Efficacy and safety of abiraterone acetate plus prednisolone in patients with early metastatic castration-resistant prostate cancer who failed first-line androgen-deprivation therapy: a single-arm, phase 4 study.

AIM: The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy. METHODS: Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (<4.0 ng/mL) during first-line androgen deprivation therapy were enrolled and administered abiraterone acetate (1000 mg) plus prednisolone (10 mg). A minimum of 48 patients were required according to Simon's minimax design. The primary endpoint was prostate-specific antigen response rate (≥50% prostate-specific antigen decline by 12 weeks), secondary endpoints included prostate-specific antigen progression-free survival and overall survival. Safety parameters were also assessed. RESULTS: For efficacy, 49/50 patients were evaluable. Median age was 73 (range: 55-86) years. The median duration of initial androgen deprivation therapy was 32.4 (range: 13.4-84.1) weeks and 48 patients experienced prostate-specific antigen progression within 1-year after initiation of androgen deprivation therapy. prostate-specific antigen response rate was 55.1% (95% confidence interval: 40.2%-69.3%), median prostate-specific antigen-progression-free survival was 24.1 weeks, and median overall survival was 102.9 weeks (95% confidence interval: 64.86 not estimable [NE]). Most common adverse event was nasopharyngitis (15/50 patients, 30.0%). The most common ≥grade 3 adverse event was alanine aminotransferase increased (6/50 patients, 12.0%). CONCLUSIONS: Abiraterone acetate plus prednisolone demonstrated a high prostate-specific antigen response rate of 55.1%, suggesting tumor growth still depends on androgen synthesis in patients with early metastatic castration-resistant prostate cancer. However, prostate-specific antigen-progression-free survival was shorter than that reported in previous studies. Considering the benefit-risk profile, abiraterone acetate plus prednisolone would be a beneficial treatment option for patients with chemotherapy-naive metastatic prostate cancer who show early castration resistance.

Production of cis-11-eicosenoic acid by Mortierella fungi.

AIM: To find cis-11-eicosenoic acid (20:1ω9, EA)-producing micro-organisms. METHODS AND RESULTS: We found EA-producing fungi by screening about 300 fungal strains and identified a major fatty acid accumulated in the Mortierella fungi as EA by means of GC-MS analysis. In particular, Mortierella chlamydospora CBS 529.75 produced a high amount of EA (36.3 mg g(-1) of dried cells) on cultivation at 28°C for 4 days and then at 12°C for 3 days. In the result of lipid analysis, most of the EA was a component of triacylglycerols, not phospholipids. CONCLUSION: We found that M. chlamydospora CBS 529.75 was the best producer for the microbial production of EA. SIGNIFICANCE AND IMPACT OF THE STUDY: EA is beneficial as a raw material for medical supplies and a moisturizing component of cosmetic creams. This is the first report of microbial production of EA.

Human T-cell leukemia virus type 1 (HTLV-1) infection of mice: proliferation of cell clones with integrated HTLV-1 provirus in lymphoid organs.

Human T-cell leukemia virus type 1 (HTLV-1) is suggested to cause adult T-cell leukemia after 40 to 50 years of latency in a small percentage of carriers. However, little is known about the pathophysiology of the latent period and the reservoir organs where polyclonal proliferation of cells harboring integrated provirus occurs. The availability of animal models would be useful to analyze the latent period of HTLV-1 infection. At 18 months after HTLV-1 infection of C3H/HeJ mice inoculated with the MT-2 cell line, which is an HTLV-1-producing human T-cell line, HTLV-1 provirus was detected in spleen DNA from eight of nine mice. No more than around 100 proviruses were found per 10(5) spleen cells. Cellular sequences flanking the 3' long terminal repeat (LTR) and the clonalities of the cells which harbor integrated HTLV-1 provirus were analyzed by linker-mediated PCR. The results showed that the flanking sequences are of mouse genome origin and that polyclonal proliferation of the spleen cells harboring integrated HTLV-1 provirus had occurred in three mice. A sequence flanking the 5' LTR was isolated from one of the mice and revealed the presence of a 6-nucleotide duplication of cellular sequences, consistent with typical retroviral integration. Moreover, PCR was performed on DNA from infected tissues, with LTR primers and primers derived from seven novel flanking sequences of the three mice. Data revealed that the expected PCR products were found from lymphatic tissues of the same mouse, suggesting that the lymphatic tissues were the reservoir organs for the infected and proliferating cell clones. The mouse model described here should be useful for analysis of the carrier state of HTLV-1 infection in humans.

