OBJECTIVE Over 30% of all new psychoactive substances identified by the UN Office on Drugs and Crime in 2016 were synthetic cannabinoids.The recent emergence of MAM-2201 on the illicit market is troubling because this...OBJECTIVE Over 30% of all new psychoactive substances identified by the UN Office on Drugs and Crime in 2016 were synthetic cannabinoids.The recent emergence of MAM-2201 on the illicit market is troubling because this drug has no precedent in either the scientific or patent literature,and appears to be a novel compound developed specifically as a "graymarket" drug of abuse bystructurally combining the known synthetic cannabinoids JWH-122 and AM-2201.There is currently no published information regarding the pharmacology of MAM-2201.METHODS The present studies characterized cannabinoid-like effects of MAM-2201 in vitro(interactions with cannabinoid type 1 receptors[CB1 Rs]) and in vivo(in mice and rats).RESULTS In a radioligand binding assay using [3 H]CP55,940 in HEK cell membranes transfected with the CB1 R,MAM-2201(K i=5.4 nmol·L^(-1)),had higher binding affinity than WIN 55,212-2(K i=80 nmol·L^(-1)),and D9-THC(K i=8.3 nmol·L^(-1)).The E max values for MAM-2201 and WIN 55,212-2 in an assay of agonist inhibition of forskolin-stimulated c AMP were 85%(EC50=0.45 nmol·L^(-1)) and 95%,respectively,as compared with the D9-THC E max of 74%.In mice,MAM-2201(0.003-1.0 mg·kg^(-1),IP) produced dose-dependent cannabimimetic effects which were both more potent and more effective than those of D9-THC.MAM-2201 and D9-THC dose-dependently produced hypothermia:ED50=0.287 and 25.4 mg·kg^(-1),analgesia:ED50=0.125 and 29.4 mg·kg^(-1),and catalepsy:ED50=0.301 and18.9 mg·kg^(-1) in adult male CD1 mice.Importantly,MAM-2201 also elicited convulsant effects at a dose of 1.0 mg·kg^(-1) in 8/8 murine subjects.In rats,MAM-2201 produced dose-dependent D9-THC-like interoceptive effects in subjects trained to discriminate 3.0 mg·kg^(-1)(IP) D9-THC from saline.CONCLUSION MAM-2201 binds CB1 Rs with high affinity and agonist efficacy,and functions as a potent cannabinoid agonist in vivo across several complementary measures of cannabinoid activity in two rodent species.展开更多
Our increase in knowledge of the pathophysiology of non-infectious uveitis(NIU)and other immune-mediated diseases has been mirrored over the last two decades by the expansion of therapeutic options in the realm of imm...Our increase in knowledge of the pathophysiology of non-infectious uveitis(NIU)and other immune-mediated diseases has been mirrored over the last two decades by the expansion of therapeutic options in the realm of immunosuppressive medications.Principal among these advances is the emergence of biologics,which offer the promise of targeted therapy and the hope of reduced toxicity when compared to corticosteroids and“standard”immunosuppression.Among the biologics,monoclonal antibodies blocking tumor necrosis factor alpha(TNF-α)have been shown to be a very effective therapeutic target for uveitis and many associated systemic inflammatory diseases.Multiple TNF blockers have shown benefit for uveitis,and in 2016,adalimumab became the first biologic and non-corticosteroid immunosuppressive to obtain Food and Drug Administration(FDA)approval in the treatment of NIU.Although effective,TNF blockers are not universally so,and safety concerns such as infection and demyelinating disease must be carefully considered and ruled out prior to their use,especially in patients with intermediate uveitis with which multiple sclerosis is a known association.Ongoing study has identified novel targets for regulation in the treatment of immune-mediated and inflammatory diseases.Interferons,interleukin and Janus kinase inhibitors in addition to antibodies targeting T cell and B cell activation highlight the expanding field of treatment modalities in NIU.Ongoing study will be required to better determine the safety and efficacy of biologics in the armamentarium of immunosuppressive treatments for NIU.展开更多
