Octaarginine-modified multifunctional envelope-type nanoparticles for gene delivery.

This study describes a multifunctional envelope-type nano device (MEND) that mimics an envelope-type virus based on a novel packaging strategy. MEND particles contain a DNA core packaged into a lipid envelope modified with an octaarginine peptide. The peptide mediates internalization via macropinocytosis, which avoids lysosomal degradation. MEND-mediated transfection of a luciferase expression plasmid achieved comparable efficiency to adenovirus-mediated transfection, with lower associated cytotoxicity. Furthermore, topical application of MEND particles containing constitutively active bone morphogenetic protein (BMP) type IA receptor (caBmpr1a) gene had a significant impact on hair growth in vivo. These data demonstrate that MEND is a promising non-viral gene delivery system that may provide superior results to existing non-viral gene delivery technologies.

Chemotherapy targeting methylthioadenosine phosphorylase (MTAP) deficiency in adult T cell leukemia (ATL).

Methylthioadenosine phosphorylase (MTAP) is an important enzyme used for the salvage of adenine and methionine. Cells lacking this enzyme are expected to be sensitive to purine synthesis inhibitors and/or methionine starvation. We reported previously that the MTAP gene is deleted in adult T cell leukemia (ATL) cells. In the present study, we expanded our series and used a real-time quantitative PCR assay for accurate diagnosis of the deletion and nine of 65 primary ATL samples (13.8%) were MTAP negative. In spite of this low incidence, ATL cells showed significantly higher sensitivity to L-alanosine, an inhibitor of de novo adenosine monophosphate (AMP) synthesis, than normal lymphocytes, suggesting that the MTAP gene is inactivated not only by deletion but also by other mechanisms. Indeed, a real-time quantitative RT-PCR assay disclosed that primary ATL cells had significantly lower MTAP mRNA expression than normal lymphocytes. Since MTAP-negative ATL cell lines also showed much higher sensitivity to L-alanosine than MTAP-positive ATL cell lines, we used these cell lines to investigate whether it is possible to develop selective therapy targeting MTAP deficiency. A substrate of MTAP, methylthioadenosine (MTA) or its substitutes rescued concanavalin A (Con A)-activated normal lymphocyte proliferation from L-alanosine toxicity. All the compounds except 5'-deoxyadenosine, however, also caused the undesirable rescue of MTAP-negative ATL cell lines. 5'-Deoxyadenosine had the desired ability to rescue hematopoietic progenitor cells without rescuing ATL cell lines. These results support the rationale for a chemotherapy regimen of L-alanosine combined with 5'-deoxyadenosine rescue in MTAP-deficient ATL.

Possible involvement of mast-cell activation in aspirin provocation of aspirin-induced asthma.

BACKGROUND: Although there is increasing evidence of the importance of cysteinyl leukotrienes (LT) as mediators of aspirin-induced bronchoconstriction in aspirin-sensitive asthma, the cellular origin of the LT is not yet clear. METHODS: Urinary concentrations of leukotriene E4 (LTE4), 11-dehydrothromboxane B2, 9alpha,11beta-prostaglandin F2, and Ntau-methylhistamine were measured during the 24 h following cumulative intravenous administration of increasing doses of lysine aspirin to asthmatic patients. In addition, the urinary concentrations of these metabolites were measured on 5 consecutive days in a patient who suffered an asthma attack after percutaneous administration of nonsteroidal anti-inflammatory drugs. RESULTS: In aspirin-induced asthma patients (AIA, n=10), the basal concentration of urinary LTE4, but not the other metabolites, was significantly higher than that in aspirin-tolerant asthma patients (ATA, n=10). After intravenous aspirin provocation, the AIA group showed a 13.1-fold (geometric mean) increase in excretion of LTE4 during the first 3 h, and 9alpha,11beta-prostaglandin F2 also increased in the AIA group during the first 0-3 h and the 3-6 h collection period. Ntau-methylhistamine excretion was also increased, but to a lesser degree. Administration of aspirin caused significant suppression of 11-dehydrothromboxane B2 excretion in both the AIA and ATA groups. When the percentage of maximum increase of each metabolite from the baseline concentrations was compared between the AIA group and the ATA group, a significantly higher increase in excretion of LTE4, 9alpha,11beta-prostaglandin F2, and Ntau-methylhistamine was observed in the AIA group than the ATA group. An increased excretion of LTE4 and 9alpha,11beta-prostaglandin F2 has been detected in a patient who suffered an asthma attack after percutaneous administration of nonsteroidal anti-inflammatory drugs. CONCLUSIONS: Considering that human lung mast cells are capable of producing LTC4, prostaglandin D2, and histamine, our present results support the concept that mast cells, at least, may participate in the development of aspirin-induced asthma.

