Linear Log Dose-response Relationship Research Articles

Standard and high dose chemotherapy for advanced soft tissue sarcomas.

While significant improvements have been made in the management of localized soft tissue sarcomas, enabling the realization of better functional results and a better overall outcome, progress in metastatic disease has been less than impressive. Adriamycin and DTIC based chemotherapy programs have resulted in response rates of upto 50%, with a small but finite cure fraction, especially in conjunction with surgical resection of residual abnormalities. The decade of the 80s experienced a considerable amount of enthusiasm in exploring the role of ifosfamide and mesna, and identified its definite usefulness as an effective salvage regimen with response rates of approximately 25%-30% in adriamycin failures. Studies evaluating the role of ifosfamide as up-front line agent in combination with adriamycin have met with increased toxicities without a significant additive therapeutic benefit, probably as a result of compromised dose intensity of each individual agent. The steep linear log-dose response relationship of alkylating agents and adriamycin constitutes the theoretical rationale for use of higher doses of chemotherapy, which have become feasible, with the advent of growth factors for bone marrow support. While this approach seems promising in its infancy, with improved complete and overall response, its ultimate effect on survival is anxiously awaited. The limited experience available in the literature with even more aggressive approaches like marrow ablative doses of chemotherapy followed by bone marrow transplantation, have been uniformly disappointing, with extremely short lived responses and extremely high morbidity and cost. As clinical research continues to improve our understanding and ability to implement the currently available therapeutic armamentarium, the search for newer and better drugs needs to continue.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-adrenoceptor responses to high doses of inhaled salbutamol in patients with bronchial asthma.

1. Fourteen asthmatics (mean +/- s.e. mean baseline FEV1 62 +/- 6% of predicted) were given cumulative doubling doses of salbutamol by metered-dose inhaler as follows: 100 micrograms, 200 micrograms, 500 micrograms, 1000 micrograms, 2000 micrograms, 4000 micrograms. 2. Airways, tremor, haemodynamic and cyclic AMP responses were measured at each dose increment (made every 20 min). 3. There was a linear log dose-response relationship for each airways parameter (FEV1, VC, sGaw, FEF 50%). The plateau in the dose-response curve was not reached within our dose range. These changes were also mirrored in cyclic AMP responses. 4. There was a wide range in maximum airways response expressed in terms of absolute increase over baseline (95% confidence intervals: delta FEV1 667-1483 ml; delta VC 689-1695 ml; delta sGaw 0.92-4.50 s-1 kPa-1; delta FEF 50% 0.94-2.15 l s-1). Patients with a lower baseline showed a greater response in terms of percent increase in FEV1 (r = -0.83, P less than 0.001). There was however, no correlation between baseline airway calibre and the dose required for maximum bronchodilatation. 5. There were objective increases (mean +/- s.e. mean) in both heart rate (maximum delta HR of 14 +/- 5 beats min-1 at 4000 micrograms) and tremor power (maximum delta Tr of 115 +/- 44% at 2000 micrograms). These were not dose limiting side-effects as subjective symptoms were infrequent at higher doses. 6. Higher than conventional doses of salbutamol given by metered-dose inhaler may produce a distinct improvement in airways response without significant side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Prothoracicotropic hormone bioassay:Bombyxlarva assay

Summary An assay for the prothoracicotropic hormone (PTTH) has been established using in situ activation of the prothoracic glands (PG) of Bombyx mori in its larva-to-larva development. The timing of PTTH release was estimated by examining developmental response of 4th instar larvae to brain removal and neck ligation, and changes in the haemolymph ecdysteroid titer and ecdysone-releasing activity of PG in vitro during the development. Injection of Bombyx brain extracts into 4th instar larvae neck-ligated shortly before full activation of PG elicited larval moulting rather than precocious pupation in headless larvae. This developmental shift was regarded as due to the action of PTTH, and the PTTH unit has been defined from a linear log dose-response relationship. Materials chromatographically fractionated from Bombyx brain extracts were examined for the presence of stage- and species-specific PTTH molecules by using this Bombyx larva assay and Bombyx and Samia pupa assays previously developed. The same fra...

