Kegg Pathway: Azoles

Mycoses. 2009 Nov 3;
Rüping MJ, Müller C, Vehreschild JJ, Böhme A, Mousset S, Harnischmacher U, Frommolt P, Wassmer G, Drzisga I, Hallek M, Cornely OA

Summary Antifungal prophylaxis during first remission induction chemotherapy for acute myelogenous leukaemia requires broad spectrum Azoles. In a clinical trial, therapeutic drug monitoring (TDM) of antifungal prophylaxis with voriconazole 200 mg bid was evaluated in a population of six patients. High pressure liquid chromatography was applied. Trough levels were obtained 24 h after the last voriconazole dose. Median time of voriconazole exposure prior to sample acquisition was 16 days (range 9-21). The mean voriconazole concentration was 486 mug l(-1) and ranged from 136 mug l(-1) to 1257 mug l(-1). Among possible or probable treatment-related adverse events, elevated liver function tests were the most frequent. Five of six patients developed fever during neutropenia, but none of them developed pulmonary infiltrates or other signs of invasive fungal infection while on voriconazole prophylaxis. Future investigations might aim at identifying drug level thresholds that allow for minimum toxicity and optimum efficacy of antifungal prophylaxis.

J Environ Pathol Toxicol Oncol. 2009; 28(3): 223-30
Yang W, Chen J, Zhou L

Massage, one form of physical therapy, is widely used for a large number of musculoskeletal disorders, but its exact mechanism still remains to be elucidated. One hypothesis is that the shear stress caused by massage may induce cutaneous mast cells to release histamine, thereby improving the local tissue microcirculation of blood. In the present work, a mast cell line (rat basophilic leukemia cells, RBL-2H3) was used in vitro to study cellular responses to the stimulus of shear stress generated by a rotating rotor in a cell dish. The intracellular calcium ([Ca2+]c) was studied by confocal fluorescence microscopy with Fluo-3/AM staining and the released histamine was measured with a fluorescence spectrometer using o-phthalaldehyde (OPA) staining. An elevation of [Ca2+]c occurred immediately after the shear stress, followed by histamine release. However, both [Ca2+]c increase and histamine release disappeared when a Ca2+-free saline was used, indicating that the rise in the [Ca2+]c is due to a Ca2+ influx from the extracellular buffer. Furthermore, Ruthenium red, a transient receptor potential vanilloid (TRPV) inhibitor, could effectively block the shear stressinduced histamine release, suggesting that TRPV membrane proteins are the likely targets of the shear stress. Because histamine is a well-known mediator of microvascular tissue dilation, these results may have an important impact on understanding the mechanism involved in massage therapy.

J Environ Pathol Toxicol Oncol. 2009; 28(3): 209-21
Hait-Darshan R, Babushkin T, Malik Z

Wilson's disease (Wd) is a genetic disorder resulting in Cu2+ accumulation, and is caused by mutations in the ATP7B gene, the copper transporter. In vivo studies show a correlation between Cu2+ accumulation and malfunction of the heme biosynthesis pathway. In this study, we describe multiple effects of Cu2+ accumulation on heme synthesis, which, in turn, affect proteasomal activity. Cu2+ toxicity was examined in two hepatocellular carcinoma cell lines, HepG2 and Hep3B, with Hep3B cells containing an integrated hepatitis B virus genome. Exposure of HepG2 and Hep3B cells to Cu2+ inhibited the enzymes PBGD and ALAD of the heme synthesis pathway and, in parallel, upregulated heme oxygenase-1 (HO-1). Proto-porphyrin IX (PpIX) and the heme pool were reduced as a result of these processes. PpIX synthesis was found to be lower in cells expressing the mutant ATP7B (P1134P), compared to those expressing the WT enzyme. Proteasomal activity was inhibited under Cu2+ treatment in HepG2 cells; however, Cu2+ induced marked proteosomal acceleration in Hep3B cells. Under these conditions, Ub-conjugated proteins were gradually accumulated, whereas treatment with bathocuproine disulfonic acid (BCS), a Cu2+ chelator, reversed this effect. In conclusion, our data suggest that copper downregulates the heme synthesis pathway in hepatocellular cells and further reduces it in the presence of mutated ATP7B.