Long-lasting memory of sounds combined with reward in rats.

We investigated the effects of sound stimuli combined with reward on the subsequent sound discrimination. Water-deprived rats were exposed to one of two sounds (S+ or S-) in a trial, and licking a spout only during the presentation of S+ was rewarded with water. The percentage of trials in which licking occurred was calculated separately for S+ and S-, and sound discrimination was estimated from the difference in the percentage. S+ and S- were significantly discriminated during an 8 h period. In the second test after 1-2 weeks, sound discrimination for the same S+ and S- was significantly better than that for the S+ of the previous S- and S- of the previous S+. These findings indicate that the memory of the sounds combined with reward in the first test was maintained for 1-2 weeks.

Sequence dependence of post-tetanic potentiation after sequential heterosynaptic stimulation in the rat auditory cortex.

1. To investigate the mechanisms for the coding stimulus sequence in the auditory cortex (AC), post-tetanic potentiation (PTP) was recorded after sequentially combined heterosynaptic stimulation was applied in rat AC slices. 2. Brief tetanic stimulation (TS) was applied at two sites on AC slices at intervals of 0.5-10 s. PTP of field potentials was induced by the earlier TS, rather than the later TS. PTP was followed by sequence-dependent long-term potentiation (LTP). 3. Using Ca(2+) imaging in the slices loaded with rhod-2, a Ca(2+) indicator, a sequence-dependent distribution of PTP was found in AC slices. 4. The sequence-dependent PTP in excitatory postsynaptic potentials (EPSPs) was observed in supragranular pyramidal neurons. 5. The sequence dependence of PTP was not significantly affected by 1 microM bicuculline, an antagonist of GABA(A) receptors, or 100 microM 2-hydroxysaclofen, an antagonist of GABA(B) receptors. 6. Depolarization and firing recorded in pyramidal neurons during the later TS were less vigorous than when the slices were incubated in the control medium. However, this suppression of the responses during the later TS was not observed in the presence of 50 microM atropine, an antagonist of muscarinic receptors. 7. PTP was induced by the earlier and later TS in the presence of 50 microM atropine, so that the sequence dependence of PTP was abolished. Pirenzepine (50 microM), an antagonist of muscarinic M1 receptors, but not methoctramine (30 microM), an antagonist of M2 receptors, eliminated the sequence dependence of PTP. 8. These findings suggest that the sequence dependence of PTP in AC might have a role in the temporal processing of auditory information on the scale of seconds.

Mechanisms of fluconazole resistance in Candida albicans isolates from Japanese AIDS patients.

Four Candida albicans isolates, TIMM 3163, TIMM 3164, TIMM 3165 and TIMM 3166, with reduced fluconazole susceptibility were obtained from three AIDS patients in Japan, and the mechanisms of their drug resistance were studied. All isolates showed lower levels of intracellular accumulation of fluconazole than ATCC 10231, a susceptible control strain of C. albicans. Increased amounts of CDR1 and CDR2 mRNA encoding putative ATP binding cassette (ABC) transporters were associated with the azole resistance of all TIMM isolates, apart from TIMM 3164. In addition, increased Cdr1p levels were immunodetected in the cell membrane fractions of all the TIMM strains except for TIMM 3164. Gene amplification was not responsible for CDR1 overexpression and there were no significant differences in the mRNA levels of CDR3 or CDR4 (ABC transporters) in the azole-susceptible and -resistant cells. CaMDR1 (a major facilitator superfamily) gene expression was not observed in any of the resistant isolates or the control strain. These results suggest that energy-dependent drug efflux associated with increased expression of CDR1 and CDR2 is involved in the fluconazole resistance mechanisms in two of the four isolates, TIMM 3165 and TIMM 3166. TIMM 3164 demonstrated energy-dependent drug efflux without overexpression of CDR1-4 or CaMDR1, indicating that some other pump may be operating. Despite showing low levels of drug efflux and overexpression of CDR1 and CDR2, efflux in TIMM 3163 was not energy dependent, suggesting that the expressed Cdr1p non-functional Cdr1p and that other resistance mechanisms may operate in this strain.

[Epidemiologic study of diabetic retinopathy in nine hospitals in the Aomori area].