[Pharmacokinetics of cisplatin and methotrexate in a patient suffering from advanced ureteral tumor accompanied by chronic renal failure, undergoing combined hemodialysis and systemic M-VAC chemotherapy].

The pharmacokinetics of cisplatin and methotrexate were determined in a patient suffering from advanced ureteral tumor accompanied by chronic renal failure undergoing 4 consecutive cycles of M-VAC chemotherapy and hemodialysis. No significant difference was observed in t1/2, AUC or CLtot of total platinum between the patient with the chronic renal failure and patients with normal renal function. The AUC and CLtot of free platinum in the patient with the chronic renal failure were higher and lower, respectively, than in the patients with normal renal function. The free cisplatin rebounded remarkably after the end of dialysis, which may be partly attributed to an increase in the AUC and decrease in CLtot. However, the dialysis index was about 75 and 85% in the 3rd and 4th cycles, respectively. The t1/2 and CLtot of methotrexate in the patient with the chronic renal failure tended to be longer and smaller than those in patients with normal renal function, respectively. Seventy-two hours after administration, the methotrexate level was 0.02 microM, which was not at the high-risk level of high-dose therapy. After four cycles of M-VAC therapy, the rest of the right ureteral tumor was extirpated and the clinical response was CR. In conclusion, it is considered that cisplatin and methotrexate can be given to a patient with chronic renal failure. However, the cisplatin and methotrexate serum levels must be monitored, even after very low doses.

Pharmacological effects of tolterodine on human isolated urinary bladder.

Tolterodine, (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine+ ++, is an antimuscarinic drug developed for the treatment of overactive bladder with symptoms of frequency, urgency and urge incontinence. We investigated the effects of tolterodine and its major active metabolite, DD 01 (PNU-200577), (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropa namine, on the contractions induced by carbachol, KCl, CaCl2 and electrical field stimulation in human isolated urinary bladder smooth muscles, using the muscle bath technique. Specimens of human urinary bladder were obtained from 20 patients who underwent total cystectomy due to malignant bladder tumor. The detrusor preparations were taken from the intact part of the dome region of the bladder. Carbachol (10(-9)-10(-2) M) caused concentration-dependent contraction of human detrusor smooth muscles. Tolterodine (10(-9)-10(-6) M), DD 01 (10(-9)-10(-6) M), oxybutynin (10(-8)-10(-6) M), propiverine (10(-8)-10(-6) M), atropine (10(-9)-10(-6) M), pirenzepine (10(-8)-10(-5) M), methoctramine (10(-8)-10(-5) M) and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) (10(-9)-10(-6) M) caused typical shifts to the right of the concentration-response curves for carbachol, except for higher concentrations (10(-5) M) of oxybutynin and propiverine, which caused a decrease of about 30% of the maximum contractile responses to carbachol. All the slopes of the regression lines of Schild plots were close to unity, and the rank order of pA2 values was: atropine = DD 01 = tolterodine = 4-DAMP = oxybutynin > propiverine = pirenzepine > methoctramine. Tolterodine (10(-9)-10(-6) M) and DD 01 (10(-9)-10(-6) M) did not inhibit the KCl-induced (80 mM) and CaCl2-induced (5 mM) contractions, while oxybutynin (10(-8)-10(-5) M) and propiverine (10(-8)-10(-5) M) significantly inhibited the contractions. Electrical field stimulation (2-60 Hz) caused frequency-dependent contraction of human detrusor smooth muscles, which were significantly inhibited by various drugs. In the presence of 10(-6) M atropine, tolterodine and DD 01 did not inhibit the residual contractions induced by electrical field stimulation at any of the frequencies, while oxybutynin (10(-5) M) and propiverine (10(-5) M) significantly inhibited the atropine-resistant part of the contractions. The results suggest that the inhibitory effects of tolterodine and DD 01 are mediated only by their antimuscarinic action, which is equal to that of oxybutynin and significantly greater than that of propiverine, and that tolterodine and DD 01 have neither Ca2+ channel antagonist action nor inhibitory effect on the atropine-resistant part of the contractions in human detrusor smooth muscles. These findings support the usefulness of tolterodine as a therapeutic drug for overactive bladder with symptoms of frequency, urgency and urge incontinence.

