Escape Phenomenon Research Articles

The pure antiandrogen RU 23908 (Anandron), a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review.

The nonsteroidal antiandrogen RU 23908 ( Anandron ) weakly interacts with the prostatic cytosolic androgen receptor and shows a fast dissociation rate. When administered to immature castrated rats up to the daily dose of 100 mg/kg, it is devoid of any androgenic activity but efficiently blocks the growth-promoting activity of androgens on ventral prostate and seminal vesicle weight, thus showing the characteristics of a pure antiandrogen. In intact animals, on the other hand, the antiandrogen administered alone exerts only a partial inhibition of prostate and seminal vesicle weight. This is due to the property of the pure antiandrogen to neutralize the inhibitory feedback effect of androgens at the pituitary level on the LH responsiveness to LHRH, as illustrated in vitro in rat anterior pituitary cells in culture as well as in vivo in intact and castrated animals. In intact animals, neutralization of the inhibitory feedback action of endogenous androgens leads to an increased LH and testosterone secretion, which partly overcomes the direct action of the antiandrogen at the level of the prostate and seminal vesicles. In fact, the plasma testosterone concentration is more than doubled 6 hr after the administration of 10 mg of RU 23908 while plasma LH and testosterone levels are increased by 7- and 17-fold, respectively, after 14 days of similar daily treatment. Efficient neutralization of the androgenic action at the prostatic level in intact animals thus requires prevention of this escape phenomenon through inhibition of LH secretion. Although inhibition of LH release can be achieved by estrogen and progestins, an optimal inhibitory effect on the prostate is obtained by the combined administration of the antiandrogen with an LHRH agonist that causes a specific blockage of testicular androgen biosynthesis as well as an inhibition of the LH responsiveness to LHRH.

Tetracycline treatment of periodontal disease in the beagle dog.

Bone‐seeking radio pharmaceutical uptake (BSRU) was used to examine alveolar bone metabolism in a longitudinal study of tetracyclinc efficacy ID beagle dogs. BSRU was measured in untreated control dogs and in beagles receiving either 250 mg or 500 mg oral tetracycline‐HCI daily for 16 months. The rate of boneless was determined from radiographs taken semiannual!)’for a 6‐month pretremment period and for a 24‐month treatment period. Measurements of BSRU obtained ai month 16 of treatment were correlated with rates of bone loss determined radiographically in an attempt to determine whether BSRU was indicative of the subsequent rate of boneless. A reduced rate of alveolar bone loss was found in the 500 mg tetracycline group at month 16 of the study relative to the untreated controls which was consistent with the decreased bone‐seeking radio pharmaceutical uptake observed in this group. A significantly increased BSRU (p < .0001) was found in the 250 mg tetracycline group at month 16 of study relative to the untreated and 500 mg tetracycline groups. A rapid increase in the rale of bone loss in the 250 mg tetracycline group which was not detectable prior to 16 months of treatment became evident radiographically by 24 months. Thus, increased BSRU in the 250 mg teiracyclinc group appeared to detect the loss of the effect of telracycline on reducing the rate of alveolar bone resorplion in these beagles several months prior to radiographic evidence of the loss of the effect of tetracycline (escape phenomenon).

Mineralocorticoid escape in man: role of renal prostaglandins.