PURPOSE: To examine the prevalence of diabetic retinopathy and the relationship between diabetic retinopathy and systemic risk factors. METHODS: A cross sectional study of diabetic retinopathy was conducted on 1,826 eyes of 913 randomly selected patients with type 2 diabetes in 9 central hospitals in Aomori Prefecture and the surrounding district. Retinopathy levels and maculopathy were assessed by binocular funduscopy, fundus photography and, if necessary, by fluorescein angiography. Multiple logistic regression analysis was performed to determine independent effects of systemic risk factors on diabetic retinopathy. RESULTS: The prevalence of background retinopathy was 31%, of preproliferative retinopathy 5%, and of proliferative retinopathy 5% in all patients. However, in 3 hospitals in which the patients were routinely examined by fluorescein angiography, background retinopathy was found to be present in 60%, preproliferative retinopathy in 5%, and prolifertive retinopathy in 7%. Maculopathy was found in 8% of diabetic patients and the prevalence was 11% in the eyes with background retinopathy, 40% with preproliferative retinopathy, and 50% with proliferative retinopathy. Multiple logistic regression analysis showed that retinopathy was significantly associated with duration of diabetes, methods of diabetic control, hypertension, nephropathy, and neuropathy. CONCLUSION: The detection rate of background diabetic retinopathy by fluorescein angiography was twice as sensitive as that by binocular funduscopy and fundus photography. The prevalence of maculopathy increases with the progression of retinopathy. Several systemic risk factors have significant association with diabetic retinopathy and maculopathy.

[The new portable system for home enteral nutrition, Portermate, made a patient possible go out for a long time: report of a case].

The patient, who is received home enteral nutrition (HEN) for a long time in a day, has problems on moving all days. Now, we tried Portermate, which is new portable devices for HEN, in his clinical care. The patient is chronic pancreatitis, and his clinical problems becomes to be worse after he ate. He was under total enteral nutrition via jejunostomy. His clinical complications were almost controlled after HEN, but he has a few complains receiving enteral nutrition. He would not move easily, for an old HEN system was not compact to move. Portermate made him go everywhere he wanted any time. It extremely improved his QOL under HEN. He continues to use Portermate.

[Activities of antimicrobial agents against 5,180 clinical isolates obtained from 26 medical institutions during 1998 in Japan. Levofloxacin--Surveillance Group].

The surveillance study was conducted to determine the antimicrobial activity of fluoroquinolones (ofloxacin, levofloxacin, ciprofloxacin, tosufloxacin) and other 20 antimicrobial agents against 5,180 clinical isolates obtained from 26 medical institutions during 1998 in Japan. The resistance to fluoroquinolones was remarkable in Enterococci, methicillin-resistant staphylococci and Pseudomonas aeruginosa from UTI. However, many of the common pathogens such as Streptococcus pneumoniae including penicillin-resistant isolates, methicillin-susceptible Stahylococcus aureus, Moraxella catarrhalis, the family of Enterobacteriaceae, Haemophilus influenzae including ampicillin-resistant isolates have been kept to be susceptible to fluoroquinolones. About 90% of P. aeruginosa isolates from RTI were susceptible to fluoroquinolones. In conclusion, the results from this surveillance study suggest that fluoroquinolones are useful in the treatment of various bacterial infections including respiratory infections.

Structure-activity relationships of a new antifungal imidazole, AFK-108, and related compounds.

Fungicidal activity of widely used imidazole antifungal drugs in topical applications is not so strong in spite of their fungistatic activities against dermatophytes and pathogenic yeasts. In order to improve fungicidal activity of imidazole antifungal agents, a series of novel imidazole derivatives having a hydrophobic substituent derived from isoprenoid were synthesized. The efficacy of these compounds was evaluated with respect to direct cell-membrane damaging activity, ergosterol biosynthesis inhibition, minimum growth-inhibitory concentration (MIC) and therapeutic effect for experimental dermatophytosis of guinea pigs. Among the newly synthesized compounds, the geranyl derivative named AFK-108 (2a) showed the highest in vivo fungicidal activity with both cell membrane damaging activity and ergosterol biosynthesis inhibition in vitro.

Histological distribution of class III alcohol dehydrogenase in human brain.

