Is there a rational basis for cannabinoids research and development in ocular pain therapy? A systematic review of preclinical evidence.

BACKGROUND: Purpose of the present systematic review is to investigate preclinical evidence in favor of the working hypothesis of efficacy of cannabinoids in ocular pain treatment. METHODS: Literature search includes the most relevant repositories for medical scientific literature from inception until November, 24 2021. Data collection and selection of retrieved records adhere to PRISMA criteria. RESULTS: In agreement with a priori established protocol the search retrieved 2471 records leaving 479 results after duplicates removal. Eleven records result from title and abstract screening to meet the inclusion criteria; only 4 results are eligible for inclusion in the qualitative synthesis impeding meta-analysis. The qualitative analysis highlights the antinociceptive and anti-inflammatory efficacy of Δ8-tetrahydrocannabinol, cannabidiol and its derivative HU-308 and of new racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229. Moreover, CB2R agonists RO6871304 and RO6871085 and CB2R ligand HU910 provide evidence of anti-inflammatory efficacy. CB2 agonist HU308 reduces of 241% uveitis-induced leukocyte adhesion and changes lipidome profile. Methodological and design issues raise concern of risk of bias and the amount of studies is too small for generalization. Furthermore, the ocular pain model used can resemble only inflammatory but not neuropathic pain. CONCLUSIONS: The role of the endocannabinoid system in ocular pain is underinvestigated, since only two studies assessing the effects of cannabinoid receptors modulators on pain behavior and other two on pain-related inflammatory processes are found. Preclinical studies investigating the efficacy of cannabinoids in ocular inflammatory and neuropathic pain models are needed to pave the way for clinical translation.

Salubrinal reduces expression and activity of MMP13 in chondrocytes.

OBJECTIVE: Stress to the endoplasmic reticulum (ER) and inflammatory cytokines induce expression and activity of matrix metalloproteinase 13 (MMP13). Since a synthetic agent, salubrinal, is known to alleviate ER stress and attenuate nuclear factor kappa B (NFκB) signaling, we addressed a question whether upregulation of MMP13 by ER stress and cytokines is suppressed by administration of salubrinal. METHODS: Using C28/I2 human chondrocytes, we applied ER stress with tunicamycin and inflammatory distress with tumor necrosis factor α (TNFα) and interleukin 1ß (IL1ß). RNA interference with siRNA specific to NFκB p65 (RelA) was employed to examine a potential involvement of NFκB signaling in salubrinal's action in regulation of MMP13. We also employed primary human chondrocytes and evaluated MMP13 activity. RESULTS: The result showed that tunicamycin activated p38 mitogen-activated protein kinase (MAPK), while inflammatory cytokines activated p38 MAPK and NFκB. In both cases, salubrinal significantly reduced expression and activity of MMP13. Silencing NFκB reduced inflammatory cytokine-driven upregulation of MMP13 activity. CONCLUSIONS: The results demonstrate that salubrinal downregulates expression and activity MMP13 through p38 and NFκB signaling, suggesting its potential usage to treat degenerative diseases such as osteoarthritis.

Measurement of vitamin E metabolites by high-performance liquid chromatography during high-dose administration of alpha-tocopherol.

METHOD: alpha-Tocopherol and gamma-tocopherol are metabolized into 2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2,7,8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC), respectively. We analyzed alpha- and gamma-CEHC concentrations in human serum and urine by high-performance liquid chromatography during administration of alpha-tocopherol. Fourteen healthy adult male volunteers received 1,200 IU per day of RRR-alpha-tocopherol for 28 days. Blood and urine samples were obtained on days 0, 14, 28, and 56. RESULTS: During alpha-tocopherol administration, the plasma gamma-tocopherol concentration decreased significantly, but there was marked elevation of the alpha-tocopherol concentration. Increased concentration of alpha-CEHC and gamma-CEHC in both serum and urine indicated the acceleration of vitamin E metabolism. CONCLUSION: High-dose administration of alpha-tocopherol caused an increase of gamma-tocopherol metabolism, which might have caused a decrease of the plasma gamma-tocopherol concentration.

Clinical trial of a combination of rice bran fiber and cholestyramine for promotion of fecal excretion of retained polychlorinated dibenzofuran and polychlorinated biphenyl in Yu-Cheng patients.

A clinical trial using the combination of rice bran fiber (RBF) and cholestyramine (CHO) was carried out on Yu-Cheng patients in 1993-1994. By the analysis of blood and stool samples collected from the patients before and after (or during in the case of stool), it was verified that the administration of RBF and CHO is effective for excretion of polychlorinated biphenyl (PCB) (p < 0.05) and polychlorinated dibenzofuran (PCDF), especially 2, 3, 4, 7, 8-pentachlorodibenzofuran (p < 0.05). However, the degree of effectiveness varied upon individual patients from 60 to 160% for 2, 3, 4, 7, 8-pentachlorodibenzofuran, from 30 to 110% for 1, 2, 3, 4, 7, 8-hexachlorodibenzofuran and from 50 to 190% for PCB, respectively.

[Levels of PCDDs, PCDFs and coplanar PCBs in the blood and stool of Taiwanese Yu-Cheng patients].

Levels of PCDDs, PCDFs and coplanar PCBs were measured in the blood and stool obtained from seventeen patients with Yu-Cheng in Taiwan. The average total concentrations of PCDDs, PCDFs and coplanar PCBs in the blood collected from Yu-Cheng patients in January 1993 and August 1994 were 590 and 570 pg Toxic Equivalents (TEQs)/g lipid, respectively. The concentrations of PCDDs, PCDFs and coplanar PCBs in the blood of patients were 21, 540 and 10 pg TEQs/g fat, respectively. On the other hand, the fecal excretion of PCDDs, PCDFs and coplanar PCBs were 26, 720 and 15 pg TEQs/day, respectively. The composition of congeners in the feces was quite similar to the one in the blood. The half lives were estimated as 9.1 and 8.6 years for 2, 3, 4, 7, 8-pentachlorodibenzofuran and 1, 2, 3, 4, 7, 8-hexachlorodibenzofuran based on fecal excretion, respectively.