The role of renal prostaglandins (PGE2 and PGF2 alpha) and kallikrein in the renal escape from excess mineralocorticoid has been evaluated in 10 normal volunteers on a high sodium diet. Escape from 9-alpha-fluorohydrocortisone (9-alpha-FF) administered for 12 days (0.6 mg daily) occurred within 4-5 days when 345 +/- 50 mmol sodium had accumulated. Indomethacin, a cyclooxygenase inhibitor, was then administered for 3 days while maintaining 9-alpha-FF. This was followed by a further cumulative gain of 105 +/- 28 mmol sodium after which escape resumed. Potassium balance remained negative throughout the study. Both PGE2 and PGF2 alpha excretion increased significantly under 9-alpha-FF from respective control values of 220 +/- 50 and 818 +/- 86 ng/24 h. to 610 +/- 317 and 1213 +/- 132 ng/24 h at the time of escape. Concomitantly urinary kallikrein increased from 1.1 +/- 0.2 to 2.5 +/- 0.3 units/24 h. Creatinine clearance increased from a mean baseline value of 111 +/- 4 to 123 +/- 4 ml/min during the same period. Indomethacin produced an inhibition of prostaglandin excretion without significant alteration of kallikrein excretion. Overall these results and particularly the transient sodium retention induced by indomethacin at the time of mineralocorticoid escape, suggest that prostaglandins may contribute to the escape phenomenon, whereas the role of kallikrein does not appear to be determinant.

The label escape error: Determination of the active bone-forming surface in histologic sections of bone measured by tetracycline double labels

Twenty healthy female beagles, all postbreeding age, were given two bone-labeling agents. Transilial bone biopsies were obtained and embedded undecalcified. Double-labeled, single-labeled, and unlabeled surfaces were determined along with the interlabel width on unstained sections under fluorescent light. Mean osteon thickness was determined on toluidine bluestained sections. A mathematical model for predicting the amount of singly labeled surface was tested and compared to the amount of surface actually found occupied by single labels of either color. We found that the model accurately predicted the amount of singly labeled surface and that the amount of singly labeled surface labeled by one agent was equal to that labeled by the other ( r = 0.977, P < .001). We conclude that singly labeled surfaces in these animals were so labeled because bone formation either began or ended in the interval between administration of the two labels and that the proposed model accurately predicts this quantity of singly labeled surface without the need to measure any singly labeled surface. This label escape phenomenon must be taken into account when measuring bone formation rates by tetracycline labeling, and the model should be used whenever it is suspected that single labels appear that are not due to label escape.

Combined long-term treatment with an LHRH agonist and a pure antiandrogen blocks androgenic influence in the rat.

Daily administration for 5 months of the potent LHRH agonist (D-Ser(TBU)6, des-Gly-NH2(10)) LHRH ethylamide (250 ng) in combination with the pure antiandrogen RU23908 (5 mg) to adult male rats causes a marked inhibition of ventral prostate and seminal vesicle weight to 9% and 15% of control, respectively. At the doses used, owing to readjustments of the pituitary-testicular axis, neither treatment alone has an effect on prostate weight and exerts only minimal inhibitory effects on seminal vesicle weight. Whereas treatment with the LHRH agonist alone markedly inhibits testicular LH and PRL receptor levels, the antiandrogen alone stimulates the concentration of the two receptors and reverses the inhibitory effect of the LHRH agonist treatment on LH receptors. Treatment with the LHRH agonist decreases plasma PRL levels, whereas the antiandrogen increases the concentration of circulating LH and FSH by 250%. Treatment with the LHRH agonist decreases the concentration of testosterone and its precursors of the delta 4-pathway while stimulating 5 alpha-reductase activity in both the absence and presence of simultaneous treatment with the antiandrogen. The present data show that blockage of the delta 4-steroidogenic pathway induced by treatment with an LHRH agonist prevents the escape phenomenon observed during long-term treatment with a pure antiandrogen, and permits maximal inhibitory effects of the two treatments on secondary sex organ weight. Such combined treatment with an LHRH agonist (to block androgen formation) and an antiandrogen (to neutralize remaining androgens of testicular and adrenal origin) should be the hormonal therapy of choice in prostatic carcinoma.

Early effects of cervical sympathetic stimulation on cerebral, ocular and cochlear blood flow.