T Wave Amplitude as a Quantitative Index of Regional Myocardial Sympathetic Responsiveness

Alterations in T wave morphology have been quantitated in seven open chest anesthetized dogs by simultaneous recording of electrograms from 10 epicardial sites across the anterior left ventricular wall under basal conditions, following left sympathetic stimulation (LSS) at 2, 4, 8, 12, and 16 Hz and during noradrenaline infusions (NAI) of 0.125, 0.25, 0.50, and 1.0 micrograms/kg/min. Overdrive atrial pacing at 175 beats/min was employed and rate of rise of left ventricular pressure (dP/dt) monitored. Linear log dose-response relationships were found between both peak T amplitude and left ventricular dP/dt for NAI between 0.125 and 0.50 micrograms/kg/min (peak T wave amplitude 4.0 +/- 0.9 to 1.4 +/- 0.7 mV). Following LSS, T wave amplitude responses were highly variable both between animals and between electrode sites in individual studies. A linear log dose-response relationship was found at stimulation frequencies between 8 and 16 Hz (T amplitude 3.9 +/- 1.4 to 1.8 +/- 1.2 mV). Changes in QT interval were minor and inconsistent. It is concluded that changes in peak T wave amplitude may provide a useful index of regional myocardial sympathetic responsiveness following NAI, but are more variable following LSS.

Foot-and-mouth disease vaccination: a multifactorial study of the influence of antigen dose and potentially competitive immunogens on the response of cattle of different ages

Groups of 68 and 66 cattle aged 12 and 24 months respectively were each subdivided into 16 groups and inoculated with foot-and-mouth disease vaccines containing O1 Campos, A24 Cruzeiro and C3 Pando virus strains. The 140S antigen mass of the O1 and A24 valencies was varied while that of C3 was held constant. Multifactorial comparisons between the 21 day serum neutralising antibody titres showed that over most of the range there was a linear log dose response relationship. Doubling the antigen dose increased the serum antibody titres against both A24 Cruzeiro and O1 Campos by approximately 0.15 log10. The A24 antigen was about 30 times more immunogenic than the O1 with C3 intermediate between the two. At high antigen doses the responses flattened but the level at which this occurred depended on the immunogen administered. No difference could be demonstrated between the responses of 12- and 24-month-old cattle and there was no evidence of competitive inhibition or enhancement between the virus strains included in the vaccines.

SHORT-TERM REGULATION OF LH AND FSH SECRETION IN CYCLIC WOMEN

ABSTRACT The effects of two consecutive LH-RH injections at 120 min intervals with either a varying first or second LH-RH dose on pituitary gonadotrophin response were investigated in 15 eugonadal women to study pituitary secretory processes. Each volunteer underwent a total of 4 LH-RH double stimulation tests. In group I (n = 8) the first LH-RH dose of each of the 4 tests was fixed at 25 μg, whereas the second LH-RH dose consisted of either 6, 25, 100 or 400 μg. In group II (n= 7) the first LH-RH dose varied between 6 and 400 μg, while the second LH-RH dose was kept constant at 25 μg. Serum gonadotrophin and serum ovarian steroid levels were determined by radioimmunoassay before and after LH-RH administration. The volunteers in both groups served as their own controls. A linear log-dose response relationship was found between the various doses of LH-RH injected and the corresponding LH and FSH elevations elicited. However, the dose of the first LH-RH injection also significantly influenced the gonadotrophin reaction after the second LH-RH injection in a linear log-dose response relationship. Serum levels of oestradiol, 17-hydroxyprogesterone and progesterone significantly increased in response to the elevated serum gonadotrophin levels after LH-RH stimulation during the 4 h test period, but the rise did not correlate to the LH-RH dose used. The results indicate that LH-releasing hormone stimulates not only the release, but also the synthesis of LH and FSH in a dose-related manner. These findings are consistent with our previously reported concept that the magnitude of LH and FSH response to the first LH-RH injection reflects the "storage capacity", while the increase observed after the second LH-RH injection represents the "synthesis capacity" of the gonadotrophs.

