Enzalutamide-warfarin interaction necessitating warfarin dosage adjustment: A case report of successful clinical management.

WHAT IS KNOWN AND OBJECTIVES: Enzalutamide package labeling recommends avoiding concurrent warfarin use due to potential reductions in warfarin concentrations via enzalutamide-associated hepatic enzyme induction. A case of successful management of this interaction via warfarin adjustments is reported. CASE DESCRIPTION: A 77-year-old Caucasian male, previously relatively stable on warfarin 42-45 mg weekly, reported to clinic after the recent start of enzalutamide and subsequent hospitalization with a subtherapeutic International Normalized Ratio (INR). A 50% increase in weekly warfarin dose resulted in a therapeutic INR. Enzalutamide was temporarily discontinued, and a 33% weekly warfarin dose decrease resulted in two therapeutic INRs. WHAT IS NEW AND CONCLUSION: This is the first case to highlight the clinical significance of this interaction, noting that patients taking enzalutamide may require approximately 30%-50% adjustment in their warfarin dosage to maintain a therapeutic INR.

Temporal relationship of the pulsatile fluctuation of luteinizing hormone and progesterone in cattle: a time series cross-correlation analysis.

The temporal relationship between the pulsatile patterns of plasma luteinizing hormone (LH) and progesterone (P4) was studied in mid-luteal (ML) and early-pregnant (EP) dairy cows. Blood samples were collected (via external jugular vein cannulae) at 10-min intervals for 16 h in 5 ML cows (d 10 to 12 of the cycle) and for 10 h in 5 EP cows (d 52 to 56 of gestation). Concentrations of LH and P4 were determined by radioimmunoassays and a time series cross-correlation analysis was utilized to evaluate the temporal relationship between them. A pulsatile pattern was found for both hormones in both groups, and in all animals LH peaks were uniformly followed by P4 peaks. In 80% of the cows in both groups the highest cross-correlation occurred between samples LH(n) and P4 (n + 1) (n = sample number), suggesting that a lag time of about 10 min is necessary for luteal stimulation. Results from both groups demonstrate that P4 is released from the corpus luteum in a pulsatile manner and that its release is at least partially dependent upon the pulsatile pattern of plasma LH. Correlation coefficients between LH and P4 mean level, basal levels, peak frequencies and peak amplitudes obtained in both groups indicate that the conceptus alters the hypothalamic-pituitary-ovarian relationship found in the ML cows, suggesting the existence of another factor(s) acting along with LH to release P4 in EP cows.

Comparison between rat prolactin radioimmunoassay and bioassay values under different experimental and physiological conditions.

Serum rat PRL concentrations were compared using values determined by RIA and the Nb2 lymphoma cell bioassay (Nb2BA). Rat serum samples were obtained under different physiological conditions and after the administration of pharmacological agents known to affect PRL secretion. Of the treatments examined, estrogen, morphine bromocriptine and haloperidol significantly altered the relationship between Nb2BA and RIA estimates of PRL. The estrogen-induced increase in PRL levels of ovariectomized females and the proestrus surge of PRL in intact females led to higher bioassay than RIA estimates of PRL. Treatment with haloperidol, bromocriptine and morphine altered the relationship, favoring immunoreactive more than bioactive hormone, and reversing the pretreatment Nb2BA/RIA ratio. No discrepancies between estimates of PRL by the two assays were noted in untreated males, diestrous, estrous and ovariectomized females, or following ether or TRH administration. These results confirm previous observations of discrepancies between rat serum bioassay and RIA estimates, and the data suggest that different forms of prolactin are present in the circulation at different times.

Ovariectomy leads to a rapid increase in rat placental lactogen secretion.

Serum placental lactogen (rPL) levels were measured by RIA in late pregnant rats subjected to a number of endocrine ablations. Adrenalectomy or unilateral ovariectomy had no significant effect on serum rPL levels. Hypophysectomy of the dam at midpregnancy resulted in a significant increase in serum rPL at late pregnancy. Bilateral ovariectomy of day-14 or -16 pregnant rats led to a rapid increase in serum rPL levels for 2 days followed by a gradual decrease as fetuses were reabsorbed or aborted. Adrenalectomy combined with ovariectomy led to sustained, elevated levels of serum rPL which were greater than those seen with bilateral ovariectomy alone. When progesterone (4 mg/rat X day) and estrone (500 ng/rat X day) or 17 beta-estradiol (100 or 200 ng/rat X day) were administered to ovariectomized pregnant rats, serum rPL remained elevated and the conceptuses were retained. In conclusion our studies have shown that ovarian and adrenal factors influence rPL secretion.

