AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - results of two parallel first-in-human phase I studies.

BACKGROUND: AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD). METHODS: In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule. RESULTS: In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (≥50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1. CONCLUSION: AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.

High-pressure, rapid-inflation pneumatic compression improves venous hemodynamics in healthy volunteers and patients who are post-thrombotic.

PURPOSE: Deep vein thrombosis (DVT) is a preventable cause of morbidity and mortality in patients who are hospitalized. An important part of the mechanism of DVT prophylaxis with intermittent pneumatic compression (IPC) is reduced venous stasis with increased velocity of venous return. The conventional methods of IPC use low pressure and slow inflation of the air bladder on the leg to augment venous return. Recently, compression devices have been designed that produce high pressure and rapid inflation of air cuffs on the plantar plexus of the foot and the calf. The purpose of this study is to evaluate the venous velocity response to high-pressure, rapid-inflation compression devices versus standard, low-pressure, slow-inflation compression devices in healthy volunteers and patients with severe post-thrombotic venous disease. METHOD: Twenty-two lower extremities from healthy volunteers and 11 lower extremities from patients with class 4 to class 6 post-thrombotic chronic venous insufficiency were studied. With duplex ultrasound scanning (ATL-Ultramark 9, Advanced Tech Laboratory, Bothell, Wash), acute DVT was excluded before subject evaluation. Venous velocities were monitored after the application of each of five IPC devices, with all the patients in the supine position. Three high-pressure, rapid-compression devices and two standard, low-pressure, slow-inflation compression devices were applied in a random sequence. Maximal venous velocities were obtained at the common femoral vein and the popliteal vein for all the devices and were recorded as the mean peak velocity of three compression cycles and compared with baseline velocities. RESULTS: The baseline venous velocities were higher in the femoral veins than in the popliteal veins in both the volunteers and the post-thrombotic subjects. Standard and high-pressure, rapid-inflation compression significantly increased the popliteal and femoral vein velocities in healthy and post-thrombotic subjects. High-pressure, rapid-inflation compression produced significantly higher maximal venous velocities in the popliteal and femoral veins in both healthy volunteers and patients who were post-thrombotic as compared with standard compression. Compared with the healthy volunteers, the patients who were post-thrombotic had a significantly attenuated velocity response at both the popliteal and the femoral vein levels. CONCLUSION: High-pressure, rapid-inflation pneumatic compression increases popliteal and femoral vein velocity as compared with standard, low-pressure, slow-inflation pneumatic compression. Patients with post-thrombotic venous disease have a compromised hemodynamic response to all IPC devices. However, an increased velocity response to the high-pressure, rapid-inflation compression device is preserved. High-pressure, rapid-inflation pneumatic compression may offer additional protection from thrombotic complications on the basis of an improved hemodynamic response, both in healthy volunteers and in patients who were post-thrombotic.

The Caenorhabditis elegans gene T23G5.5 encodes an antidepressant- and cocaine-sensitive dopamine transporter.

A small subset of neurons in the nematode Caenorhabditis elegans utilizes the catecholamine dopamine (DA) as a neurotransmitter to control or modulate movement and egg-laying. Disruption of DA-mediated behaviors represents a potentially powerful strategy to identify genes that are likely to participate in dopaminergic systems in man. In vertebrates, extracellular DA is inactivated by presynaptic DA transport proteins (DATs) that are also major targets of addictive agents, including amphetamines and cocaine. We used oligonucleotides derived from the C. elegans genomic locus T23G5.5 to isolate and characterize T23G5.5 cDNAs. Our studies predict that mRNAs from this locus encode a 615-amino-acid polypeptide with twelve stretches of hydrophobicity suitable for transmembrane domains, similar to that found in vertebrate catecholamine transporters. The inferred translation product bears highest identity (43-47%) to catecholamine (DA, norepinephrine, epinephrine) transporters within the GAT1/NET gene family and possesses conserved residues implicated in amine substrate recognition. Consistent with these findings, HeLa cells transfected with the C. elegans cDNA exhibit saturable and high affinity DA transport (Km = 1.2 microM) that is dependent on extracellular Na+ and Cl- and blocked by inhibitors of mammalian catecholamine transporters, including norepinephrine transporter- and DAT-selective antagonists, tricyclic antidepressants, and the nonselective amine transporter antagonists cocaine and D-amphetamine. These studies validate the T23G5.5 locus as encoding a functional catecholamine transporter, providing important comparative sequence information for catecholamine transporter structure/function studies and a path to identify regulators of dopaminergic signaling via genetic or pharmacologic manipulation of C. elegans cDNA in vivo.

Clinical applications of thrombolytic therapy for arterial and graft occlusion.

Catheter-directed thrombolysis and intraoperative intra-arterial thrombolysis are important adjuncts to how we care for patients with acute arterial and bypass graft occlusions. Of importance is that intra-arterial thrombolysis not to be thought of as a competitor to operative revascularization, but rather as an adjunct to what can be accomplished, which enables the responsible physician to offer the best care for these patients.

Molecular cloning and characterization of an L-epinephrine transporter from sympathetic ganglia of the bullfrog, Rana catesbiana.

