Constant Daily Dose Research Articles

An increased initial follicle-stimulating hormone/luteinizing hormone ratio does not affect ovarian responses and the outcomes of in vitro fertilization

The tenet that a combination of human follicle-stimulating hormone (hFSH)/human menopausal gonadotropin (hMG) improves follicular recruitment was assessed by randomly treating ovulatory women either with hFSH/hMG on days 3 and 4 of the cycle followed by two ampules of hMG daily or with a constant daily dose of 2 ampules of hMG. Estradiol (E2) levels on the day of human chorionic gonadotropin (hCG) and the mean number of mature, immature and atretic oocytes per cycle did not differ between the two groups. Likewise, fertilization, cleavage, and pregnancy rates were similar for the two treatments. When daily hormone levels were compared in 11 patients during two successive treatment cycles with both stimulation protocols, the temporal pattern of FSH accumulation was repeated in both cycles, but FSH levels were significantly higher when patients received hFSH/hMG. Nevertheless, during both cycles, E2 reached similar peak levels and the mean number of follicles per cycle on the day of hCG administration was not different. We conclude that routine use of hFSH/hMG does not improve the success of an in vitro fertilization (IVF) program and that higher FSH levels do not change the individuality of ovarian response in the same woman.

Acute Hemodynamic Effects of Piroximone (MDL 19,205) in Patients with Moderate Congestive Heart Failure: Comparison with Sodium Nitroprusside

Piroximone (MDL 19,205), a new imidazolone derivative, was given intravenously to 14 patients with congestive heart failure (NYHA class II-III), while under constant daily doses of digitalis and diuretics. In the first 3 patients, we determined the dose safely eliciting a favorable hemodynamic response. The subsequent 11 patients received 1 mg/kg of piroximone intravenously, and the hemodynamic effects were compared with those of sodium nitroprusside (SN) at a dose-lowering mean blood pressure by 10-20 mm Hg. Piroximone increased heart rate (13.2 +/- 2.0 beats/min, mean +/- SEM) and lowered mean arterial pressure (9 +/- 2.3 mm Hg). Both agents reduced similarly wedge pressure (6.5 +/- 2.9 and 9 +/- 2.9 mm Hg, respectively, for SN and piroximone) and total peripheral resistance. Cardiac index was increased less by SN (15%) than piroximone (48%) (p less than 0.001), and stroke work index significantly enhanced only by piroximone (p less than 0.001). The changes in loading conditions induced by the two agents being similar, it is likely that piroximone not only acts by peripheral vasodilation, but also possesses positive inotropic properties. Myocardial oxygen demand, assessed indirectly by tension-time index, was not affected by piroximone. Thus, piroximone appears to combine well-balanced vasodilator and inotropic properties which make this new agent potentially very useful for the management of congestive heart failure.

Effects of nicotine and d-amphetamine on intracranial self-stimulation in a shuttle box test in rats.

Rats were permitted to turn on and off electrical stimulation of the medial forebrain bundle, by alternating between two photobeams running along opposite walls of a shuttle box. Entry into one beam (the "ON" beam) triggered the delivery of a succession of short, regularly occurring (1 Hz) pulse trains, which could be terminated by breaking the other ("OFF" beam). The two beams were frequently reversed. When this occurred, the rat was given a free period of 10 s in which to reorient, and brain stimulation reward was then assessed by the amount of time spent receiving brain stimulation (SST) within a fixed interval of time. SST increased with increasing current intensity. After training, subjects were tested for 10 consecutive days, alternately with saline and nicotine bitartrate (0.4 mg/kg SC base), and received a constant daily dose of the drug (0.4 mg/kg). Initially, nicotine visibly impaired motor performance for several minutes after injection, which may at least partly explain the observed reduction of SST; both effects waned across successive nicotine tests. Later in each 78 min session, nicotine consistently increased SST over a range of current, and drugged subjects entered the photobeams more frequently even when electrical stimulation was unavailable. d-Amphetamine sulphate (0.25, 0.75 mg/kg SC salt), given 15 min before testing, also increased SST and stimulated responding. The possible effects of motor impairment or activation on SST are discussed, and it is concluded that nicotine and d-amphetamine may have enhanced the rewarding properties of medial forebrain bundle stimulation.

