Dimethyl Sulfoxide Enhances Acetylcholine-Induced Contractions in Rat Urinary Bladder Smooth Muscle by Inhibiting Acetylcholinesterase Activities.

Dimethyl sulfoxide (DMSO) has been used not only as an experimental solvent, but also as a therapeutic agent for interstitial cystitis. The therapeutic effects of DMSO on interstitial cystitis are presumed to involve anti-inflammatory and analgesic effects. However, the effects of DMSO on urinary bladder smooth muscle (UBSM) have not been fully investigated. Thus, in this study, we investigated the effects of DMSO on rat UBSM contractions, and these effects were compared with those of acetone, which has a structure in which the sulfur of DMSO is replaced with carbon. DMSO (0.5-5%) enhanced acetylcholine (ACh)-induced contractions, whereas acetone (3 and 5%) suppressed them. Additionally, DMSO (5%) suppressed carbachol-induced contractions. DMSO/acetone (0.5-5%) inhibited 80 mM KCl-induced contractions in a concentration-dependent manner; however, the inhibitory effects of DMSO were weaker than those of acetone. The enhancing/suppressing effects of DMSO and acetone were almost completely abolished by wash out. DMSO and acetone (0.5-5%) inhibited recombinant human acetylcholinesterase (rhAChE) activity in a concentration-dependent manner. At 0.5 and 1%, the inhibitory effects of DMSO on rhAChE activity were more potent than those of acetone. These findings suggest that DMSO can enhance ACh-induced UBSM contractions and promote urinary bladder motility by inhibiting acetylcholinesterase (AChE), although DMSO also inhibits Ca2+ influx-mediated UBSM contractions. In addition, the sulfur atom in DMSO might play an important role in its enhancing effect on ACh-induced contractions by inhibiting AChE, as acetone did not enhance these contractions.

Inhibition of Recombinant Human Acetylcholinesterase Activity by Antipsychotics.

BACKGROUND/AIMS: Extrapyramidal symptoms (EPS) are representative side effects of antipsychotics, caused by their inhibitory action on dopaminergic nerves in nigrostriatal pathways. EPS could be also caused by direct augmentation of cholinergic effects, for example, by acetylcholinesterase (AChE) inhibition. We investigated the potential inhibitory effects of 26 clinically available antipsychotics on the activity of recombinant human AChE (rhAChE) to predict the role of antipsychotic-induced AChE inhibition in EPS onset. METHOD: The degree of rhAChE activity inhibition was calculated using the 5,5'-dithio-bis-(2-nitrobenzoic acid) method. RESULTS: At a concentration of 10-5 mol/L, haloperidol, bromperidol, timiperone, nemonapride, pimozide, risperidone, blonanserin, aripiprazole, and brexpiprazole inhibited rhAChE activity by >20%. Risperidone, aripiprazole, and brexpiprazole inhibited rhAChE activity in a concentration-dependent manner, and their effects were more potent than those of other antipsychotics. The inhibitory effects of these 3 drugs were evident from 10-6 mol/L, and their pIC50 values were 4.74 ± 0.04, 4.80 ± 0.04, and 4.93 ± 0.06, respectively. Notably, the concentration range in which aripiprazole inhibited rhAChE activity (≥10-6 mol/L) overlapped with its clinically achievable blood levels. CONCLUSION: Aripiprazole may cause EPS at clinical dosages by augmenting cholinergic effects via AChE inhibition, in addition to its suppressive effect on dopaminergic neurons.

New Diterpenes with a Fused 6-5-6-6 Ring System Isolated from the Marine Sponge-Derived Fungus Trichoderma harzianum.

New diterpenes, namely, trichodermanins F-H, with a fused 6-5-6-6 ring system were isolated from the fungus Trichoderma harzianum OUPS-111D-4 separated from a marine sponge Halichondria okadai. These chemical structures were elucidated by 1D and 2D NMR as well as high-resolution fast atom bombardment mass spectrometry (HRFABMS) spectral analyses. We established their absolute stereostructures by application of the modified Mosher's method or circular dichroism (CD) spectroscopy. In addition, their cytotoxicities were assessed using several cancer cell lines, with 1 and 2 exhibiting modest activities.

Inter-Technique Consistency and Prognostic Value of Intra-Procedural Angiographic and Echocardiographic Assessment of Aortic Regurgitation After Transcatheter Aortic Valve Implantation.

BACKGROUND: We investigated the relationship between intraprocedural angiographic and echocardiographic AR severity after TAVI, and the clinical robustness of angiographic assessment. Methods and Results: In 74 consecutive patients, the echocardiographic circumferential extent (CE) of the paravalvular regurgitant jet was retrospectively measured and graded based on the VARC-2 cut-points; and angiographic post-TAVI AR was retrospectively quantified using contrast videodensitometry (VD) software that calculates the ratio of the contrast time-density integral in the LV outflow tract to that in the ascending aorta (LVOT-AR). Seventy-four echocardiograms immediately after TAVI were analyzable, while 51 aortograms were analyzable for VD. These 51 echocardiograms and VD were evaluated. Median LVOT-AR across the echocardiographic AR grades was as follows: none-trace, 0.07 (IQR, 0.05-0.11); mild, 0.12 (IQR, 0.09-0.15); and moderate, 0.17 (IQR, 0.15-0.22; P<0.05 for none-trace vs. mild, and mild vs. moderate). LVOT-AR strongly correlated with %CE (r=0.72, P<0.0001). At 1 year, the rate of the composite end-point of all-cause death or HF re-hospitalization was significantly higher in >mild AR patients compared with no-mild AR on intra-procedural echocardiography (41.5% vs. 12.4%, P=0.03) as well as in patients with LVOT-AR >0.17 compared with LVOT-AR ≤0.17 (59.5% vs. 16.6%, P=0.03). CONCLUSIONS: VD (LVOT-AR) has good intra-procedural inter-technique consistency and clinical robustness. Greater than mild post-TAVI AR, but not mild post-TAVI AR, is associated with late mortality.

[SF-36 and EQ-5D in the evaluation of QOL in the osteoporotic patients as the generic questionnaires].

Health-related quality of life (HRQOL) , abbreviated as QOL, can be evaluated by various questionnaires, which are classified as generic and disease-targeted ones. Generic questionnaires are further subdivided into profile-type and preference-based ones. SF-36 and EQ-5D are the best known examples for the former and the latter, respectively. In SF-36 and its shortened one SF-8, the subjects' QOL is expressed by several profiles or subscales. Their advantages include well-conducted validation and availability of national norms. In EQ-5D, a single value representing the subjects' QOL status (utility) is obtained through 5 questions. These generic questionnaires are applicable to patients with various diseases or even to healthy citizens. In contrast, disease-targeted questionnaires lack such features, but can include items that are specifically related to the disease but devoid of general applicability. Thus, generic and disease-targeted questionnaires have their own pros and cons. Selection of the questionnaires depends on the object of the study.