Autoregulatory mechanisms may be expected to modify effects of vasomotor nerve stimulation in many tissues. Attempts were made to reveal a distinct early, but transient effect of cervical sympathetic stimulation on cerebral, retinal and cochlear blood flow. The labelled microsphere method was used to determine regional blood flow during electrical stimulation of the cervical sympathetic chain for 15-25 s and 5 min. At a frequency of 6 Hz there was 5% reduction in cerebral flow at 15-25 s and 7% at 5 min. In the choroid plexus the mean reduction was 22% at 15-25 s but decreased 10% after 5 min. In the cerebellum, optic nerve and retina, sympathetic stimulation had no appreciable effect on the blood flow. In the cochlea and iris, the blood flow reductions were 25 and 32%, respectively, on both occasions. In the choroid, vasoconstriction increased with time, whereas in the masseter muscle there was a decrease. Thus in the present experiments no indication was found of an autoregulatory escape phenomenon in the brain, the eye or the cochlea. Some escape was noted in the masseter muscle.

Is there an active mechanism limiting the influence of the sympathetic system on the cerebral vascular bed? Evidence for vasomotor escape from sympathetic stimulation in the rabbit

The influence of the cervical sympathetic chain on cerebral circulation in the rabbit was studied by means of 3 complementary techniques. Two dynamic techniques involving chronically implanted probes were used: blood flow in the caudate nucleus (CN) was measured by thermal clearance; tissue PO 2 and PCO 2 in the same structure were measured by mass spectrometry. Other variables measured continuously and simultaneously included arterial blood pressure (BP), PaO 2 and PaCO 2. The third technique was a tissue sampling method based on the Fick principle and using 14C 1 ethanol as tracer. Blood flow in 7 regions was measured at stable BP, PaO 2 and PaCO 2. Stimulation of the sympathetic chain at 15 Hz induced mean maximal decreases in CN blood flow of 23.9% (thermal clearance) and 24.4% (ethanol technique). Mean decrease of PO 2 in the CN at 15 Hz was 16.6%. Significant falls in blood flow were observed with the ethanol technique in all 7 structures measured. During prolonged stimulation (> 1 min) CN blood flow and PO 2 were found to escape towards the baseline level, which was sometimes even exceeded during the stimulation (blood flow). Stimulation frequency had only a very moderate influence on the rate of escape, and no evidence of a metabolic mechanism was found, although injection of barbiturate decreased the escape. These results are discussed with respect to the conflicting evidence on the effects of sympathetic stimulation in the brain, and to possible mechanisms for the escape phenomenon.

Vasomotor escape from adrenaline, noradrenaline or acetylcholine in the dog hind limb.

The noradrenaline, adrenaline and acetylcholine-induced vasoregulatory escape was demonstrated in the vascular bed of intact of skinned and denervated dog's hind limb. Escape effect disappeared or decreased markedly under elevation tissue pressure in the examined hind limb. These data indicate that tissue pressure factor may take part in the mechanism of the escape phenomenon.

Vasodilatation and modulation of vasoconstriction in canine subcutaneous adipose tissue caused by activation of β‐adrenoceptors

The present experiments were undertaken to study the balance between vascular alpha- and beta-adrenoceptors in canine subcutaneous adipose tissue during sympathetic nerve stimulation and noradrenaline injections. Propranolol potentiated and prolonged the vasoconstrictor response to close i.a. injections of noradrenaline. The vasoconstriction induced by brief nerve stimulation (0.5 to 8 Hz) was, however, unaltered by the beta-adrenoceptor blockade. During prolonged nerve stimulation the vasoconstrictor response was well maintained at 1.5 Hz but at 4 Hz there was a gradual escape. The escape phenomenon at 4 Hz was diminished by propranolol. The beta1-selective antagonist practolol, like propranolol, potentiated and prolonged the vasoconstriction induced by noradrenaline injections and reduced the vasoconstrictor escape during prolonged nerve stimulation at 4 Hz. Furthermore, the vasodilatation induced by noradrenaline injection or nerve stimulation during alpha-adrenoceptor blockade was diminished by practolol. Practolol also blocked the lipolytic response to noradrenaline and nerve stimulation. The beta2-selective antagonist H35/25 blocked the effects of the beta2-selective agonist salbutamol but failed to alter noradrenaline as well as nerve stimulation induced vascular and lipolytic beta-adrenoceptor responses. The present results provide further support for the hypothesis that vascular beta-adrenoceptors in adipose tissue are humoral (noninnervated), preferentially activated by circulating noradrenaline. Moreover, both vascular and lipolytic beta-adrenoceptors activated by noradrenaline in adipose tissue are best classified as beta1-adrenoceptors.