A physician in clinical practice does not usually order autoantibody testing to aid subsequent diagnosis or for monitoring disease activity in patients with psoriasis or psoriatic arthritis(PsA),although a variety of ...A physician in clinical practice does not usually order autoantibody testing to aid subsequent diagnosis or for monitoring disease activity in patients with psoriasis or psoriatic arthritis(PsA),although a variety of autoantibodies are present in these patients.Our understanding of autoantibodies in psoriasis and PsA is limited.Early investigations of autoantibodies in psoriasis were focused on the known autoantibodies in rheumatic diseases.For instance,anti-nuclear antibodies(ANAs)are often found in patients with psoriasis or PsA,but anti-double-stranded DNA or anti-extractable nuclear antigens are rarely identified.Therefore,ANAs have not been considered valuable in diagnosing PsA or predicting prognosis to manage PsA.Moreover,the roles of ANAs in the pathogenesis of PsA remain unknown.[1,2]Autoantibodies associated with rheumatoid arthritis(RA)have been investigated in PsA for their presence and association with the disease.For instance,antibodies against citrullinated proteins(ACPAs),which are highly specific to RA,are found in 5.0%to 17.5%of PsA patients.In several studies,a more erosive disease has been observed in PsA patients with ACPAs than in ACPA-negative PsA patients.[3,4]These findings imply that ACPAs in patients with PsA may be capable of inducing bone loss,which has been observed in RA patients with antibodies against citrullinated vimentin.展开更多
Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because ...Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because of the large number of voxels in the brain,multiple comparison correction(MCC)must be performed to reduce false positive rates,and a smaller P value(usually including either liberal or stringent MCC)is widely recommended[1].展开更多
Schnitzler syndrome is a rare disease of adult-onset with main features including chronic urticarial rash, recurrent fever, arthralgia or arthritis, monoclonal gammopathy of undetermined significance (MGUS), and marke...Schnitzler syndrome is a rare disease of adult-onset with main features including chronic urticarial rash, recurrent fever, arthralgia or arthritis, monoclonal gammopathy of undetermined significance (MGUS), and marked systemic inflammation. Schnitzler syndrome is often underdiagnosed. Patients with Schnitzler syndrome may present to dermatologists and allergists for urticaria, hematologists for MGUS, or rheumatologists for arthritis. It is important to recognize Schnitzler syndrome for its remarkable response to interleukin (IL)-1 blockade. Besides, many cases of Schnitzler-like syndromes do not meet the diagnostic criteria of classical Schnitzler syndrome but display excellent response to IL-1 inhibitors. The overly produced IL-1 is the result of a somatic mosaic gain of function mutation ofNLRP3 (nucleotide-binding oligomerization domain [NOD]-like receptor [NLR] family pyrin domain containing 3) gene in some patients with Schnitzler-like syndromes. Inflammasome activation is evident in patients with classical Schnitzler syndrome although noNLRP3 gene mutation is identified. Collectively, Schnitzler syndrome and Schnitzler-like syndromes represent a spectrum of IL-1 mediated adult-onset autoinflammatory diseases.展开更多
Tumor necrosis factor(TNF)becomes a well-known name largely owing to the success of its antagonists in therapy of inflammatory diseases.[1,2]In 1975,in searching for cancer therapeutic agent.