Sequential inhibition of polyamine synthesis. A phase I trial of DFMO (alpha-difluoromethylornithine) and methyl-GAG [methylglyoxal-bis(guanylhydrazone)

Both DFMO and methyl-GAG inhibit sequential enzymatic reactions in the pathway of polyamine biosynthesis. Since polyamines may be important factors in proliferation of cancer cells, we initiated a phase-I study of these agents in patients with advanced cancer. DFMO was given by mouth at a constant daily dose of 4 g/m2 starting on day 1 of the treatment protocol. The dose of methyl-GAG ranged from 200 to 700 mg/m2 administered IV every 2 weeks beginning on day 4. Twenty-two patients were entered into the protocol. Toxic reactions to this therapy were dose-related and included nausea, fatigue, diarrhea, and myelosuppression. One patient with colon cancer experienced a greater than 50% decrease in measurable disease but developed severe myelotoxicity. While DFMO was well tolerated, the combination of drugs appeared to cause substantially more hematologic and gastrointestinal toxicity than encountered during our recent experience with methyl-GAG used alone. We suggest that future studies of this drug combination carefully evaluate levels of polyamines and inhibition of enzymatic activity to minimize toxicity.

Dose-time dependency of tumor formation by chronic UV exposure.

Abstract‐An animal experiment is presented which involved a total of 223 albino hairless mice (Skh hr 1). These mice, excluding 24 of them which served as controls, were divided over 6 groups, each of which received a different but constant daily dose of UV radiation from fluorescent sunlamps (Westinghouse FS40TL12). The range of daily doses encompassed a factor of 33. Data on the response of each group as a whole are presented. The group responses are measured in two ways: (1) the proportion of tumor bearing mice (prevalence), and (2) the average number of tumors per survivor (yield). The data provide information on the variation of the group response with time, daily dose and tumor size.The relationship between the daily dose and the duration of the treatment till 50% of the mice have tumors is given for several sizes of tumors. From these results, and from direct measurements of tumor growth, it appears that the growth of tumors is virtually dose‐independent and, in consequence, only the initiation of tumors is dose‐dependent. This implies that the theoretical model of UV‐tumorigenesis presented by Blum (1959). based on UV‐accelerated growth, is incorrect. It is pointed out that, in similarity to chemo‐ and radiotumorigenesis, the total dose delivered to a mouse for the induction of tumors has to be higher if a high daily dose is used than if a low daily dose is used. It seems as though an animal becomes more resistant to the UV‐stimuius as the rate at which the stimulus is presented is increased: an adaptive phenomenon.

Seasonal variation of serum thyrotropin concentration and thyrotropin response to thyrotropin-releasing hormone in patients with primary hypothyroidism on constant replacement dosage of thyroxine.

Ten patients with primary hypothyroidism (aged 32--66 yr), replaced on constant daily doses of L-T4 (mean +/- SD, 1.90 +/- 0.22 micrograms/kg BW), were used to examine seasonal variations in serum levels of thyroid-related hormones for a period of 14 months. Basal and peak TSH concentrations after TRH (500 micrograms) were higher in winter than in summer. Summer values for basal TSH were all normal (normal range, less than 4.8 microU/ml), while winter values were supranormal in 5 of 10 patients. Summer values for peak TSH were subnormal or normal (normal range, 5.0--40.0 microU/ml), while winter values were supranormal in 3 patients, with the remaining values being normal [log basal TSH, 0.511 +/- 0.438 vs. 0.084 +/- 0.244 (P less than 0.05); log peak TSH, 1.394 +/- 0.410 vs. 1.017 +/- 0.423 (P less than 0.05)]. Serum resin T3 uptake, T4, free T4 index(FT4I), T3, free T3 index, and rT3 levels did not vary seasonally, although T4 and FT4I tended to fall in the winter. The summer and winter QKd interval (the interval from the onset of a QRS complex in the electrocardiogram to the appearance of the Korotkoff sound at diastolic pressure), basal metabolic rate, and serum cholesterol concentrations were all within the normal range. Basal and peak TSH after TRH were inversely correlated with serum T4 and FT4I levels. The basal TSH concentration was further inversely correlated with the seasonally altering ambient temperature. These results indicate that during the treatment of primary hypothyroidism with constant doses of T4, 1) serum TSH and its response to TRH show seasonal variation, 2) the hypersecretion TSH in the winter is related to small changes in serum T4 and FT4I levels, and 3) the seasonal variation in the serum TSH concentration may need to be taken into consideration when evaluating the adequacy of a T4 replacement dose.