The distributions of class III alcohol dehydrogenase (ADH), a glutathione-dependent formaldehyde dehydrogenase, and class I ADH in the human brain were examined immunohistochemically. The most intense immunostaining of class III ADH was observed in the dendrites and cytoplasm of cerebellar Purkinje cells. Scattered cerebral cortical neurons in layers IV and V, and some hippocampal pyramidal neurons were also immunopositive. The neuronal distribution of class III ADH resembled that of the vulnerable neurons in patients with hypoxic encephalopathy, which in view of the intense staining in the Purkinje cells, raises the possibility that this enzyme contributes to the hypoxia and cerebellar degeneration suffered by chronic alcoholics. Perivascular and subependymal astrocytes, which contribute to the maintenance of the cerebral cellular milieu and isolate the brain from the systemic circulation and cerebrospinal fluid, were also class III ADH positive. As the substrates of this enzyme include intrinsic toxic formaldehyde, inflammatory intermediate of 20-hydroxy-leukoteiene B4, and possibly ethanol, the distribution of class III ADH immunostaining indicates this enzyme contributes to the defence of the brain against degenerative processes. The finding that, unlike ependymal cells, subependymal astrocytes were class III ADH positive, suggests this enzyme may be useful for differentiating astrocytes and ependymal cells.

[Episodic and semantic memory after traumatic brain injury in a child].

In an early-life, a memory disturbance affects the learning and school record directly. Furthermore, it may cause the problem of maltreatment or adaptation difficulty for school life. We report a child amnesia caused by a traumatic brain injury when she was 9 years old. We examined her episodic and semantic memory. We developed 3-steps tasks of recognition and recall for the post-accident episodic memory. First, the examiner presented the patient with four words orally including a label of her episode, and asked her to choose one that she felt familiar with (the recognition of the episodic label). Second, if the word she selected was correct, she was required to recall the episode related to the word (the recall of the episode). Third, if she could not recall the episode herself correctly, she was required to choose a correct sentence about the episode (the recognition of the episode). She could not recall episodes correctly, but produced confabulation instead. She showed, however, good recognition of each episode. Furthermore, we performed recognition tests of time, person, and place about the same post-accident episodes, which were poor especially for time. In semantic memory tasks, we examined about kanji characters (ideogram) learned from the first grade to the sixth grade and mathematical knowledge learned from the second grade to the sixth grade at elementary school ("What centimeters is equal to one meter?" or "Tell me the formula of the size of a circle." etc). We found that she showed a retrograde impairment for about one year. For both episodic and semantic memory, she showed an anterograde impairment. Because of the anterograde amnesia she could not acquire new facts, and also showed para-amnesia or confabulation. In a child with brain damage, neuropsychological assessment is important in predicting effect of rehabilitation and recovery of school performance.

Long-term potentiation of Ca2+ signal in the rat auditory cortex.

The Ca2+ signal in supragranular layers of the rat auditory cortex (AC) was studied in slice preparations using rhod-2, a Ca2+ indicator. White matter stimulation elicited an increase in the Ca2+ signal, which was maximal in the image taken 34 ms after stimulation. This peak time was the same as that of the Ca2+ signal in pyramidal neurons injected with rhod-2. The intensity of the Ca2+ signal was proportional to the amplitude of the field potentials in supragranular layers. The Ca2+ signal was inhibited almost completely by 200 microM Ni2+ , but only slightly by 50 microM D-2-amino-5-phosphonovalerate (APV), an NMDA-receptor antagonist. Tetanic stimulation of the white matter or supragranular layers elicited long-term potentiation (LTP) of the Ca2+ signal in AC slices, but the potentiation was not clear in slices of the visual cortex (VC). The induction of LTP of the field potentials in AC slices was blocked by 50 microM APV or 50 microM Ni2+. These results indicate that Ca2+ influx through Ni2+ -sensitive Ca2+ channels in pyramidal neurons is potentiated by tetanic stimulation in parallel with LTP of neural activities and might be important for the induction of LTP in AC slices.

Irreversible impairment of inhibitory neurons and nitric oxide release in the neocortex produced by low temperature and hypoxia in vitro.

Brain ischemia causes irreversible hyperexcitability, which may be attributed to irreversible impairment of inhibitory neurons. However, the conditions required for selective and irreversible impairment of inhibitory interneurons in vitro are unknown. In this study, we found that a combination of low temperature and hypoxia produced hyperexcitability in the neocortex. Neocortical tissue blocks isolated from rats were exposed to low temperature (1-3 degrees C) for 45 min and subsequently to room temperature (21-23 degrees C) for 60 min in the non-oxygenated medium. In experimental slices prepared from the processed blocks, hyperexcitability, similar to that elicited by an antagonist of GABA(A) receptors, was observed. Exposure of the neocortical tissue blocks to low temperature alone or room temperature alone did not elicit hyperexcitability. The excitability of pyramidal neurons, excitatory synaptic transmission and inhibitory effects of an agonist of GABA(A) receptors were normal in experimental slices. However, excitation of pyramidal neurons was inhibited after local stimulation of inhibitory neurons in control slices, but not in experimental slices. Nitric oxide (NO) release from cortical interneurons was also markedly reduced in experimental slices. These results indicate that irreversible impairment of neocortical inhibitory neurons was produced by low temperature combined with hypoxia produced in vitro.

