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.

EEG differences between male alcoholics in withdrawal and those stabilized in treatment.

There is evidence that alcohol abuse and withdrawal produces cerebral impairment, some of which may be temporary and some permanent. This impairment has been found to be relatively specific in terms of brain areas affected. Recently our laboratory reported evidence that psychometrically measured impairment was systematically related to the energy in high frequency (beta-2) bands of the EEG. In the present study we attempted to determine the EEG patterns for male alcoholics undergoing withdrawal in comparison to patients who had been stabilized.

Data preprocessing applied to human average visual evoked potential P100-N140 amplitude, latency, and slope.

Data preprocessing, using principal components and Varimax rotation, was applied to 26 human average visual evoked potential (AVEP) variables representing bilateral amplitudes, latencies, and slopes from the P100 and N140 peaks. Five orthogonal factors, which accounted for about 80% of the variance, were found to describe the data from control subjects, stabilized alcoholics, and chronic nonparanoid schizophrenics. Tests of orthogonality and variance explained were employed to evaluate the results of the analysis.

Synthesis of a fine neurological electrode by plasma polymerization processing.

This research is part of a continuing program for the development of a coaxial depth electrode for research and diagnostic studies of neurological diseases. The requirements for this electrode include (1) strength and resistance to buckling sufficient to ensure self-forced penetration of brain tissue to a depth of 6 cm; (2) biocompatibility of the materials employed; (3) resistance to brittle fracture; and (4) a total diameter of less than 200 micrometer to minimize tissue damage. Earlier synthesis efforts using chemical vapor deposition techniques have been successful, although the process yield was 40% and an outer insulating layer had yet to be deposited. Plasma polymerization processes have been employed to realize an increase in the yield and provide an outer insulating layer. The starting material is W-26 at.% Re wire, nominally 125 micrometer in diameter. Hexamethyldisilazane(CH3)3SiNHSi(CH3)3 is used to deposit the insulating layers. The paper describes factors influencing the choice of materials, deposition techniques, and properties of electrodes.

Electroencephalographic similarities between chronic alcoholics and chronic, nonparanoid schizophrenics.

We compared the EEG power spectral density patterns for chronic, nonparanoid schizophrenics and age-matched chronic alcoholic and control subjects. Bilateral precentral (F-T) and postcentral (C-O) derivations were used in the analysis. The nonparanoid schizophrenics and alcoholics showed increased low-frequency activity (0 to 6 Hz) in all derivations in comparison to the control subjects. Chronic alcoholics were found to have increased high-frequency activity primarily in the precentral derivations. Nonparanoid schizophrenics showed increased power in the high-frequency bands predominantly in the left precentral derivation. We discuss the implications of patterns of differences concerning the issue of nonspecificity of the EEG in psychiatry.

EEG signs of brain impairment in alcoholism.

EEGs were recorded for two groups of chronic alcoholics who scored at opposite extremes on the Shipley Institute of Living Scale. The groups were matched in terms of age and drinking history variables and were compared to age-matched control subjects for left and right precentral (F-T) and postcentral (C-O) placements. Significant ANOVA findings were obtained primarily in high-frequency bands in the three group comparison. A significant linear trend was found for power as a function of degree of impairment from controls to moderately impaired alcoholics to severely impaired alcoholics in frequency bands above 14 Hz. The trend was most pronounced in the F-T derivations. Implications of the findings with respect to cortical atrophy in alcoholism are discussed.

Evoked response and after-discharge thresholds to electrical stimulation in temporal lobe epileptics.

The records of electrical stimulation of 30 psychomotor epileptics were examined for threshold levels of evoked responses and after-discharge production. Comparisons were made between anatomical sites, operated and nonoperated structures, and different disease states. It was found that patients with hippocampal sclerosis (HS) had higher thresholds in structures on the operated side. The patients with lesions other than HS were found to differ from those with hippocampal sclerosis in that there were no differences found between their diseased and nondiseased structures. For both patient groups, the amygdala had a much higher threshold for after-discharge production than either the hippocampus or the hippocampal gyrus.

Alcoholism: averaged visual evoked response amplitude-intensity slope and symmetry in withdrawal.

Alcohol withdrawal has been characterized in terms of some EEG changes but seldom in terms of the averaged evoked response. Characteristics of the AER, such as amplitude, latency, and the least-squares slope of the AER amplitude as a function of stimulus intensity, have been found to change as a function of arousal and to separate some psychiatric groups. Seventeen alcoholics in withdrawal, 27 stabilized alcoholics, and 30 control volunteer subjects participated in an experiment to determine the changes in AER characteristics in withdrawal. Four stimulus intensities were presented to the subjects from a Grass PS 22 photostimulator with the flash sources 102 cm from the nasion. AER amplitude, the slope of the amplitude as a function of stimulus intensity, and bilateral symmetry scores were calculated for group comparison. Withdrawal and stabilized alcoholics were found to have significantly greater AER amplitudes at all intensity levels. Greater A-I slope from the right hemisphere and higher symmetry were found for withdrawal alcoholics than the other two groups.

Physiological and psychological effects of methadone in man.

Methadone hydrochloride-maintenance outpatients were compared to abstinent exaddicts on physiological and psychological measures, and to normal subjects on physiological measures. The battery of psychological tests measure cognitive abilities and mental state. Methadone depressed respiration rate below other groups; abstinent subjects had higher heart rates than methadone or control subjects. No other physiological differences appeared. Electroencephalographic spectral analysis disclosed that the location of the alpha peak was at the lowest frequency in the methadone group, next lowest being the abstinent group. Discriminant functions based on a weighted combination of variables (frequencies) successfully distinguished the EEGs of the three groups. Both discriminant analysis and multiple regression analysis indicated that EEG changes were dose-dependent. Methadone subjects performed significantly poorer on several tests of learning and immediate recall compared to absitinent subjects.