Decision-making processes in augmentative communication.

The potential population for augmentative communication is large, yet no objective assessment criteria exist. This article provides the clinician with a series of matrices designed to facilitate assessment decision making and implementation of augmentative communication. The first matrix addresses the appropriateness of augmentative communication. In the matrix the clinician will find an indepth, systematic decision-making procedure for aiding in the choice of augmentative procedures as primary or complementary methods of communication. The second matrix provides the clinician with information on modes of augmentative communication. These modes include manual systems, communication boards, and electronic devices. The third matrix focuses on code information. Particular attention is given to visual and manual codes. Together, the matrices provide the clinician with an objective procedure for evaluating and organizing available clinical information on nonspeaking clients.

Ovarian factors inhibit and fetal factors stimulate the secretion of rat placental lactogen.

Removal of fetuses at day 14 of gestation (Ftx14) in the pregnant rat leads to a marked suppression of serum levels of rat placental lactogen (rPL-II). One might attribute this to compromised placental growth in the absence of a fetus. However, if ovariectomy and fetectomy (Ftx14 Ovx14) are carried out at the same time, a great increase in serum rPL-II levels is seen. This occurs despite a significant decrease in placental weight. When Ftx14 was performed on day 14 and Ovx was delayed 1, 2, or 3 days, the expected large increase in serum rPL-II was progressively attenuated compared to that seen when Ftx and Ovx were carried out simultaneously. Daily administration of 17 beta-estradiol (4 micrograms/rat X day) to Ftx14 Ovx14 pregnant rats resulted in a significant suppression of rPL-II and elevation of rPRL levels, a reversal of what is seen for these hormones in untreated Ftx14 Ovx14 animals. To test whether 17 beta-estradiol was acting through rat PRL (rPRL), serum levels of rPRL were elevated in Ftx13 Ovx13 animals with pimozide (0.6 mg/kg), a dopamine receptor blocker. There was no effect of this treatment on rPL-II levels. In late pregnancy (day 17) serum rPL-II levels remained high after removal of half the fetuses (1/2 Ftx), compared to the rapid fall in pregnant rats in which all fetuses were removed (Ftx17). Serum levels were also elevated in 1/2 Ftx animals compared to those in which half of the fetuses and placentas were removed by hemi-hysterectomy, suggesting that the increase in rPL-II levels in 1/2 Ftx animals was due to a stimulatory effect of the remaining fetuses on all of the placentas. These results indicate that the presence of the fetus is necessary for the normally observed increase in rPL-II levels in late pregnancy. In conclusion, fetal stimulators and ovarian inhibitors influence rPL-II secretion.

Cysteamine induces depletion of both immunological and biological prolactin activity in the anterior pituitary and blood of the rat.

Previous studies have shown that cysteamine [2-aminoethanethiol (CSH)], given in vivo or in vitro, rapidly but reversibly depletes immunoreactive PRL from the anterior pituitary (AP) through a mechanism which, in vitro, does not appear to involve the dopamine (DA) receptor. In the present investigation, these effects of CSH were explored further with emphasis on determining whether CSH; (1) depletes biological as well as immunological PRL activity from the AP and blood, (2) has effects on plasma PRL in chronically cannulated male rats, (3) alters the PRL response to drugs which stimulate the secretion of the hormone, and (4) acts in vivo via DA receptors to deplete PRL. CSH produced a dose-dependent depletion of both immunological and biological PRL activity from the AP and blood. In chronically cannulated animals, PRL levels in the plasma were undetectable 90 min after CSH administration and remained so for 4 h. However, by 24 h plasma PRL in treated animals had returned to control levels. The PRL response to both domperidone and morphine was virtually abolished in CSH-treated animals. Blockade of DA receptors by pretreatment with domperidone did not alter the ability of CSH to reduce AP PRL stores. These results indicate that CSH: 1) alters both biological and immunological PRL activity by a rapid but reversible effect, and 2) circumvents the DA receptor to deplete pituitary PRL content. Thus, CSH or similar compounds may serve as a prototype for a new class of drugs which can be used in the treatment of hyperprolactinemia.

The development of an objective observation tool for parent-child interaction.