基金supported by Drug Enforcement Administration,National Center for Toxicological Research(protocol#E0763601)University of Arkansas for Medical Sciences
文摘OBJECTIVE Over 30% of all new psychoactive substances identified by the UN Office on Drugs and Crime in 2016 were synthetic cannabinoids.The recent emergence of MAM-2201 on the illicit market is troubling because this drug has no precedent in either the scientific or patent literature,and appears to be a novel compound developed specifically as a "graymarket" drug of abuse bystructurally combining the known synthetic cannabinoids JWH-122 and AM-2201.There is currently no published information regarding the pharmacology of MAM-2201.METHODS The present studies characterized cannabinoid-like effects of MAM-2201 in vitro(interactions with cannabinoid type 1 receptors[CB1 Rs]) and in vivo(in mice and rats).RESULTS In a radioligand binding assay using [3 H]CP55,940 in HEK cell membranes transfected with the CB1 R,MAM-2201(K i=5.4 nmol·L^(-1)),had higher binding affinity than WIN 55,212-2(K i=80 nmol·L^(-1)),and D9-THC(K i=8.3 nmol·L^(-1)).The E max values for MAM-2201 and WIN 55,212-2 in an assay of agonist inhibition of forskolin-stimulated c AMP were 85%(EC50=0.45 nmol·L^(-1)) and 95%,respectively,as compared with the D9-THC E max of 74%.In mice,MAM-2201(0.003-1.0 mg·kg^(-1),IP) produced dose-dependent cannabimimetic effects which were both more potent and more effective than those of D9-THC.MAM-2201 and D9-THC dose-dependently produced hypothermia:ED50=0.287 and 25.4 mg·kg^(-1),analgesia:ED50=0.125 and 29.4 mg·kg^(-1),and catalepsy:ED50=0.301 and18.9 mg·kg^(-1) in adult male CD1 mice.Importantly,MAM-2201 also elicited convulsant effects at a dose of 1.0 mg·kg^(-1) in 8/8 murine subjects.In rats,MAM-2201 produced dose-dependent D9-THC-like interoceptive effects in subjects trained to discriminate 3.0 mg·kg^(-1)(IP) D9-THC from saline.CONCLUSION MAM-2201 binds CB1 Rs with high affinity and agonist efficacy,and functions as a potent cannabinoid agonist in vivo across several complementary measures of cannabinoid activity in two rodent species.
文摘Our increase in knowledge of the pathophysiology of non-infectious uveitis(NIU)and other immune-mediated diseases has been mirrored over the last two decades by the expansion of therapeutic options in the realm of immunosuppressive medications.Principal among these advances is the emergence of biologics,which offer the promise of targeted therapy and the hope of reduced toxicity when compared to corticosteroids and“standard”immunosuppression.Among the biologics,monoclonal antibodies blocking tumor necrosis factor alpha(TNF-α)have been shown to be a very effective therapeutic target for uveitis and many associated systemic inflammatory diseases.Multiple TNF blockers have shown benefit for uveitis,and in 2016,adalimumab became the first biologic and non-corticosteroid immunosuppressive to obtain Food and Drug Administration(FDA)approval in the treatment of NIU.Although effective,TNF blockers are not universally so,and safety concerns such as infection and demyelinating disease must be carefully considered and ruled out prior to their use,especially in patients with intermediate uveitis with which multiple sclerosis is a known association.Ongoing study has identified novel targets for regulation in the treatment of immune-mediated and inflammatory diseases.Interferons,interleukin and Janus kinase inhibitors in addition to antibodies targeting T cell and B cell activation highlight the expanding field of treatment modalities in NIU.Ongoing study will be required to better determine the safety and efficacy of biologics in the armamentarium of immunosuppressive treatments for NIU.
文摘A physician in clinical practice does not usually order autoantibody testing to aid subsequent diagnosis or for monitoring disease activity in patients with psoriasis or psoriatic arthritis(PsA),although a variety of autoantibodies are present in these patients.Our understanding of autoantibodies in psoriasis and PsA is limited.Early investigations of autoantibodies in psoriasis were focused on the known autoantibodies in rheumatic diseases.For instance,anti-nuclear antibodies(ANAs)are often found in patients with psoriasis or PsA,but anti-double-stranded DNA or anti-extractable nuclear antigens are rarely identified.Therefore,ANAs have not been considered valuable in diagnosing PsA or predicting prognosis to manage PsA.Moreover,the roles of ANAs in the pathogenesis of PsA remain unknown.[1,2]Autoantibodies associated with rheumatoid arthritis(RA)have been investigated in PsA for their presence and association with the disease.For instance,antibodies against citrullinated proteins(ACPAs),which are highly specific to RA,are found in 5.0%to 17.5%of PsA patients.In several studies,a more erosive disease has been observed in PsA patients with ACPAs than in ACPA-negative PsA patients.[3,4]These findings imply that ACPAs in patients with PsA may be capable of inducing bone loss,which has been observed in RA patients with antibodies against citrullinated vimentin.