Interactive effects or ACTH and growth hormone on adrenocortical hormone secretion

The effects of ACTH and growth hormone (GH) on adrenocortical hormone secretion were studied in a 13-year-old girl with GH and thyrotropin deficiency but normal ACTH function. Cortisol secretion was measured by the sum of the urinary excretions of tetrahydrocortisol(THF), allotetrahydrocortisol(ATHF), and tetrahydrocortisone(THE). Adrenal androgen secretion was measured by the sum of androsterone(A) and etiocholanolone(E). The patient took a constant daily dose of desiccated thyroid(150mg) during 5 successive periods: 3-day control, 3 days of IM ACTH (0.5mg/kg daily), 12-day post-ACTH control, 6 days of IM human GH (3.5mg daily), and 3 days of ACTH + GH at the previous doses. Control excretion of THF + ATHF + THE was 6.0mg/g creatinine and of A+E was 2.9mg/g creatinine; these values confirm normal endogenous ACTH function. Taking these levels as 100, excretion of ccrtisol and androgen metabolites rose to 240 and 190 respectively during ACTH and decreased to 107 and 105 respectively during the last 3 days of the post-ACTH control period. During the GH period, they fell to 66 and 72 respectively. When ACTH was added to GH, they rose to 170 and 103 respectively. Thus GH given alone depressed secretion of both cortisol and adrenal androgens; this could be due to depression of endogenous ACTH secretion or to interference with the effect of ACTH on the adrenal. The data from the combined GH-ACTH period are compatible with either mechanism.

448 INTERACTIVE EFFECTS OF ACTH AND GROWTH HORMONE ON ADRENOCORTICAL HORMONE SECRETION

The effects of ACTH and growth hormone (GH) on adrenocortical hormone secretion were studied in a 13-year-old girl with GH and thyrotropin deficiency but normal ACTH function. Cortisol secretion was measured by the sum of the urinary excretions of tetra-hydrocortisol (THF), allotetrahydrocortisol (ATHF), and tetra-hydrocortisone (THE). Adrenal androgen secretion was measured by the sum of androsterone (A) and etiocholanolone (E). The patient took a constant daily dose of desiccated thyroid (150 mg) during 5 successive periods: 3-day control, 3 days of I.M. ACTH (0.5 mg/kg daily), 12-day post-ACTH control, 6 days of I.M. human GH (3.5 mg daily),and 3 days of ACTH + GH at the previous doses. Control excretion of THF + ATHF + THE was 6.0 mg/g creatinine and of A + E was 2.9 mg/g creatinine; these values confirm normal endogenous ACTH function. Taking these levels as 100, excretion of cortisol and androgen metabolites rose to 240 and 190 respectively during ACTH and decreased to 107 and 105 respectively during the last 3 days of the post-ACTH control period. During the GH period, they fell to 66 and 72 respectively. When ACTH was added to GH, they rose to 170 and 103 respectively. Thus GH given alone depressed secretion of both cortisol and adrenal androgens; this could be due to depression of endogenous ACTH secretion or to interference with the effect of ACTH on the adrenal. The data from the combined GH-ACTH period are compatible with either mechanism.

Effect of naproxen on the steady-state serum concentration and anticoagulant activity of warfarin.

The purpose of this investigation was to determine whether the anti-inflammatory drug naproxen interacts with warfarin during prolonged administration of both drugs. Healthy adults received oral doses of warfarin daily for 26 days. Naproxen, 375 mg twice daily, was given from the eleventh through the twentieth days. Naproxen administration had no apparent effect on the steady-state concentrations of free and total (free and protein-bound) warfarin in serum, despite a small but statistically significant increase of the warfarin-free fraction in serum. There was no apparent difference between the prothrombin times (at a constant daily dose of warfarin) observed before, during, and after administration of naproxen.

Digoxin, whole body potassium and the electrocardiogram.

Previous studies have shown a significant linear relationship between the PTQ-index (a combination function of the PR-interval, corrected QT-time and T-wave depression in the ECG) and serum digoxin level in chronically treated patients. The relationship was confirmed in the present study and it was shown that it could be changed by concomitant administration of potassium chloride or furosemide, and that there was marked interindividual variation in response. An inverse linear relationship between PTQ-index and whole body potassium was found during chronic administration of a constant daily dose of digoxin, but no such relationship was found for serum potassium.

