Background: Diabetic retinopathy (DR) has become a worldwide concern in recent years because of the high prevalence and vision-threat. The limited therapies have been in stark contrast to its high prevalence. On top of that, almost all the treatments, like laser, are applied only at the end stage of this disease. However, with the development of network pharmacology, a traditional Chinese medicine (TCM), Compound Danshen Dripping Pill (CDDP), may bring some new insights into the early intervention of DR. Methods: The active compounds and potential targets of CDDP and DR-related targets were collected from the TCMSP, UniProt, GeneCards and OMIM databases. And protein-protein interactions (PPI) information was achieved from the STRING database. The gene enrichment analysis of GO and KEGG was carried out by "clusterPro ler" in R software. The collected data was then used to form network maps of compound-target and PPI, or visualized by the software of Cytoscape. Results: 54 compounds and 50 targets were identi ed for CDDP against DR. Among the predicted effective compounds, 29 tanshinones from Radix Salviae (Danshen) were identi ed. And the core targets might be estrogen receptor (ESR1), androgen receptor (AR), caspase-3 (CASP3), Interleukin-6 (IL6) and vascular endothelial growth factor A (VEGFA) in 50 targets. There were 266 signi cantly correlated biological processes such as steroid hormone response, oxidative stress and apoptosis enriched out. Besides, The 50 targets signi cantly participate in 97 pathways and mainly enriched in advanced glycation end products (AGE)-receptor for advanced glycation end products (RAGE), uid shear stress and atherosclerosis, apoptosis and VEGF signal pathway et al. Conclusions: The mechanisms of CDDP for treating DR may involve multi-compound, multi-target and multi-pathway synergistic effects. It may participate in the regulation of steroid hormone response, oxidative stress, apoptosis and hemodynamics in diabetic retina. Tanshinones and luteolin from Radix Salviae were probably responsible for the effectiveness of CDDP on DR.

A series of novel 3-(3-substituted-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro- 1-methylpyridines (substituted-TZTP; 5a-l, 7a-h, 8, 9c-n, 11, 13j) were synthesized and tested for central muscarinic cholinergic receptor affinity by using [3H]-oxotremorine-M (Oxo-M) and [3H]-pirenzepine (Pz) as ligands. The potency and efficacy of the compounds for the pharmacological defined M1 and M2 muscarinic receptors were determined on isolated electrically stimulated rabbit vas deferens and on spontaneously beating isolated guinea pig atria, respectively. Selected compounds were also tested for M3 activity in the isolated guinea pig ileum. The C1-8 alkoxy-TZTP 5a-l analogues all displaced [3H]-Oxo-M and [3H]-Pz with low nanomolar affinity. Depicting chain length against Oxo-M binding and against Pz binding the unbranched C1-8 alkoxy-TZTP (5a-h) derivatives produced U-shaped curves with butoxy- (5d) and (pentyloxy)-TZTP (5e) as the optimum chain length, respectively. This U-shaped curve was also seen in the ability of the compounds 5a-h to inhibit the twitch height in the vas deferens preparation. The (pentyloxy)- (5e) and the (hexyloxy)-TZTP (5f) analogues produced an over 90% inhibition of the twitch height with IC50 values in the low picomolar range. In both the atria and in the ileum preparations 5f had low efficacy and potency. With the (alkylthio)-TZTP (7a-h) analogues the structure-activity relationship was similar to the one observed with the alkoxy (5a-h) analogues, but generally 7a-h had higher receptor affinity and was more potent than the corresponding 5a-h. However, the C3-8 alkyl-TZTP (9c,e,g,h) analogues had 10-100 times lower affinity for the central muscarinic receptors than the corresponding alkoxy and alkylthio derivatives, and their efficacy in the vas deferens preparation was too low to obtain IC50 values. The unsubstituted TZTP (11) compound was a potent but nonselective muscarinic agonist. The two 3-(3-butoxy/(hexyloxy)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahy dro-1- methylpyridines (butoxy/hexyloxy)-OZTP; 19a/b) were also synthesized and tested. Both 19a and 19b had much lower affinity for the central muscarinic receptors than 5d and 5f, and the efficacy of 19a,b was too low to give IC50 values in the vas deferens preparation. Therefore, the C5-6 (alkyloxy)/(alkylthio)-TZTP's represent a unique series of potent functional M1 selective muscarinic agonists.

Xanomeline is a novel muscarinic receptor agonist relatively devoid of parasympathomimetic side effects. Xanomeline had high affinity for muscarinic receptors and much lower affinity for a variety of other neuronal receptors in radioligand binding assays. Functional studies in cell lines transfected with the muscarinic receptor subtypes demonstrated that xanomeline had higher potency and efficacy for m1 and m4 receptors than m2, m3, and m5 receptor subtypes. Similarly, in isolated tissue studies, xanomeline had higher potency and efficacy for M1 receptors in rabbit vas deferens than at M2 receptors in guinea pig atria or M3 receptors in guinea pig bladder. Secretion of soluble amyloid precursor protein from m1 cell lines was potently stimulated by xanomeline. In vivo, xanomeline robustly stimulated phosphoinositide hydrolysis in brain, consistent with m1 agonism. Xanomeline produced modest increases in brain acetylcholine levels and did not produce bradycardia, suggesting little, if any, m2 agonist activity in vivo. Additionally, xanomeline did not induce nonselective cholinergic agonist side effects such as tremor, hypothermia and salivation. In animal behavior studies, xanomeline reduced locomotion and blocked memory deficits that were induced by a muscarinic antagonist in a passive avoidance paradigm. Xanomeline was found to be safe and reasonably well tolerated in safety studies in humans. In a placebo controlled double blind clinical trial of 6 months duration, xanomeline halted cognitive decline in patients with Alzheimer's disease. Furthermore, behavioral symptoms associated with Alzheimer's disease such as hallucinations, delusions and vocal outbursts were significantly decreased by xanomeline treatment. Additional clinical trials are under way to assess the novel therapeutic effects of xanomeline. Drug Dev. Res. 40:158–170, 1997. © 1997 Wiley‐Liss, Inc.

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Objective: The purpose of this pilot study was to collect preliminary information for a study to determine the immediate effects of a single unilateral chiropractic manipulation to the lower cervical spine on handgrip strength and free-throw accuracy in asymptomatic male recreational basketball players. Methods: For this study, 24 asymptomatic male recreational right-handed basketball players (age = 26.3 ± 9.2 years, height = 1.81 ± 0.07 m, body mass = 82.6 ± 10.4 kg [mean ± SD]) underwent baseline dominant handgrip isometric strength and free-throw accuracy testing in an indoor basketball court. They were then equally randomized to receive either (1) diversified left lower cervical spine chiropractic manipulative therapy (CMT) at C5/C6 or (2) placebo CMT at C5/C6 using an Activator adjusting instrument on zero force setting. Participants then underwent posttesting of isometric handgrip strength and free-throw accuracy. A paired-samples t test was used to make within-group pre to post comparisons and between-group pre to post comparisons. improved by 0.7 kg (mean) in the CMT group (P = .710). Free-throw accuracy increased by 13.2% in the CMT group (P = .058). The placebo CMT group performed the same or more poorly during their second test session. Conclusions:The results of this preliminary study showed that a single lower cervical spine manipulation did not significantly impact basketball performance for this group of healthy asymptomatic participants. A slight increase in free-throw percentage was seen, which deserves further investigation. This pilot study demonstrates that a larger study to evaluate if CMT affects handgrip strength and free-throw accuracy is feasible.

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