortisone administered twice revealed the latent status. Each subsequent pregnancy reaffirmed her basic diabetic defect. Finally subsequent to a breast abscess she became permanently diabetic requiring a large daily dose of insulin. Vascular disorders of retinopathy and neuropathy have also been observed to start or become worse during pregnancy. An increasing incidence of with increasing parity has been recorded but only with parity over 6 (p = .01). Parity was not related to the incidence or severity of retinopathy. It has been suggested that the prediabetic woman may be more fertile than average. Pregnancy has been shown to cause no lasting diabetogenic effect.

IS PREGNANCY DIABETOGENIC ?

It has been shown that pregnancy often worsens known increases the insulin requirement in juvenile type and may produce a state of temporary diabetes in women who were previously considered normal. That in these apparently normal women pregnancy has uncovered a latent or prediabetic state is illustrated in a case history. This patient developed a severe diabetic ketosis during her 1st pregnancy. Between pregnancies her glucose tolerance curve was normal but the added stress of 50 mg of cortisone administered twice revealed the latent status. Each subsequent pregnancy reaffirmed her basic diabetic defect. Finally subsequent to a breast abscess she became permanently diabetic requiring a large daily dose of insulin. Vascular disorders of retinopathy and neuropathy have also been observed to start or become worse during pregnancy. An increasing incidence of with increasing parity has been recorded but only with parity over 6 (p = .01). Parity was not related to the incidence or severity of retinopathy. It has been suggested that the prediabetic woman may be more fertile than average. Pregnancy has been shown to cause no lasting diabetogenic effect.

OSTEOSCLEROSIS AFTER INTERMITFENT ADMINISTRATION OF LARGE DOSES OF VITAMIN D IN THE RAT

When large daily doses of vitamin D were administered to rats endochondral growth was inhibited and bone resorption occurred; later in the process uncalcified matrix (osteoid) like that seen in rickets formed on trabecular margins. When vitamin D was given only for a short period and then discontinued, little resorption of bone was seen during the withdrawal period and wide seams of osteoid material appeared which eventually calcified in an irregular manner. When normal endochondral growth was resumed a wide transverse band of dense bone with enclosed cartilaginous cores was left in the marrow cavity. If, after a few days, a second large dose of the vitamin was given resorption again occurred and calcification of osteoid material was accelerated, the first microscopic sign being a dense, wide, granular, deeply staining line at the junction of the bone and new osteoid. After a second withdrawal period a second layer of osteoid formed; eventually another transverse band appeared in the metaphysis. If this hypervitaminosis D cycle (+4 -12) was continued rats continued to form new bone with relatively little remodelling, so that after three such cycles bones became dense and hard. Histological study showed that little marrow cavity remained in either skull, vertebrae or epiphyses and a dense mass of bone enclosing cartilage cores filled the metaphysial part of the long bones. In addition, ankylosis ofteeth, calcification of spinal ligaments and widespread metastatic calcification were present. When hypervitaminosis D cycles (+1 -12, +1 -21) were adjusted to produce minimal resorptive changes a wide range of bone change was observed. This varied from uniform dense metaphysial bone containing abnormal cartilage matrix arranged in longitudinal striations, dense transverse bands parallel to the epiphysial cartilage, to remnants of dense trabeculae extending into the marrow cavity. Bone changes in osteopetrosis structurally closely resembled the induced bone changes in the rat. It is concluded that an important mechanism in the production of osteopetrosis is an accentuated rhythm of bone change like that shown experimentally to be produced in these animals. It is emphasised that these changes are but part of a range of bone disorders associated with abnormalities of cycles of resorption and deposition of bone, the type of change differing with the nature of the cycles.