Surgical treatment for non-tuberculous mycobacterial pulmonary disease: analysis of prognostic factors.

BACKGROUND: The surgical treatment for non-tuberculous mycobacterial pulmonary disease (NTM-PD) has an important adjunctive role and reported outcomes have been generally good; however, the prognostic factors remain unclear.METHODS: Sixty-one patients with NTM-PD who underwent surgical resection for a therapeutic purpose from January 2000 to March 2017 at five affiliated institutions were enrolled. We explored the factors that influence complications and prognosis by retrospectively referring to the medical records.RESULTS: The mean age of the present cohort was 61.8 ± 11.4 years. The pathogen was Mycobacterium avium complex in 49 patients, M. abscessus in 5. The most common indications were refractory to medication in 39. The surgical techniques employed were lobectomy or further resection in 49, sublobar resection in 8, with video-assisted thoracoscopic surgery in 21. Sputum culture conversion rate was 95.1%. Univariate analysis of factors associated with deterioration revealed significant differences related to age (P = 0.025), pre-operative albumin level (P = 0.001) and development of postoperative complications (P = 0.037), while pre-operative albumin level alone was a significant factor in multivariate analysis (P = 0.009).CONCLUSION: Outcomes after resection were generally good in the present cases. Nutritional status, as indicated by albumin level, may affect prognosis after surgical treatment.

Solitary pulmonary nodules due to non-tuberculous mycobacteriosis among 28 resected cases.

BACKGROUND: In some patients, non-tuberculous mycobacteria (NTM) infections manifest in solitary nodules (solitary nodular [SN] type) generally caused by Mycobacterium avium complex (MAC). In patients treated using surgical resection, the American Thoracic Society guidelines state that postoperative chemotherapy is not necessary in the absence of lesions, although there have been a few reports of such cases. METHODS: Twenty-eight patients diagnosed with NTM who underwent solitary pulmonary nodule resection at Toneyama Hospital, Osaka, Japan, between January 2000 and October 2012 were enrolled. We evaluated the influence of the surgical procedure and chemotherapy on outcomes in this retrospective study. RESULTS: Of the 28 patients, 12 were males and 16 were females; the mean age was 58.6 ± 13.2 years. Twenty-five patients were asymptomatic and bronchoscopy was performed in 18; only 2 had a definitive diagnosis of NTM. The pathogen responsible was MAC in 27 patients and M. kansasii in 1. The surgical procedure used was wedge resection in 22 patients, segmentectomy in 1 and lobectomy in 5. Postoperative chemotherapy was administered to 9 patients. Twenty-six patients had no recurrence. CONCLUSION: We believe that wedge resection is a valid surgical intervention for SN type NTM; additional postoperative chemotherapy is unnecessary in cases with no residual lesions in the operated lung lobe.

Evaluation of the inhibitory and induction potential of YM758, a novel If channel inhibitor, for human P450-mediated metabolism.

This study was designed to examine the in vitro metabolism of YM758, a novel cardiovascular agent, and to evaluate its potential to cause drug interactions and induction of CYP isozymes. After incubation with pooled human liver microsomes, YM758 was converted to two major metabolites (AS2036313-00, and YM-394111 or YM-394112). The formation of AS2036313-00, and YM-394111 or YM-394112 were mediated by CYP2D6 and CYP3A4, respectively, which was elucidated by using a bank of human liver microsomes and recombinant CYP enzymes in combination with the utilization of typical substrates and inhibitors. The Ki values of YM758 for midazolam, nifedipine, and metoprolol metabolism ranged from 59 to 340 microM, being much higher than the YM758 concentration in human plasma. The formation of AS2036313-00, and YM-394111 or YM-394112 was inhibited by quinidine and ketoconazole with Ki values of 140 and 0.24 microM, respectively, which indicates that YM758 metabolism may be affected by coadministration of strong CYP2D6 and 3A4 inhibitors in vivo, given the clinical plasma concentrations of quinidine and ketoconazole. After human hepatocytes were exposed to 10 microM YM758, microsomal activity and mRNA level for CYP1A2 were not induced while those for CYP3A4 were slightly induced. The tested concentration was much higher than that in human plasma, which suggests that the induction potential of YM758 is also negligible.

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.

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.

Nerve growth factor modulates Fc gamma receptor expression on murine macrophage J774A.1 cells.

We assessed the effect of nerve growth factor (NGF) on Fcgamma receptor (FcgammaR) expression on murine monocyte-macrophage J774A.1 cells. Flow cytometric analysis showed that treatment with various doses of NGF led to a rapid increase of FcgammaRI and FcgammaRII/III expression in a dose-dependent manner. Northern blot analysis with digoxigenin-labeled oligonucleotide probes demonstrated that NGF induced a marked increase in mRNA synthesis of FcgammaRI and FcgammaRII, but not FcgammaRIII. Since pretreatment with K-252a, a tyrosine kinase inhibitor, inhibited the stimulatory effect of NGF completely, the FcgammaR expression augmented by NGF may be mediated through p140trk with a tyrosine kinase domain. These results suggest that NGF may be a novel cytokine that is able to increase FcgammaRI and FcgammaRII expression on macrophages.

Inhibitory effects of a novel aromatase inhibitor, YM511, on growth of endometrial explants and insulin-like growth factor-I gene expression in rats with experimental endometriosis.