Measurement of acetylcholine released from rabbit detrusor smooth muscle using HPLC with electro-chemical detection coupled with microdialysis procedure.

We measured the amount of acetylcholine (ACh) released from rabbit detrusor smooth muscles induced by electrical field stimulation (EFS) using microdialysis procedure. The dialysis probe was inserted through the detrusor muscle strip and was continuously perfused with a Ringer solution containing physostigmine sulfate, at a rate of 2 microl/min. The strip was suspended in an organ bath filled with the modified Krebs-Henseleit solution and then EFS was delivered. The isometric force was recorded and monitored in each muscle preparation. The dialysates were collected every 10 min. ACh was determined by a high performance liquid chromatography with electro-chemical detection. The contraction of the muscle strip and ACh release induced by EFS were increased in a frequency and duration dependent manner. There were some differences between frequency response curves of contraction and frequency dependent ACh release. In the contractile response, the maximum contractions were observed at lower frequencies, while ACh releases reached the maximum at higher frequencies. There was a significant, but not simple correlation between EFS-induced contraction and ACh release. The results suggest that this new method is useful to investigate the ACh release from rabbit detrusor smooth muscles, and that other neurotransmitters than ACh possibly contribute to EFS-induced contraction.

Pharmacologic actions of temiverine (p-INN) and its active metabolite, RCC-36, on isolated human urinary bladder muscle.

BACKGROUND: Temiverine (p-INN) is a newly synthesized drug that is expected to have anticholinergic action. We investigated the pharmacologic actions of temiverine and its active metabolite, RCC-36, on isolated human bladder. METHODS: Effects of temiverine and RCC-36 on the detrusor contractions induced by acetylcholine, potassium chloride (KCl), calcium chloride (CaCl2), and electric field stimulation were evaluated using the muscle-bath technique, and compared with the effects of atropine and oxybutynin. RESULTS: Atropine (10(-9) to 10(-6) mol/L), oxybutynin (10(-8) to 10(-5) mol/L), temiverine (10(-8) to 10(-5) mol/L), and RCC-36 (10(-8) to 3 x 10(-6) mol/L) caused a parallel shift to the right of the concentration-response curves to acetylcholine stimulation. The rank order of pA2 value was atropine > oxybutynin = RCC-36 > temiverine. Atropine did not suppress the maximum contractile response to acetylcholine, but the other drugs significantly suppressed this at the higher concentrations. Each drug caused a concentration-dependent inhibition of KCl (80 mmol/L)-, and CaCl2 (5 mmol/L)-induced contractile responses. Rank order of maximum inhibition was RCC-36 = temiverine > oxybutynin > atropine. Each drug caused a concentration-dependent inhibition of electric field-induced contraction with or without 10(-6) mol/L atropine pretreatment. Maximum inhibitions of temiverine and RCC-36 were significantly greater than that of oxybutynin. CONCLUSION: Atropine, oxybutynin, temiverine, and RCC-36 have different efficacies and potencies of anticholinergic and calcium antagonistic activity on isolated human detrusor muscles. Furthermore, temiverine and RCC-36 have significant inhibitory actions toward the atropine-resistant part of contractions, which may be related to the calcium antagonistic actions of these compounds.

Hyperimmunoglobulinemia D in idiopathic retinal vasculitis.

BACKGROUND: We examined four patients who exhibited both idiopathic retinal vasculitis and elevated serum IgD levels. Uveitis caused by Behçet's disease is also associated with high levels of serum IgD. Therefore, the clinical features of these patients were investigated and the possible relationship between retinal vasculitis and elevated serum IgD was examined after undertaking a study of increased IgD levels in patients diagnosed with uveitis. METHODS: The study population was composed of 110 patients: 49 with Behçet's disease, 15 with sarcoidosis, 10 with Vogt-Koyanagi-Harada disease, and 36 with other forms of uveitis. IgD measurements were performed using modifications of the latex photometric immunoassay. Surface IgD (sIgD) expression in peripheral lymphocytes was determined by immunofluorescence, and the correlation between serum IgD levels and the percentage of sIgD-positive cells was examined. RESULTS: Twelve of the 110 patients had an elevated serum IgD. Eight of the 12 had Behçet's disease, and 4 were diagnosed with idiopathic retinal vasculitis. These 4 patients were HLA-A24+ females whose ages ranged from 8 to 25 years. A linear correlation between the serum IgD levels and the percentage of sIgD-positive cells was found. CONCLUSION: Hyperimmunoglobulinemia D state was found in Behçet's disease and idiopathic retinal vasculitis. These diseases may represent a new clinical entity characterized by signs of retinal vasculitis and hyperimmunoglobulinemia D that results from abnormal B cell activation and immune complex-mediated responses.