J Antimicrob Chemother. 2009 Nov 3;
Cornely OA, Maertens J, Bresnik M, Ullmann AJ, Ebrahimi R, Herbrecht R

Objectives To analyse the potential antagonism between Azoles, which inhibit ergosterol synthesis, and polyenes, which bind directly to ergosterol in cell membranes, in patients receiving sequential azole-polyene treatment. Methods In an earlier randomized, double blind study of liposomal amphotericin as initial therapy for invasive filamentous fungal infection (IFFI), a 3 mg/kg/day dose had a favourable overall response rate of 50% and 12 week survival rate of 72%. No improved outcome was seen with 10 mg/kg/day for the first 14 days. The study population was further analysed for the effect of prior azole exposure on treatment responses to liposomal amphotericin B. The protocol allowed prior treatment with Azoles for prophylaxis or empirical therapy, and for up to 4 days for the confirmed IFFI before starting liposomal amphotericin B. Outcomes were compared for subsets of patients based on receipt of any azole and receipt of voriconazole during the 30 day screening period prior to study treatment. Results Of 201 patients with data review board-confirmed IFFI, 116 (57.7%) received prior Azoles and 36 (17.9%) received prior voriconazole. Favourable responses were achieved in 57 (49.1%) patients with prior azole exposure, in 39 (45.9%) without prior azole and in 13 (36.1%) with prior voriconazole. Numbers of patients alive at 12 weeks were 74 (63.8%) with any prior azole, 56 (65.9%) without prior azole and 26 (72.2%) after prior voriconazole. No differences were statistically significant. Conclusions Prior treatment with any azole or specifically with voriconazole did not seem to impact on overall response or survival in patients treated with liposomal amphotericin B for confirmed IFFI.

Am J Psychiatry. 2009 Nov; 166(11): 1298
Werremeyer A

Radiat Res. 2009 Nov; 172(5): 607-16
Zhang Q, Hu JZ, Rommereim DN, Murphy MK, Phipps RP, Huso DL, Dicello JF

Herein we demonstrate that high-resolution magic angle spinning (MAS) 1H NMR can be used to profile the pathology of bone marrow rapidly and with minimal sample preparation. The spectral resolution obtained allows several metabolites to be analyzed quantitatively. The level of NMR-detectable metabolites in the epiphysis + metaphysis sections of mouse femur were significantly higher than that observed in the diaphysis of the same femur. The major metabolite damage to bone marrow resulting from either 3.0 Gy or 7.8 Gy of whole-body gamma radiation 4 days after exposure were (1) decreased total choline content, (2) increased fatty acids in bone marrow, and (3) decreased creatine content. These results suggest that the membrane choline phospholipid metabolism (MCPM) pathway and the fatty acid biosynthesis pathway were altered as a result of radiation exposure. We also found that the metabolic damage induced by radiation in the epiphysis + metaphysis sections of mouse femur was higher than that of the diaphysis of the same femur. Traditional histopathology analysis was also carried out to correlate radiation damage with changes in metabolites. Importantly, the molecular information gleaned from high-resolution MAS 1H NMR complements the pathology data.

Curr Alzheimer Res. 2009 Oct; 6(5): 431-7
Kalinin S, Richardson JC, Feinstein DL

Agonists of the peroxisome proliferator activated receptor gamma (PPARgamma) have been shown to reduce inflammatory responses in several animal models of neurological diseases and conditions and to reduce amyloid burden in transgenic mice expressing mutant forms of human amyloid precursor protein. However, the effects of activating the related receptor PPARdelta (PPARdelta), which is expressed at higher levels in the brain than PPARgamma, on inflammation and amyloid burden have not been explored. In this study we tested the effects of the selective PPARdelta agonist GW742 in 5xFAD mice which harbor 3 mutations in amyloid precursor protein and 2 mutations in presenilin 1, develop plaques by 5-6 weeks of age, and show robust inflammation and neuronal damage. Oral delivery of GW742 significantly reduced amyloid plaque burden in the subiculum region of 3-month old male and female 5xFAD mice. GW742 also significantly reduced astrocyte activation, suggesting anti-inflammatory effects on glia cells. The changes in plaque burden were accompanied by increased expression of the amyloid degrading enzymes neprilysin and insulin degrading enzyme, while in transfected HEK293 cells, GW742 activated a neprilysin promoter driving luciferase expression. These results suggest that, as found for some PPARgamma agonists, PPARdelta agonists can also reduce amyloid burden likely to be mediated by effects on amyloid clearance.