Estrogen deprivation therapy effectively prevents progress of endometriosis but the precise mechanism by which estrogen stimulates growth of endometriotic implants is still unknown. We examined effects of hypoestrogenic state induced by ovariectomy, gonadotropin-releasing hormone agonist (leuprolide) or aromatase inhibitor (YM511), on growth of experimental endometrial explant, a section of endometrium transplanted under the renal capsule, in rats. Ovariectomy gradually reduced the volume of endometrial explants for 21 days. YM511 (0.1 mg/kg) and leuprolide (1 mg/rat) completely reduced volume of endometrial explants but they differed widely in the onset of inhibitory action. YM511 prevented growth of explants on day 4 but leuprolide had no inhibitory effect until day 15. YM511 dose-dependently reduced volume of endometrial explants and its minimum effective dose was 0.04 mg/kg. Insulin-like growth factor-I (IGF-I) mRNA expression in endometrial explant and uterus was examined on day 4. YM511 decreased IGF-I expression in endometrial explant and uterus by 58% and 48%, respectively. Reductions of the extent of IGF-I expression by YM511 and ovariectomy were comparable. A significant correlation between the volume and IGF-I mRNA expression in endometrial explant suggests that local expression of this gene may play an important role in stimulating growth of endometrial explants.

Functional properties of murine macrophages promoted by nerve growth factor.

The stimulating effect of nerve growth factor (NGF) on phagocytosis, parasite killing, and interleukin-1beta (IL-1beta) production of murine peritoneal macrophages was assessed. In the presence of various doses of NGF, macrophages showed the increased phagocytosis of both nonspecific hydrophilic microspheres and sheep red blood cells (SRBC) opsonized with anti-SRBC antibodies (Ab) or complement in a dose-dependent manner. NGF also enhanced killing of Leishmania donovani promastigotes by macrophages, and its ability was comparable with that of an optimal dose of recombinant granulocyte-macrophage colony-stimulating factor or recombinant interferon-gamma. The addition of NGF to peritoneal macrophages and monocyte-macrophage J774A.1 cells led to a significant release of IL-1beta in a dose-dependent manner and expression of IL-1beta mRNA. Because pretreatment of peritoneal macrophages and J774A.1 cells with K-252a, a tyrosine kinase inhibitor, completely suppressed these NGF-mediated stimulating effects and p140trk phosphorylation and because flow cytometric analysis with specific Ab against two distinct NGF receptors showed the expression of p140trk, unlike p75LNGFR, on the surface of macrophages, the stimulating activity of NGF to murine macrophages may be mediated through p140trk. Thus, NGF may act as an activator for murine macrophages in the process of inflammatory and immune actions.

Inhibitory effect of a novel non-steroidal aromatase inhibitor, YM511 on the proliferation of MCF-7 human breast cancer cell.

The proliferation of MCF-7, human breast cancer cell line, was stimulated by testosterone and estradiol. The aromatase activity in MCF-7 cells, which catalysed the conversion of testosterone to estradiol, was inhibited by a novel non-steroidal aromatase inhibitor, YM5111, with the IC50 of 0.2 nM, indicating that its inhibitory activity was 5.5 times more potent than that of CGS 16949A. YM511 inhibited the proliferation of MCF-7 stimulated by testosterone but did not inhibit the cell proliferation stimulated by estradiol. The IC50 values of YM511 for cell growth and DNA synthesis were 0.13 nM and 0.18 nM, respectively, demonstrating that YM511 was about 3-5 times more potent than CGS 16949A and had no anti-estrogenic or cytotoxic activity. YM511 significantly inhibited testosterone-stimulated transcriptional activation of estrogen-responsive element (ERE) in MCF-7 cells transfected transiently with ERE-luciferase reporter plasmid. The IC50 of YM511 for transactivation was 0.36 nM, suggesting that its inhibitory potency was comparable to the inhibition of aromatase activity of MCF-7 cells. These data may indicate that the inhibition by YM511 of cell proliferation of MCF-7 is attributed to the decreased production of estrogen due to the inhibition of aromatase activity. YM511 may be useful in the treatment of estrogen-dependent cancers.

The potent and selective inhibition of estrogen production by non-steroidal aromatase inhibitor, YM511.

YM511 inhibited aromatase activities in microsomes from rat ovary and human placenta competitively (IC50s: 0.4 and 0.12 nM, respectively). YM511 was about 3 times more potent than other aromatase inhibitors, such as CGS 16949A, CGS 20267 and R 76713. YM511 decreased the contents of estradiol stimulated by pregnant mare's serum gonadotropin in rat ovary with an ED50 of 0.002 mg/kg, indicating that YM511 was equipotent to CGS 20267 and 3 times more potent than the other two inhibitors. Serum estradiol levels in female rats were reduced by YM511 at 0.01 mg/kg into the ovariectomized range. YM511 at 1 mg/kg for 2 weeks decreased rat uterine weight to levels comparable to ovariectomy, showing it was 10 times more potent than other inhibitors. But the maximal inhibitory effect of tamoxifen failed to reach ovariectomized level. YM511 slightly inhibited production of other steroid hormones in vitro and in vivo. The IC50s of YM511 for aldosterone and cortisol production from adrenal cells were from 5500 to 9800 times higher than that for rat ovarian aromatase and 130,000 times higher for testosterone production, indicating that YM511 is a highly specific aromatase inhibitor. The data suggest that YM511 may be a potent and selective agent for suppressing estrogen-dependent action without affecting serum levels of other steroid hormones.