To address the need for objective evaluation of parent-child interactions, the investigators created a taxonomy of interactional behaviors used by parents and preverbal/early verbal children. This taxonomy was used by four judges to rate 40 1-min videotaped segments of parent-child freeplay, and the results were compared to four judges' subjective ratings of the same segments. Based on statistical analysis, the taxonomy was shortened to include only those objective behaviors that were highly correlated with the overall subjective ratings. The resultant 10-item taxonomy is discussed in relation to language development and to implications for therapy.

Inhibition of the postovariectomy depletion of hypothalamic luteinizing hormone releasing hormone (LHRH) by suckling.

A study was undertaken to further the understanding of the mechanism by which suckling inhibits the release of pituitary LH and depresses the postovariectomy rise of plasma LH in lactating mammals. To that end, the effect of suckling (10 pups/animal) for 1 or 3 weeks on the LHRH content of the hypothalamus and preoptic area (POA) in ovariectomized and intact rats was examined. Controls consisted of intact and 1 or 3 week ovariectomized, nonlactating animals. Following decapitation, the brains were rapidly removed and blocks containing the POA and the hypothalamus (with median eminence) were isolated. Tissue was extracted with acetic acid and LHRH quantitated via validated RIAs utilizing 2 antisera specific for different portions of the LHRH molecule. Ovariectomy of nonlactating, diestrous animals resulted in a significant decline in hypothalamic LHRH, reaching 50% of control levels by 3 weeks. During the same intervals, plasma LH increased dramatically to 20- and 60-fold over intact controls by 1 and 3 weeks, respectively. In contrast, LHRH levels were not decreased at 1 or 3 weeks in ovariectomized rats which were suckled, at which time plasma LH was greatly depressed. When intact animals were evaluated, the suckling stimulus failed to induce a detectable change in LHRH content of the hypothalamus of LHRH in the POA between any of the treatment or control groups. These data from ovariectomized rats suggest that suckling inhibits LHRH release from the hypothalamus and hence provides an explanation for the depression of plasma LH observed in suckled ovariectomized and intact animals.

Immunocytochemical evidence that suckling inhibits the postovariectomy depletion of median eminence luteinizing hormone releasing hormone.

Suckling has been demonstrated to impair the release of pituitary luteinizing hormone (LH) and to prevent the dramatic increase in plasma LH observed following ovariectomy. In the present study, the effect of suckling (10 pups/animal) for either 1 or 3 weeks on the relative amount of luteinizing hormone releasing hormone (LHRH) present in the hypothalamus and preoptic area of ovariectomized and intact rats was examined using immunocytochemical methodology. Controls consisted of nonlactating animals which were either intact (diestrous) or ovariectomized for 1 or 3 weeks. Brains were removed following transcardial perfusion of phosphate-buffered formalin and Bouin's fixative. After dehydration, clearing and paraffin embedding, the brains were sectioned and LHRH localized by an indirect immunoperoxidase technique. A positive reaction denoting the presence of immunoreactive LHRH was observed over axons and termini throughout the rostral to caudal extent of the median eminence (ME) and surrounding the organum vasculosum of the lamina terminalis (OVLT) in the preoptic area. Ovariectomy resulted in a progressive decline in the concentration of LHRH within the ME as evidenced by a reduction in the intensity of the staining reaction and in the number of axons over which the reaction was observed. In contrast, brains from ovariectomized rats which had been suckled appeared to have concentrations of LHRH in the ME equal to or greater than that of the diestrous controls. Similarly, the concentrations of LHRH In the ME of intact, suckled rats did not differ significantly from that of the diestrous controls. Neither ovariectomy nor suckling produced any observable change in the relative concentration of LHRH located near the OVLT. These data demonstrate that suckling prevents the depletion of LHRH from the ME following ovariectomy and provide evidence for mechanism by which the suckling stimulus may suppress plasma LH.

Argon laser destruction of cutaneous telangiectatic lesions.

An ophthalmological slit lamp argon laser was used on 8 patients with multiple cutaneous and mucosal telangiectasis; 6 patients had telangiectatic lesions of various etiologies and 2 had hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). Bleeding from trauma was the primary symptom with cosmesis as a secondary consideration. The telangiectatic lesions were photocoagulated using the argon laser with precise microscopic control. The optimum dose was determined by varying the spot diameter, beam power, shutter speed and number of applications until the lesions were visually ablated. All treatments were accomplished on an outpatient basis with no anesthesia or sedation and minimal reported patient discomfort. No lesions have recurred over a 12 month follow-up.