A Superfusion System Technique for the Study of the Sites of Action of Glucocorticoids in the Rat Hypothalamus- Pituitary-Adrenal Systemin Vitro. I. Pituitary Cell Superfusion

Rat anterior pituitary cells were placed in a superfusion column and were stimulated by rat hypothalamic extract. The rate of ACTH secretion was monitored by collecting fractions eluting from the column every 2 min. Dispersed rat adrenocortical cells were used to determine the amounts of ACTH in the superfusate. ACTH appeared in the medium 6-12 sec after stimulation of the cells. A linear log dose-response relationship existed between 1/8 to 1 rat hypothalamus extract and the amounts of ACTH released. Repeated pulses of CRF stimulation of the same column of pituitary cells resulted in repeated, identical peaks of ACTH. Constant stimulation caused a plateau in hormone release that lasted as long as the stimulus was present. The stimulated, but not the basal ACTH release, could be inhibited by superfusion with corticosterone in vitro (0.2 mug/ml), or by treating the pituitary donor animal in vivo with corticosterone (5 mg/100g BW), cortisol or dexamethasone. Adrenalectomy of the donor animal caused increases in the basal and the stimulated ACTH release.

Relative Activities of Some Metabolites and Analogs of Cholecalciferol in Stimulation of Tibia Ash Weight in Chicks Otherwise Deprived of Vitamin D

Nine metabolites and analogs of cholecalciferol (CC) were tested for ability to increase tibia ash weight in chicks otherwise deprived of vitamin D. All of the compounds promoted bone mineralization in a linear log dose-response relationship. The maximal response obtained for any compound was an approximate doubling in bone ash weight compared to vehicle-treated controls. Relative potencies, based upon the calculated ash weight doubling dose, were as follows: 1 alpha, 25-(OH)2-CC = 1 alpha-OH-CC greater than CC greater than 25-OH-CC greater than 24R, 25-(OH)2-CC = 1 alpha,24R, 25-(OH)3- CC greater than 5,6-trans-25-OH-CC greater than 1 alpha, 24S, 25- (OH)3-CC greater than 5,6-trans-CC greater than 24S, 25-(OH)2-CC.

The stimulation of corticosteroidogenesis in the interrenal of the elasmobranch Dasyatis sabina by mammalian ACTH

1. The interrenal tissue of Dasyatis sabina responded in vitro to the presence of mammalian ACTH by an increased release of steroid. 2. The steroid released in response to stimulation by mammalian ACTH had the mobility of l α-OH-corticosterone which is the normal product of the elasmobranch interrenal in vivo or when stimulated in vitro by elasmobranch pituitary homogenates. 3. The response of the elasmobranch interrenal to mammalian ACTH is dose dependent with a linear log dose-response relationship.

Induction of luteinizing hormone (LH) release and ovulation in rats, hamsters, and rabbits by synthetic luteinizing hormone-releasing factor (LRF).

The efficacy of synthetic LRF in inducing LH release in the estrogen progesteroneblocked, chronically ovariectomized rat and ovulation in the cycling rat, hamster, and rabbit was established. Synthetic LRF was highly effective by various modes of administration, but there were differences in the time course and magnitude of the LH release response depending on the route, and differences in the quantity of LRF required to induce ovulation depending on the species. Following the intracarotid injection of LRF, serum LH peaked at 10 min and a linear log dose—response relationship was obtained over the range of 1 to 5O ng per rat. After the oral administration of 1 mg of LRF, serum LH concentrations were increased to a maximum (27– fold) by 30 min, then steadily declined, reaching basal levels by 90 min. A sustained effect of LRF (10 or 100 μg/rat) on LH secretion was noted following intravaginal dosing using a repository vehicle; serum LH was significantly increased by 10 min, maximal at 30 min, and remained elevated for at least an additional 90 min. LRF, given sc in μg quantities or orally in mg amounts, induced ovulation in chlorpromazine (CPZ)—blocked proestrous rats. The lowest sc dose of LRF yielding 100% ovulation (MED100) in the CPZ—blocked proestrous rat was 1 μg (3.7 μg/kg body wt) whereas in the phenobarbital—blocked proestrus hamster the MED100 was 0.01 μg (0.11 μg/kg body wt). In estrous rabbits, an iv dose of 2.5 μg of LRF (0.88 μg/kg body wt) was the MED100 for induction of ovulation, a value intermediate to that of the rat and hamster. The administration of pharmacological doses (1000 times or more the MED100) to cycling rats, hamsters, or rabbits at a time coincident with the endogenous surge of ovulating hormone failed to induce superovulation. These results demonstrate that synthetic LRF is highly efficacious by several routes of administration in stimulating LH release and ovulation in three rodent species. (Endocrinology92: 1515, 1973)