An escape phenomenon from water and sodium retention induced by propranolol in rats.

Rats given a daily dose of propranolol 45 mg/kg b.wt retain water and sodium for 4 days, escaping during the 5th and 6th days in which their excretions are larger than basal values. Afterwards, in the period studied, they make a new retention and clearing is less accentuated. No relationship could be found between these retentions and plasma renin activity or renal renin content.

Cimetidine treatment in Zollinger-Ellison syndrome.

Total gastrectomy is the accepted method of symptomatic treatment for the Zollinger-Ellison syndrome (ZES) but has disabling side-effects. However, treatment with H2-receptor antagonists has proved promising. The usefulness of this series of drug was first demonstrated with metiamide2,3 but despite the fact that only a small number of patients was studied, some practical and theoretical problems appeared: drug toxicity, assessment of efficacy of long term treatment, with variations consisting of an escape phenomenon or, conversely, prolonged secretory inhibition.1,2

The LH and FSH responses to LH-releasing hormone (LH-RH) in girls with true precocious puberty treated with cyproterone acetate

Ten girls with precocious puberty ranging in age from 7 to 10 7/12 years who were treated with oral cyproterone acetate on a long term basis, were subjected to LH-RH tests, prior to and 3 to 16 months after the institution of therapy. Cyproterone acetate was given in doses from 60 to 153 mg/m2, which proved to be clinically effective, as evidenced by the slowing down of sexual maturation. The basal levels of LH were found to be unaffected by therapy and corresponded to the pubertal stages of the individual girls. The peak increment of LH after LH-RH stimulation was markedly suppressed by the therapy. FSH secretion and its responsiveness to LH-RH was not affected by cyprotereone acetate. The basal levels of FSH were higher during therapy than before, but the peak FSH increment remained the same. An escape phenomenon in the LH peak response was evident in 2 patients upon retesting after prolonged therapy. It is possible that the antigonadotrophic action of cyproterone acetate is due to its progestational nature.

Influence of intestinal inhibitory reflex on mesenteric blood flow through an intestinal segment of the dog.

The variations in both tonus and rhythmical motility of the intestinal musculature are known to affect profoundly intestinal blood flow. In the present study, the influence of marked reflex inhibition of intestinal tone on the blood flow through an intestinal segment was investigated in the dog. Experiments were performed under conditions of both normal circulation and cross-circulation. Inhibitory reflex was elicited by elevating the intraluminal pressure of a loop or by electrical stimulation of the intestinal wall. Fluctuations of blood flow during the intestinal inhibitory reflex were observed with normal circulation. Arterial and venous blood flows decreased in the initial period of intestinal relaxation, and recovered within 30 sec although reflex inhibition still remained. This is an autoregulatory escape phenomenon. In successive periods, arterial and venous blood flows decreased again due to "the venous-arteriolar response" and then recovered to the quiescent level. The decrease in venous blood flow corresponded to an increase of the degree of oxygen saturation in the venous blood. The decreases in arterial and venous blood flows were observed during the inhibitory reflex even when the intestinal circulation was maintained by the cross-circulation. Two different patterns, i.e., the parallel and reversed patterns, were distinguished in correlation with venous blood flow and oxygen saturation. The autoregulatory escape phenomenon could not be elicited in the experiments in the cross-circulation system because variation of the systemic blood pressure during inhibitory reflex was limited to +/-4%.

Infective larvae of Brugia: escape from mosquitoes into water and subsequent oral infectivity in jirds.