Pattern of plasma luteinizing hormone in the cyclic cow: dependence upon the period of the cycle.

Docile cows were used to characterize the pattern of plasma LH in systemic circulation during three periods [day 3 (early luteal), day 10 or 11 (midluteal) and day 18-19] of the estrous cycle. Blood samples were collected at 10-min intervals for 24 continuous h during each period. Concentration of LH, as measured by RIA, was analyzed by time domain and frequency domain methods of time series analysis. During all periods of the cycle studied, LH fluctuated in a pulsatile manner. During the early luteal period, pulses were classified as low amplitude (delta LH, 0.3-1.8 ng) and high frequency (20-30 pulses/24 h), with each cow exhibiting an inherent rhythmic pattern. However, during the midluteal period, pulses were classified as high amplitude (delta LH, 1.2-7.0 ng) and low frequency (6-8 pulses/24 h), without an inherent rhythmic pattern. Even though patterns differed between the early and midluteal periods in all cows, mean LH concentrations were different (P less than 0.05) in only one cow. On day 18 or 19, two cows exhibited a preovulatory surge of LH. Throughout the surge, LH fluctuated in a pulsatile manner, with a frequency more like the early luteal than the midluteal period. Amplitude of the pulses was greater during the ascending than during the descending portion of the surge. These results suggest that LH fluctuates in a pulsatile manner in the plasma of the cyclic cow, and that the pattern is dependent upon the period of the estrous cycle and is probably modulated by ovarian steroids.

Time-dependent loss of radioimmunoassayable levels of progesterone following ambient temperature incubation of heparinized bovine blood.

Plasma progesterone levels in heparinized blood collected at 10 min intervals for 8 continuous hours from four nulliparous Holstein cows on day 3 (early luteal), day 10 or 11 (mid-luteal) and day 18 or 19 of the estrous cycle were found to decline over time when blood was incubated at ambient temperature. The loss was more obvious during the mid-luteal collection period than either the day 3 or day 18 or 19 periods in all cows. This appeared to be associated more with high progesterone levels on day 10 or 11 rather than with differences in the period of the estrous cycle. There was an average decrease in progesterone levels of 3.4, 1.0 and 1.5 ng/ml between samples having the shortest and longest incubation periods on day 10 or 11, day 3 and day 18 or 19, respectively. This apparent decrease in levels of progesterone from bovine blood indicates need in the future for careful consideration concerning the handling of bovine blood collected for subsequent radioimmunoassay (RIA) of progesterone. Further work to elucidate the mechanism which is responsible for the apparent loss is also warranted.

Evidence for central nervous system (CNS) involvement in inhibition of luteinizing hormone (LH) release by dopamine receptor stimulation.

A pharmacologic study using 2-Br-alpha-ergocryptine (CB-154), a dopamine (DA) receptor agonist, the pimozide, a specific DA receptor antagonist, was undertaken to evaluate effects of manipulation of the DA system on plasma LH levels and on the ability of the pituitary to release LH following LHRH stimulation. Intraveneous administration of CB-154 lowered plasma LH levels in ovariectomized rats. Prior treatment with pimozide blocked the effect of CB-154, supporting dopaminergic system mediation in the observed response. Inhibition of LH release by pharmacologic stimulation of DA receptors did not appear to occur at the level of the pituitary, as pituitary release of LH following LHRH was not altered in CB-154 treated rats.

In vitro spontaneous thrombin generation in human factor-IX concentrates.

A series of in vitro studies designed to ascertain the potential in vivo thrombogenicity of human factor IX-containing concentrates is described. Using concentrates obtained from several different Centres the fibrinogen clotting time with some preparations was less than 6 h and/or the recalcification time of normal plasma was shortened. In some preparations, however, the plasma recalcification time was lengthened. Further studies revealed that all diluted factor-IX concentrates generated thrombin after recalcification, and that the rate of thrombin generation appeared to be characteristic of a particular preparation. This characteristic has been designated the TGt50, which is the incubation period in minutes, after recalcification, required to obtain a 50 s clotting time of a fibrinogen substrate. The TGt50 was found to correlate most strongly with recalcification time of celite exhausted plasma (P less than 0.001), but no correlation was observed between it and the immunological antithrombin III or factor-VIII antigen levels. Evidence is presented which suggests that the thrombin generation test and recalcification time of celite exhausted plasma may represent suitable in vitro quality control assays for factor-IX concentrates.