Dose-response relationship of luteinizing hormone to luteinizing hormone--releasing hormone in man.

In previous clinical studies with highly purified porcine luteinizing hormone-releasing hormone (LH-RH), administration of the somewhat arbitrarily chosen doses of 700-1500 mug resulted in increased serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The present study determined the minimum effective dose as well as the relationship of the response of serum LH and FSH to the dose of LH-RH administered. Three normal men received i.v. injections of 1.1-810 mug of LH-RH. A dose of 10 mug of LH-RH caused a statistically significant elevation in serum LH. 30 mug of LH-RH significantly increased serum FSH levels. A highly significant linear trend was observed in the log dose-response curve. The results indicate that both LH and FSH release occurs in man with doses of LH-RH much lower than previously used and that a linear log dose-response relationship can be obtained.

Physiological evidence for 'short-loop' feedback effects of ACTH on hypothalamic CRF.

Hypothalamic CRF activity in male rats has been measured by an improved pituitary incubation method. A linear log dose-response relationship was obtained between the amount of hypothalamic extract added to the incubation medium and the plasma corticosterone levels of hypophysectomized ACTH assay rats, following injection of the incubation medium. The hypothalamic CRF activity in long-term hypophysectomized rats (1–6 weeks) was 3 to 4 times greater than that found in extracts from intact rats. Hypophysectomy of shorter duration (2–4 days) did not result in a significant change in hypothalamic CRF activity. The CRF activity of extracts of hypothalami from chronically adrenalectomized rats (3–6 weeks) was half of that found in extracts from sham-adrenalectomized controls. Adrenalectomy of shorter duration (1 week) did not result in a significant change in hypothalamic CRF activity. The elevated hypothalamic CRF levels seen in hypophysectomized rats was not altered by subsequent adrenalectomy. Injection of ACTH into hypophysectomized-adrenalectomized rats reduced hypothalamic CRF content to 1/8 the levels found in hypophysectomized-adrenalectomized controls. These results suggest a direct action of ACTH on the hypothalamus, and provide evidence for a ‘short-loop’ feedback system between ACTH and CRF. These findings do not rule out the possibility that adrenal steroids, as well as other factors, may influence the rate of synthesis and/or release of CRF, but they do indicate that circulating ACTH levels may play a significant role in this regulation.

Existence of a linear log dose response in the bioassay for a hypothalamic somatotrophin stimulating factor as based on rat pituitary somatotrophin content.

A linear log-dose response relationship was found in a 6-point assay between crude, rat stalk-medianeminence (SME) acid (0.1N HC1) extracts and in vivo pituitary STH depletion as based on the tibia test. Pressor and antidiuretic activities of these extracts were abolished by treating extracts with sodium thioglycollate. Precision index of this assay was 0.087 ±0.15 and it showed a parallelism between a 3-point tibial response to a highly purified growth hormone (NIH-GH-B-12). The results indicate that, in vivo, somatotrophin stimulating factor (SSF) assay using rat SME treated with thioglycollate is a valid base for conclusions regarding the significance of SSF or activity thereof, in physiological experiments.

On the significance of serum dilution and cortisol antagonism in the rat fat pad bioassay of insulin.