Published work showed that third-stage larvae (L-3s) escape into water from dead or dying, Brugia pahangi-infected, Aedes aegypti. The present study revealed the same escape phenomenon among B. pahangi-infected Armigeres subalbatus, Anopheles quadrimaculatus, and Aedes togoi, and among Brugia malayi-infected Ae. aegypti and Ae. togoi. L-3s maintained in water or in Lum's solution for 3 hours retained infectivity when tested in orally or subcutaneously exposed jirds; furthermore, L-3s recovered from mosquitoes dead for 24 to 48 hours were also infective by either portal of entry in jirds. Since L-3s may escape and remain infective in the field, it is conceivable that natural filarial infections might thus be acquired orally by definitive hosts.

Clinical Study on Early Changes in Thyroid Function of Hyperthyroidism Treated with Propylthiouracil and a Relatively Small Dose of Iodide

In order to compare the acute effects of three kinds of antithyroid agents of iodide (I-), propylthiouracil (PTU) and PTU combined with iodide (PTU+I-) on thyroid function in hyperthyroid patients with diffuse goiter, serum concentrations of thyroxine (T4), triiodothyronine (T3), T3-resin sponge uptake (T3-RU) and free thyroxine index (FT4I) were employed as thyroid function parameters. In the group given iodine (1 mg/day) as iodinated-lecithine, the initial values of T4, T3, T3-RU and FT4I were 20.9 +/- 1.6 microng/100 ml (T4), greater than 740 ng/100 ml (T3), 49.5 +/- 2.3% (T3-RU) and 14.7 +/- 1.8 (FT4I). At the end of one week of therapy, they decreased clearly to 15.6 +/- 2.2 microng/100 ml, 457 +/- 87 ng/100 ml, 42.2 +/- 4.0% and 9.7 +/- 2.4. The so-called "escape phenomenon" from iodide inhibition was observed in serum T4, T3-RU and FT4I values at the end of two weeks of iodide therapy, while serum T3 continued to decrease but the value of T3 was far outside of the normal range. In the PTU group (300 mg/day), thyroid function parameters were 22.5 +/- 0.8 microng/100 ml (T4), greater than 592 ng/100 ml (T3), 54.9 +/- 1.0% (T3-RU) and 18.7 +/- 1.0 (FT4I) before treatment. They decreased continually week by week. At the end of four-week treatment with PTU, the value of each thyroid function parameter was 11.1 +/- 1.9 microng/100 ml, 229 +/- 56 ng/100 ml, 36.6 +/- 4.4% and 5.7 +/- 1.7. In the group of hyperthyroidism simultaneously given both PTU and iodide (300 mg/PTU and 1 mg/iodine), these thyroid function parameters decreased as well as in the group treated with PTU alone for more than two weeks. More rapid or significant decrease of T4, T3, T3-RU and ft4i in PTU+I- group than in PTU group was observed in the present study. These results suggested strongly that iodide alone was not an adequate therapy for hyperthyroidism as well known and they were also compatible with the idea that the concomitant administration of PTU and iodide was more effective in the early phase of therapy of hyperthyroidism than PTU alone.

Vascular escape in the cerebral microcirculation in the rat

The diameter of the cerebral arterioles was measured by serial photomicrography or television microscopy, and the velocity of the erythrocytes in these arterioles was recorded by the two-slit photometric method. The mean arteriolar volume flow was calculated from a flow formula. During a close intra-arterial infusion of norepinephrine or isoproterenol, the cerebral arterioles exhibited a vascular escape phenomenon from both constrictor and dilator influences. The same vascular elements that originally constrict finally dilate, and vice versa, which shows that the vascular escape phenomenon in the cerebral arteriole is attributable to the secondary relaxation or constriction of the constricted or dilated arteriolar segment, respectively.