Chronic Methylmercury Exposure in the Monkey (Macaca mulatta)

Small daily doses of methylmercury hydroxide were administered to rhesus monkeys for periods of up to 17 months. Behavioral tests of peripheral vision and of the accuracy and rapidity of hand movements did not disclose any early subtle deficits preceding the onset of obvious signs of neurotoxicity. These signs appeared suddenly and involved reduced food intake (anorexia), clumsiness of jumping, loss of fine control of the digits, and uncoordinated mastication. With a constant daily dose of 0.1 mg/kg or less, blood concentration of mercury reached a peak after about 2 months, and then decreased to about half the peak value. Subsequently, increasing the daily dose level above 0.1 mg/kg (range of 0.12-0.21 mg/kg) produced an increase of blood concentration which tended to stabilize in the range of 2.0-2.5 ppm. After several months at these elevated concentrations all animals exhibited signs of neurotoxicity.

A method for shifting from oral to intramuscular diphenylhydantoin administration.

In the first part of this study patients received constant daily doses of diphenylhydantoin (DPH) during oral, intramuscular, and subsequent oral periods. The data demonstrate that there is a profound fall in plasma DPH levels and urinary 5‐(p‐hydroxyphenyl)‐5‐ phenylhydantoin (HPPH) excretion after intramuscular (IM) administration and that this fall is followed by significant rebound when oral administration is resumed. The second part presents data for a regimen, confirmed by clinical and laboratory findings, for switching from oral to IM dosage and back without dramatic changes in plasma DPH levels or urinary HPPH excretion.

Biochemical and toxicological response of infant baboons to lead driers in paint.

In an effort to define the toxicology and disposition of lead compounds that presently exist in paint (i.e., organic driers), a controlled dose feeding study was initiated early this year with the use of 28 infant baboons as experimental animals. The infant baboon, established as a metabolic model for a child ingesting lead, will be used to determine the adequacy of present as well as recently recommended limitations for lead in paint to assure protection from this potential source of lead exposure. To accomplish this goal, research has been designed to determine basic dose-response relationships in animals ingesting constant daily doses of a dried paint, a lead octoate drier, and lead acetate. Doses for these compounds have been chosen to cover a broad range of concentrations including that recommended by the American Academy of Pediatrics from the maximum daily permissible lead ingestion, and associated estimates of paint intake by children with pica. PARAMETERS OF METABOLIC RESPONSE FOR EACH LEAD COMPOUND, INCLUDE: general clinical surveillance, lead concentrations in blood, urine and feces, erythrocytic delta-aminolevulinic acid dehydratase and free erythrocytic porphyrin. The response of several of these measures of lead exposure as a function of time will be discussed for each compound at the several dose levels administered.

Biochemical and Toxicological Response of Infant Baboons to Lead Driers in Paint

In an effort to define the toxicology and disposition of lead compounds that presently exist in paint (i.e., organic driers), a controlled dose feeding study was initiated early this year with the use of 28 infant baboons as experimental animals. The infant baboon, established as a metabolic model for a child ingesting lead, will be used to determine the adequacy of present as well as recently recommended limitations for lead in paint to assure protection from this potential source of lead exposure.To accomplish this goal, research has been designed to determine basic dose–response relationships in animals ingesting constant daily doses of a dried paint, a lead octoate drier, and lead acetate. Doses for these compounds have been chosen to cover a broad range of concentrations including that recommended by the American Academy of Pediatrics from the maximum daily permissible lead ingestion, and associated estimates of paint intake by children with pica.Parameters of metabolic response for each lead compound, include: general clinical surveillance, lead concentrations in blood, urine and feces, erythrocytic δ-aminolevulinic acid dehydratase and free erythrocytic porphyrin. The response of several of these measures of lead exposure as a function of time will be discussed for each compound at the several dose levels administered.

Plasma diphenylhydantoin levels after loading and maintenance doses.

Sixty‐one patients received 1 gm loading doses of diphenylhydantoin (DPH) followed by constant daily maintenance doses of 300 to 400 mg. Seizure control was obtained rapidly in all patients who responded to DPH. Serial plasma DPH determinations were followed in 7 patients for 4 days and in 8 patients for 50 days. One or more DPH plasma levels were obtained in the remaining 46 patients. Therapeutic DPH plasma levels (7.5 µg per milliliter) were obtained in 14 of 15 patients within 8 to 24 hours following loading dose administration. The 24 hour plasma DPH values were predictive of the long‐term steady‐state DPH plasma levels. Peaking of plasma levels occurred between 48 and 96 hours after loading. However, the few mild signs and symptoms of toxicity occurred within the first 24 hours. In the group of 61 patients, only 1 became grossly intoxicated. Patients tolerated the loading doses well, and therapeutic DPH levels were rapidly achieved with a minimum of undesirable effects.