ABSTRACT The dilution effect of normal human serum was readily detectable at small dilutions (1:3, 1:4) and was present to about the same extent both in males and females. It was found to be significantly greater in elderly as compared to younger subjects. Adrenalectomized rats had a significantly lower SILA level in undiluted serum than normal rats. Alloxan diabetic rats had a SILA level in undiluted serum, of about one third of the SILA level in normal rats. In contrast to normal human serum, any dilution effect of normal rat serum was detectable only at very high dilutions (1:27). The same pattern was found when serum from adrenalectomized and alloxan diabetic rats were assayed. The dilution effect in human serum is considered to be due mainly to a species difference. The smallest concentration of cortisol which produced a significant suppression of glucose utilization (as measured on the 14CO2 production from Glucose-1-14C) by rat epididymal fat pads in vitro, in the absence of insulin, was of the order of 0.0025 μg per ml (7 × 10−9 m). A linear log dose-response relationship was found between 0.0025 and 0.25 μg per ml and thus was well within the physiological range. Physiological concentrations of cortisol significantly suppressed the effect of submaximal concentrations of insulin on the 14CO2 production from Glucose-1-14C by the epididymal adipose tissue. A maximal insulin concentration abolished this cortisol effect. However, an extremely high concentration of cortisol (25 μg per ml) still inhibited the effect of 10 U insulin per ml to a slight extent. Addition of puromycin (5 × 10−5 m) abolished the suppressive effect of a physiological concentration of cortisol on insulin stimulated 14CO2 formation from Glucose-1-14C. The mechanism of the observed antagonism between insulin and cortisol at physiological concentrations is assumed to be of the competitive type mediated not by cortisol itself, but by a protein, the formation of which is induced by the action of cortisol.

Effect of pretreatment with androgen in the neonatal rat on LH-induced ovarian cholesterol depletion.

ConclusionsAndrogen sterilization results in the elimination of the multiphasic dose-response curve obtained with the OCD bio-assay for LH. The dose-response curve in the androgenized animals is highly reproducible, but the sensitivity of the assay is considerably reduced. The abolition of the multiphasic curve by androgen treatment suggests that endogenous LH release is responsible for the multiphasic type of response in the non-androgenized rat. A linear log dose-response relationship for LH is obtained between 0.0625 μg and 0.25 μg using a 5-hour assay time interval, and between 0.25 μg and 1.0 μg using a 7-hour assay time interval. This response is reproducible and is specific for LH.

THE IN VITRO EFFECT OF PROLACTIN ON β-GLUCURONIDASE IN THE TESTIS OF THE RAT

SUMMARY The effect of prolactin on the activity of β-glucuronidase in the testis of the rat and mouse has been studied in vitro. Prolactin increased this activity, and a linear log dose-response relationship was found to exist with doses of between 0·3 and 1·2 mg. of a preparation of prolactin containing between 20 and 25 i.u./mg. The optimal conditions for this effect have been investigated. Twenty other substances have been tested; none increased the enzymic activity, but six decreased it. Possible mechanisms for this effect are discussed.

Granuloma pouch anti-inflammatory assay: some remarks on calculation and statistical analysis of results.

ABSTRACT A statistical analysis is made of the granuloma pouch assay in the rat as a quantitative method for estimating the anti-inflammatory activity of different materials. The problems of calculating the best unbiased mean and estimates of standard error and degrees of freedom on replicate experiments are studied. Use is made of established criteria for deciding whether the means to be combined are, or are not, of the same precision, and the course to follow in each case. Emphasis is laid on the verification of the hypothesis of non-linearity between response and logarithm of dose of materials (steroids) administered. Estimating equations as well as characteristic statistical parameters are presented for all steroids tested. Results of this analysis indicate that there is a linear logdose-response relationship and that the slopes of the estimating equations for all steroids assayed do not differ significantly from that for the standard. The symbol XY50 is defined to signify the calculated dose causing 50 per cent effect in a graded response assay in which the range of response has been by arithmetic conversion arbitrarily established from 0 to 100. The reliability of obtaining estimates of relative potency as ratios of different XY50 is demonstrated theoretically and illustrated experimentally.