Escape from vasoconstriction in the gastric microcirculation

Escape of splanchnic resistance vessels from vasoconstriction due to adrenergic stimulation has been attributed to increasing submucosal blood flow due to dilation of submucosal arteriovenous anastomoses (shunts). This postulate, as applied to the rat gastric microcirculation, was studied by in vivo microscopy. Using an image-splitting TV microscope recording system, response of gastric submucosal arterioles (13–33 µm) to 3 min of left splanchnic nerve stimulation, norepinephrine superfusion, and vasopressin superfusion was measured. All stimuli produced initial vasoconstriction. Escape occurred in all rats with nerve stimulation and norepinephrine, but in only one of five with vasopressin. No shunts were seen. The study demonstrates that the gastric submucosal arterioles exhibit an escape phenomenon, suggesting that "autoregulatory escape" in other splanchnic beds also may be due to relaxation of constricted vessels and not to opening of shunts.

Escape from vasoconstriction in the gastric microcirculation.

Escape of splanchic resistance vessels from vasconstriction due to adrenergic stimulation has been attributed to increasing submucosal blood flow due to dilation of submucosal arteriovenous anastomes (shunts). This postulate, as applied to the rat gastric microcirculation, was studied by in vivo microscopy. Using an image-splittingTV microscope recording system, response of gastric submucosal arterioles (13-33 mum)to 3 min of left splanchnic nerve stimulation, norepinephrine superfision, and vasopressin superfission was measured. All stimuli produced initial vasoconstriction. Escape occurred in all rats with nerve stimulation and norepinephrine, but in onlyone of five with vasopressin. No shunts were seen. The study demonstrates that thegastric submucosal arterioles exhibit an escape phenomenon, suggesting that "autoregulatory escape" in other splanchic beds also may be due to relaxation of constricted vessels and not to opening of shunts.

Dynamics of insulin release and microtubular-microfilamentous system. VI. Effect of D2O.

The present experiments were designed to assess the extent to which the β-cell microtu-bular-microfilamentous system contributes to the release of insulin evoked by glucose or sulfonylurea in the isolated perfused rat pancreas. Deuterium oxide (100%, v/v), which is thought to interfere with micro-tubular-microfilamentous function, was found to suppress insulin release during both the early and late phases of the secretory process. The inhibitory effect of D2O was reversible. When the pancreases) were first exposed to cytochalasin B (10 µg/ml) and, thereafter, (to both cytochalasin B and D2O, an escape)phenomenon from the D2O-induced inhibition was) invariably observed in response to either glucose or sulfonylurea. This escape phenomenon supports the view that the inhibitory effect of D2O on insulin)release is mainly due to a functional sideration of the microtubular-microfilamentous system. The present data suggest, therefore, that such a system is actively, involved in both phases of insulin release. (En...

Vascular Adjustments in Dilatory Reactions

Dilatory responses of the isolated intestinal vasculature of the rat have been studied during constant infusion of acetylcholine (Ach), isoproterenol (IP) andmyotropic, i.e. Ca&lt;sup&gt;++&lt;/sup&gt; antagonistically acting doses of propranolol. The initial vasodilation was followed by a succeeding increase of flow resistance. This effect, called &lt;i&gt;‘escape phenomenon’ &lt;/i&gt;could constantly be proved during application of Ach, was dosedependent and reached a maximal escape quotient of nearly 30%. Large vasoconstrictive doses of Ach also showed an escape phenomenon indicating the probability of one basal mechanism causing the escape from vasodilation and vasoconstriction. Vasodilations evoked by infusion of IP and large doses of β-blockers showed escape reactions only in some cases. The discrepancy between the different escape behaviour can be understood by comparing the rate of development of the initial vasodilation, which was two times slower for IP and propranolol than for Ach. The escape from Ach-elicited vasodilations could be clearly reduced by myotropic acting doses of LB 46. These results demonstrate that the escape from vasodilation is not a drug-specific phenomenon but is of &lt;i&gt;myogenic &lt;/i&gt;origin. The analogy of the escape from vasodilation and vasoconstriction suggests a common basal myogenic mechanism perhaps due to changes of Ca&lt;sup&gt;++&lt;/sup&gt;-fluxes. Thus, the initial vascular reaction would represent an ‘overshoot’ and the escape an adjustment reaction in a ‘steady-state system’.