Chemical signaling by dopamine (DA) and L-norepinephrine (L-NE) at synapses is terminated by uptake via specialized presynaptic transport proteins encoded by the DA transporter (DAT) and L-NE transporter (NET) genes, respectively. In some vertebrate neurons, particularly the sympathetic neurons of amphibians, L-NE is converted to L-epinephrine (L-Epi, adrenaline) and released as the primary neurotransmitter. Although evidence exists for a molecularly distinct L-Epi transporter (ET) in the vertebrate brain and peripheral nervous system, a transporter specialized for extracellular L-Epi clearance has yet to be identified. To pursue this issue, we cloned transporter cDNAs from bullfrog (Rana catesbiana) paravertebral sympathetic ganglia and characterized functional properties via heterologous expression in non-neuronal cells. A cDNA of 2514 bp (fET) was identified for which the cognate 3.1 kb mRNA is highly enriched in frog sympathetic ganglia. Sequence analysis of the fET cDNA reveals an open reading frame coding for a protein of 630 amino acids. Inferred fET protein sequence bears 75, 66, and 48% amino acid identity with human NET, DAT, and the 5-hydroxytryptamine transporter (SERT), respectively. Transfection of fET confers Na+- and Cl--dependent catecholamine uptake in HeLa cells. Uptake of [3H]-L-NE by fET is inhibited by catecholamines in a stereospecific manner. L-Epi and DA inhibit fET-mediated [3H]-L-NE uptake more potently than they inhibit [3H]-L-NE uptake by human NET (hNET), whereas L-NE exhibits equivalent potency between the two carriers. Moreover, fET exhibits a greater maximal velocity (Vmax) for the terminal products of catecholamine biosynthesis (L-Epi > L-NE >> DA), unlike hNET, in which a Vmax rank order of L-NE > DA > L-Epi is observed. fET-mediated transport of catecholamines is sensitive to cocaine and tricyclic antidepressants, with antagonist potencies significantly correlated with hNET inhibitor sensitivity. Amino acid conservation and divergence of fET with mammalian catecholamine transporters help define residues likely to be involved in catecholamine recognition and translocation as well as blockade by selective reuptake inhibitors.

Primary leiomyosarcoma of the abdominal aorta.

Primary malignancies of the aorta are extremely rare. A review of the literature indicates that 35 documented cases of primary tumors of the aorta have been reported over the past 120 years. The histologic and morphologic characteristics of these lesions may be variable. In this case, progressive claudication of the left leg and buttocks with absent femoral pulses in a middle-aged woman was found to be a primary leiomyosarcoma of the abdominal aorta. A magnetic resonance imaging study defined a retroperitoneal space-occupying mass on the left side of the aorta at the level of the fourth lumbar vertebrae. A magnetic resonance angiographic scan of the abdominal aorta and an aortogram revealed total occlusion of the distal abdominal aorta with reconstitution at the level of the common femoral arteries bilaterally, with normal vessels more distal to that region. The patient underwent surgical exploration and resection of the retroperitoneal, infrarenal, occluding aortic mass. The mass was found to be a high-grade sarcoma displaying smooth muscle cell differentiation. The resection of this lesion, perioperative management, and pathologic characteristics of a rare primary neoplasm of the aorta are discussed in this review.

Differential effects of hypnotic suggestion on multiple dimensions of pain.

Within the framework of multidimensional pain assessment, this study extended an earlier finding that hypnotic analgesia and relaxation suggestions have differential effects on pain reduction by evaluating these strategies in subjects undergoing a cold pressor protocol. Thirty-two highly susceptible subjects were randomly assigned to an analgesia or a relaxation suggestion treatment group. Six pain reports were taken at 10-sec intervals for each experimental condition. The baseline measures served as covariates. A 2 x 2 x 2 x 6 repeated-measures analysis of covariance (ANCOVA) revealed a significant group (analgesia, relaxation) by pain dimension (intensity, unpleasantness), by condition (suggestion alone, hypnotic induction plus suggestion) interaction. Analysis of the simple-simple main effects, holding both group and condition constant, revealed that application of hypnotic analgesia reduced report of pain intensity significantly more than report of pain unpleasantness. Conversely, hypnotic relaxation reduced pain unpleasantness more than intensity. The clinical implications of the study are discussed.

The use of competitive displacement agents to resolve albumin binding problems observed during the development of a radioimmunoassay for ICI 215001.

A radioimmunoassay has been developed for the analysis of ICI 215001, a carboxylic acid metabolite of ICI D7114. The level of binding and sensitivity of the assay were good in the absence of plasma. However, the addition of plasma to the incubation medium reduced the antibody binding of radiolabelled tracer (I) from 41 to 9%. This was attributed to the high (> 99%) plasma albumin binding of ICI 215001. A series of compounds (DL-tryptophan, octanoic acid, bilirubin, ponalrestat, warfarin, phenylbutazone and salicylic acid) which all bind to plasma albumin, were examined for their effect on the tracer-antibody interaction. Warfarin and phenylbutazone were the only compounds to specifically displace the iodinated tracer from albumin; warfarin was the only compound to restore antibody binding to control levels. The warfarin concentration and the pH of the incubation medium also had a substantial effect on the magnitude of the displacement. The optimized method for the analysis of ICI 215001 in human plasma (20 microliters) used phosphate buffer (pH 6.0, 0.1 M) containing warfarin (50 micrograms ml-1), which gave an assay with the desired specificity, precision and sensitivity.

The effects of hypnotic suggestion on pain report.

Forty-five highly susceptible volunteers rated a series of shocks using 32 pain descriptors. Descriptors were given numerical values using magnitude estimation procedures. We assigned the subjects to one of three conditions, analgesia suggestion, relaxation suggestion, or no suggestion. All subjects were administered the shocks and the suggestion appropriate to the group, in both the waking and hypnotic state. The results support the existence of two dimensions of pain which are differentially responsive to suggestion. Hypnotic-analgesia suggestion altered subjects' perceptions of the intensity without changing their perceptions of the unpleasantness of the shocks. Hypnotic-relaxation suggestion reduced the unpleasantness but not the perceived intensity of the stimuli. These findings imply that research into hypnotic pain relief is more easily interpreted if pain is viewed as multidimensional in nature.