基金the National Natural Science Foundation of China(81520108016,81661148045,and 31471084 to Yu-Feng Zang81671774 and 81630031 to Chao-Gan Yan+11 种基金81571228 to Tao Wu61571047 to Xia Wu81701664 to Jian Wang,81471654 to Biao Huang81701671 to Wei-Guo Liu82001898 to Xi-Ze Jia81771820,81371519 and 81571654 to Wei Luo)Henry G Leong Endowed Professorship in Neurology to Shu-Leong Ho and Shirley YY Pang,BRC for Mental Health at South London and Maudsley NHS Foundation Trust and by the Sackler Institute to Grainne McAlonan,NIH(2R01AG006457 to Fay B.Horak1RC4NS073008-01 and P50NS062684 to Tara Madhyastha)NINDS Intramural Research Program to Mark HallettStart-up Funds for Leading Talents at Beijing Normal UniversityNational Basic Science Data Center‘‘Chinese Data-sharing Warehouse for In-vivo Imaging Brain”(NBSDC-DB-15)to Xi-Nian ZuoGrant NU20-04-00294 of the Agency for Health Research,Czech Republic to Lenka Krajcovicova and Irena Rektorova。
文摘Thousands of resting state functional magnetic resonance imaging(RS-f MRI)articles have been published on brain disorders.For precise localization of abnormal brain activity,a voxel-level comparison is needed.Because of the large number of voxels in the brain,multiple comparison correction(MCC)must be performed to reduce false positive rates,and a smaller P value(usually including either liberal or stringent MCC)is widely recommended[1].
基金Dr. Chu’s work was supported by the Innovative Award from the American College of Rheumatology Research Foundation and the VA Merit Review grant(No. I01BX005195)。
文摘Schnitzler syndrome is a rare disease of adult-onset with main features including chronic urticarial rash, recurrent fever, arthralgia or arthritis, monoclonal gammopathy of undetermined significance (MGUS), and marked systemic inflammation. Schnitzler syndrome is often underdiagnosed. Patients with Schnitzler syndrome may present to dermatologists and allergists for urticaria, hematologists for MGUS, or rheumatologists for arthritis. It is important to recognize Schnitzler syndrome for its remarkable response to interleukin (IL)-1 blockade. Besides, many cases of Schnitzler-like syndromes do not meet the diagnostic criteria of classical Schnitzler syndrome but display excellent response to IL-1 inhibitors. The overly produced IL-1 is the result of a somatic mosaic gain of function mutation ofNLRP3 (nucleotide-binding oligomerization domain [NOD]-like receptor [NLR] family pyrin domain containing 3) gene in some patients with Schnitzler-like syndromes. Inflammasome activation is evident in patients with classical Schnitzler syndrome although noNLRP3 gene mutation is identified. Collectively, Schnitzler syndrome and Schnitzler-like syndromes represent a spectrum of IL-1 mediated adult-onset autoinflammatory diseases.
基金Dr.Chu’s work was supported by an Innovative Award from American College of Rheumatology Research Foundation and by a VA Merit Review grant(No.I01BX005195)。
文摘Tumor necrosis factor(TNF)becomes a well-known name largely owing to the success of its antagonists in therapy of inflammatory diseases.[1,2]In 1975,in searching for cancer therapeutic agent.