Effects of phenobarbital on thyroxine and triiodothyronine kinetics in Graves' disease.

ABSTRACT Simultaneous measurements of the peripheral kinetics of thyroxine (T4) and triiodothyronine (T3) were made in hyperthyroid patients before and during the administration of phenobarbital (PB). The following alterations in T4 kinetics were noted during PB: Total clearance increased on the average by 18% (p < 0.05). Fecal T4 clearance, calculated from total clearance and the urinary fraction, increased by 103% (p < 0.01). Serum levels of total and free T4 tended to decline during PB, but the changes were variable in magnitude and not proportional to the increments in total clearance. Total T4 pool size and absolute disposal rate were not significantly altered during PB in the group as a whole. As controls, two hypothyroid patients who were being maintained on constant daily doses of T4 were studied. In both, total and fecal T4 clearance increased and serum T4 declined during PB administration. Hepatic T4 distribution volume rose during PB in 2 of the 3 subjects in whom this measurement was made. In ...

Effect of increasing doses of estrogen and progesterone on mammary carcinogenesis in the rat

Female Sprague-Dawley rats were fed a single dose of 20 mg DMBA at 50 days of age. Fifteen days later, groups of rats received injections in incremental or constant doses of estradiol benzoate or progesterone, alone or in combination, for the next 21 days. This hormone treatment was an attempt to mimic the effect of pregnancy on the appearance of DMBA-induced mammary tumors. The administration of incremental doses of progesterone plus a constant daily dose of estradiol benzoate, or the administration of incremental doses of progesterone alone showed a slight but insignificant stimulation of tumor appearance. Incremental doses of estradiol benzoate, either alone or in conjunction with progesterone, depressed tumor appearance.

Dissociation between thyroxine metabolism and hormonal action in phenobarbital-treated rats.

Phenobarbital injection reduces the biologic effectiveness of thyroxine in thyroidectomized rats maintained on a constant daily dose of hormone. This was inferred from measurements of total body oxygen consumption and the activity of the mitochondrial enzyme alpha-glycerophosphate dehydrogenase in liver, heart and kidney. No changes in these parameters were observed when intact rats were given phenobarbital alone. Thus, the increased hepatocellular binding and deiodination of T4 stimulated by phenobarbital is not related to the biologic action of the hormone. On the contrary, phenobarbital administration reduces the biologic effectiveness of administered thyroxine by diverting hormone from extrahepatic and from specific intrahepatic sites of action. (Endocrinology 88: 115, 1971)

Cyclophosphamide-induced cyclical neutropenia. An animal model of a human periodic disease.

An animal model of a human periodic disease, cyclical neutropenia, was produced in five of nine dogs by administration of a constant daily dose of cyclophosphamide so as to cause mild bone-marrow depression. That this would occur was predicted by a computer model in which granulopoiesis was regarded as being controlled by two feedback loops, one regulating rate of production and the other rate of release of neutrophils. Cyclical neutropenia does not appear to be a specific entity, and its periodicity, and by extension possibly that of other periodic diseases, may be due to the action of feedback control. A hypothetical possibility is that if unrecognized oscillation of blood cell numbers should develop in patients receiving marrow-depressant drugs, estimate of marrow function at any one point of time might give a wrong impression of overall drug effect.

Mammary Growth in Rats Treated with Somatotropin During Pregnancy and/or Lactation.

SummaryGroups of rats Received daily injections of 2 mg somatotropin (STH) from either day 3-19 of pregnancy or day 1-13 of lactation. Another group of rats Received graded increments (0.5-3.0 mg) of STH every 6 days during both pregnancy and lactation, Other groups of rats served as pregnancy and lactation controls. Mammary gland deoxyribonucleic acid (DNA) content was determined in all rats and milk yield was determined in all rats carried to day 14 postpartum. Significant increases in mammary DNA occurred in all rats treated with STH irrespective of dose or schedule of injections when compared to gestation controls. A significant elevation in mammary DNA above the lactation control level was also evident in rats receiving the hormone and carried to day 14 of lactation. Milk yield of rats treated with graded increments of STH was significantly greater than that of control lactators but milk yield of rats receiving a constant daily dose of the hormone did not differ from that of controls.