Expert Opin Pharmacother. 2009 Nov; 10(16): 2723-33
Krishnan-Natesan S

Terbinafine (TRB) is an allylamine antifungal agent that has been available for more than a decade. It is now used for the treatment of dermatophytic infections and onychomycosis. Despite several studies having demonstrated the efficacy of terbinafine against nondermatophytic infections including azole-resistant candidiasis, invasive aspergillosis, disseminated fusariosis and scedosporiosis, the role of TRB in the management of these infections remains greatly underappreciated. A brief review of pharmacodynamic, pharmacokinetic, in vitro and in vivo data and published case reports provides insight into the use of terbinafine as a potential adjunct in combination with Azoles, polyenes or echinocandins in the management of severe drug-resistant or refractory mycoses. Despite the lack of intrinsic fungicidal activity against several nondermatophytes, when used in combination, particularly with Azoles, TRB has demonstrated good antifungal efficacy that could be exploited in clinical practice. As comprehensive human clinical studies are not feasible with the rare occurence of these mycoses, experiments using animal models are essential to evaluate the in vivo efficacy of drug combinations. In summary, terbinafine has established itself as a drug of choice for dermatophytic infections; it must be considered in combination with other antifungal agents for the management of nondermatophytic refractory or resistant yeast/mold infections as well.

Zhongguo Zhen Jiu. 2009 Oct; 29(10): 799-803
Zhang SJ, Li SR, Li JS, Liu J, Song RX

OBJECTIVE: To compare therapeutic effects of acupuncture at local points of eye and western medicine on paralytic strabismus. METHODS: One hundred cases were randomly divided into an acupuncture group and a medication group. The acupuncture group (58 cases) was treated with acupuncture at local points of eye, Jingming (BL 1), Tongziliao (GB 1), Shangming (Extra) etc. were selected; and the medication group (42 cases) was treated with oral administration of Methycobal and Vitamin B1. After treatment of 5 courses, the therapeutic effects in the two groups were observed. RESULTS: The total effective rate of 94.8% in the acupuncture group was superior to that of 85.7% in the medication group (P<0.01); the therapeutic effects of the acupuncture group for treatment of oculomotor nerve and abducent nerve were significantly better than that of the medication group (P<0.05); the acupuncture group was better than the medication group in synoptophore examination results and improvement of rima oculi and pupil (P<0.01, P<0.05), the acupuncture group was superior to the medication group in improvement of the function of paralysis eye muscle, including medial rectus and lateral rectus except superior oblique (P<0.01, P<0.05). CONCLUSION: Acupuncture on local points of eye is an effective therapy for paralytic strabismus.

Zhongguo Zhong Yao Za Zhi. 2009 Jul; 34(13): 1658-60
Yang L, Feng X, Zhang S, Yang J, Wang H, Ge X, Jia F

OBJECTIVE: To study the processing technics of prepared slice of Rhizoma Dioscoreae for its industrial production. METHOD: The effect factors, such as stiring temperature (60, 80, 100 degrees C), stiring time (10, 20, 30 min) and the proportion of pieces and wheat bran (100: 5, 100: 10, 100: 15) were evaluated by orthogonal method. The content of allantoin in Rhizoma Dioscoreae was determine by HPLC method. RESULT: The amount of wheat bran could affect the content of allation significantly, and stiring temperature and stiring time almost had no effect on content of allantoin. The processing technics was tested by industrial produce, according to 11 batches from 4 growing regions. The result showed that the quality of industrial product was stable. CONCLUSION: That the amount of wheat bran can affect the quality of Rhizoma Dioscoreae greatly. The determined technics is simple and suitable for prepared slice of Rhizoma Dioscoreae industrival manufacture.