[Annual change of the pet in allergic patients home for ten years].

There are only few paper in Japan which reports the prevalence of pet keepers in the allergic population and also of the type of pets they keep. We made investigation on these points in 1337 allergic patients employing a questionnaire. Among 1337 patients, allergic conjunctivitis patients were found in 67, eczema patients in 118, allergic rhinitis patients in 368 and bronchial asthmatic patients in 1043. These number contained those who overlapped in symptoms. Approximately 43% of allergy patients are currently keeping the pet at present while 11.2% of the patient had kept the pet in the past. There were two peaks in the age when they began to keep a pet, 6 to 12 and 30 to 40 years of age. Trend in the past decade showed that both the dog and cat bred in foreign countries were increasing. About 80% of patients who own the foreign bred dogs keep them indoor. This ratio is increasing gradually. Another conspicuous change is the sharp increase in those who keep hamsters which occupied 20% of all the pet keeper in 1997. Percentages of the patient who recognizes the aggravation of their symptoms in eye, nose, skin and also as asthma often pet keeping is a about 10%. One out of 4 patients who keep the pet has a family member with rhinitis and/or asthma. We concluded that too many of the allergic patients keep the pet against their benefit and they must be informed that the pet could be the cause of allergy symptoms.

Long-lasting enhancement of sound discrimination ability after sound exposure in rats.

Changes in the sound discrimination ability of rats were investigated after sound exposure (SE) in a Skinner box. For estimation of the sound discrimination ability, two different amplitude-modulated (AM) sounds (S+ and S-) were presented to the rats deprived of water for 48 h. Pedal press behavior in response to only S+ was rewarded with water. The percentages of trials in which pedal press behavior occurred in response to S+ or S- were calculated separately, and test performance of the rats was determined from the difference between the percentages. Rats were exposed to AM sounds during SE of 48 h, and the sound discrimination test was carried out. Enhancement of discrimination between S+ and S- was elicited by SE in a stimulus-specific manner. Latent extinction of the pedal press behavior in response to sound stimuli was not clearly found after SE. The enhancement of test performance was detected 1-48 h after the cessation of SE, and was blocked by injection of an antagonist of N-methyl-D-aspartate receptors into the auditory cortex bilaterally, immediately before the initiation of SE. These results suggest that SE elicits enhancement of sound discrimination ability, and the responsible site is in the auditory cortex.

YM116, 2-(1H-imidazol-4-ylmethyl)-9H-carbazole, decreases adrenal androgen synthesis by inhibiting C17-20 lyase activity in NCI-H295 human adrenocortical carcinoma cells.

The concentrations of androstenedione and dehydroepiandrosterone, products of C17-20 lyase, in the medium after a 6-hr incubation of NCI-H295 cells were decreased by YM116 (2-(1H-imidazol-4-ylmethyl)-9H-carbazole) (IC50: 3.6 and 2.1 nM) and ketoconazole (IC50: 54.9 and 54.2 nM). 17Alpha-hydroxyprogesterone, a product of 17alpha-hydroxylase, was increased by YM116 (1-30 nM) and by ketoconazole (10-300 nM) and then was decreased at higher concentrations of both agents (IC50: 180 nM for YM116, 906 nM for ketoconazole), indicating that YM116 and ketoconazole were 50- and 16.5-fold more specific inhibitors of C17-20 lyase, respectively, than 17alpha-hydroxylase. Compatible with these findings, progesterone, a substrate of 17alpha-hydroxylase, was increased by these agents. Cortisol production was inhibited by YM116 and ketoconazole (IC50: 50.4 and 80.9 nM, respectively). YM116 was a 14-fold more potent inhibitor of androstenedione production than cortisol production, whereas ketoconazole was a nonselective inhibitor of the production of both steroids. YM116 and ketoconazole inhibited the C17-20 lyase activity in human testicular microsomes (IC50: 4.2 and 17 nM, respectively). These results demonstrate that YM116 reduces the synthesis of adrenal androgens by preferentially inhibiting C17-20 lyase activity.