Integration of HTLV-1 provirus into mouse transforming growth factor-alpha gene.

Human T cell leukemia virus type 1 (HTLV-1) provirus integration was investigated in mice inoculated with MT-2 cells, a HTLV-1 producing human T-cell line. From spleen DNA derived from a MT-2 cell-injected mouse, we cloned a HTLV-1 integration site by ligation-mediated PCR. The nucleotide sequence showed that HTLV-1 provirus was integrated into an intron of the mouse transforming growth factor-alpha gene in the reverse orientation. This result provides for the first time molecular evidence that mice can be infected with HTLV-1.

Comparison of the effects of various anticholinergic drugs on human isolated urinary bladder.

We investigated the effects of various anticholinergic drugs (atropine, oxybutynin, terodiline and propiverine) on the contractions induced by acetylcholine, KCl, CaCl2, and electrical field stimulation, in human isolated urinary bladder smooth muscles using the muscle bath technique. Urinary bladders were obtained from 20 patients who underwent total cystectomy due to malignant bladder tumor. The detrusor preparations were taken from the intact part of the dome of the bladder. Acetylcholine caused a concentration-dependent contraction in human detrusor preparations. Atropine (10(-9)-10(-6) M), oxybutynin (10(-8)-10(-5) M), terodiline (10(-7)-10(-5) M) and propiverine (10(-7)-10(-5) M) caused parallel shifts to the right of the concentration-response curves to acetylcholine. The rank order of pA2 values was: atropine > oxybutynin > terodiline = propiverine. Atropine did not suppress the maximum contraction to acetylcholine, while the other drugs significantly suppressed the maximum contractions at the higher concentrations. Each drug caused a concentration-dependent inhibition of the KCl (80 mM)- and CaCl2 (5 mM)-induced contractions; the maximum inhibitions of terodiline and propiverine were significantly greater than those of oxybutynin and atropine. Each drug caused a concentration-dependent inhibition of the contraction induced by electrical field stimulation; the maximum inhibitions of terodiline and propiverine were significantly greater than those of oxybutynin and atropine. The results suggest that the drugs have both anticholinergic and calcium antagonistic effects. Furthermore, it also appears that part of the human bladder contraction, which was significantly inhibited by terodiline and propiverine, is an atropine-resistant component.

[Urinary disturbance due to HTLV-1 associated myelopathy].

Patients with human T-cell lymphotropic virus type 1 associated myelopathy (HAM) have complaints of urinary disturbance frequently. Symptoms and urodynamic examinations were evaluated in untreated twenty-one patients with HAM. Although two cases (11%) had no urinary symptom, nineteen cases (89%) suffered from dysuria, pollakisuria, incontinence or urgency. The combination of irritative and obstructive urinary disturbance was a characteristic symptom in the HAM patients. In three cases the urinary symptoms preceded the gait disturbance which is a main symptom of HAM. In urodynamic study overactive bladder was found in fourteen cases (66%), although three cases (15%) showed underactive or acontractile bladder with disturbance of urinary sensation. There was no abnormal finding by urethral pressure profile (UPP), but detrusor sphincter dyssynergia (DSD) was revealed frequently by EMG. This typical dysfunction of the HAM patients was thought to be caused by destruction of the lateral column of the spinal cord.

[Study on the relation for physical properties of masticatory jelly and masticatory muscle activity].

To measure the masticatory force used for everyday foods it is desirable to base the measurements on one mouthful of food. However, one mouthful of food changes in size and hardness. The purpose of this study is to establish a formula for estimating a correlation between the amount and force of mastication, active potentials and their integrated values, and the concerned material's size and hardness no matter they are same or unified. It is possible to measure the amount of mastication for normal foods without recording electromyographically. The effective method for recording the hardness of the jelly is the application of needle plunger. The thickness divided by the hardness and multiplying the value with the volume of the material, an estimated formula is thereby established to correlate with the integrated values of mastication.