Layer-specific NO dependence of long-term potentiation and biased NO release in layer V in the rat auditory cortex.

1. We investigated the role of nitric oxide (NO) in the induction of long-term potentiation (LTP) in slices prepared from the rat auditory cortex. 2. Tetanic stimulation of layer IV elicited LTP of field potentials in layer II-III (LTPII-III) and in layer V (LTPV). The magnitude of LTPII-III measured at 30 min after tetanic stimulation was 171 +/- 9% (n = 15, mean +/- s.e.m.) of the control measured before tetanic stimulation, while that of LTPV was 138 +/- 3% (n = 17). 3. NO synthase (NOS) inhibitors had no apparent effect on LTPII-III, but LTPV was significantly suppressed (P < 0.001). This suppression of LTPV was significantly antagonized by a NO donor (P < 0.001) or a cGMP analogue (P < 0.001). 4. Small non-pyramidal neurones in the auditory cortex were stained with an anti-neuronal NOS antibody. More neurones were stained with the antibody in the deeper cortical layers. 5. We measured neocortical NO release with electrochemical NO probes. Layer IV stimulation elicited significantly more NO release in layer V than in layer II-III (P < 0.001). The amplitude of the increase in NO concentration elicited by stimulation at 20 Hz for 5 s was 380 +/- 14 pM (n = 55) in layer V and 55 +/- 8 pM (n = 5) in layer II-III. 6. NO release in layer V was partially but significantly suppressed by non-NMDA (P < 0.002) or NMDA (P < 0.002) receptor antagonists. Simultaneous application of the antagonists of the two types blocked NO release almost completely. 7. These results clearly indicate the NO dependence of the induction of LTPV, and the greater NO release in the deeper layer of the rat auditory cortex.

[Measurement of theophylline concentrations by AccuMeter--comparison with the EIA method].

Theophylline is widely used for treating patients with bronchial asthma. However, since the therapeutic concentration range is narrow, adverse reactions are frequent and often difficult to control, making monitoring of theophylline concentration mandatory for its efficient and safe use. In this study, we employed the AccMeter which allowed us to measure theophylline concentrations quickly and with ease, and compared it with EIA method. AccMeter is a kit which consists of two parts. One part consists of a chromatopaper with antitheophylline mouse monoclonal antibody fixed on it, on which a smaple is applied with enzyme-linked theophylline. The other part consists of a coloring solution. We used a part of arterial blood samples collected for gas analysis as trial samples. Both whole blood and plasma from 50 patients who did or did not receive theophlline were analysed. Plasma portions were also used for measurements by the EIA method. Results from all three measurements were almost identical, and showed good correlation. The time necessary for measurement using AccMeter was about 20 minutes. We consider this method to be useful for clinics due to its simplicity and ease of handling, and the accuracy of the results obtained.

Novel nonsteroidal inhibitor of cytochrome P450(17alpha) (17alpha-hydroxylase/C17-20 lyase), YM116, decreased prostatic weights by reducing serum concentrations of testosterone and adrenal androgens in rats.

BACKGROUND: The purpose of this study was to determine the effects of a nonsteroidal C17-20 lyase inhibitor, 2-(1H-imidazol-4-ylmethyl)-9H-carbazole (YM116), on serum concentrations of androgens and ventral prostatic weight in rats. METHODS: Serum concentrations of testosterone and of dehydroepiandrosterone sulfate and prostatic weights were measured in rats treated with YM116. RESULTS: YM116 inhibited testicular C17-20 lyase competitively (Ki, 0.38 nM), and decreased the serum testosterone concentration in gonadotropin-releasing hormone-treated rats (ED50, 0.7 mg/kg), indicating that YM116 was about 21-24 times more potent than other C17-20 lyase inhibitors such as ketoconazole and liarozole, and was twice as potent as CB7630. YM116 also reduced dehydroepiandrosterone sulfate levels in ACTH-treated castrated rats (ED50, 11 mg/kg). YM116 (40 mg/kg, p.o., for 2 weeks) was almost comparable to bilateral orchiectomy with respect to the time course and magnitude of the reduction in prostatic weight. Each of these two treatments decreased the prostatic weight 3 days following the treatment. Contrarily, leuprolide transiently increased the prostatic weight and then decreased it. YM116 (100 mg/kg) had no effect on the serum cortisol level in guinea pigs, and slightly decreased the serum aldosterone level in rats. CONCLUSIONS: YM116 is a selective C17-20 lyase inhibitor which decreases rat prostatic weight by reducing androgen production in the testes and adrenal glands.