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Objective: To observe the morphological changes on cochlear hair cells of rats in simulated weightlessness and inboard noise and to investigate the different changes in three turns of hair cells.Methods: Thirty-two healthy SD rats, all males, were randomly divided into four groups: control group, weightlessness group, noise group and weightlessness+noise groups (n=8).Then rats were exposed to-30° head down tilt as simulated weightlessness and inboard noise including steady-state noise which was (72±2) dB SPL and impulse noise up to 160 dB SPL in spaceship environment.The control group was kept in normal condition for 8 weeks.Bilateral auditory brainstem response (ABR) thresholds were tested before and after exposure respectively, and immunofluorescence staining and scanning electron microscopy (SEMs) of basilar membrane were applied after exposure.Results: ABR threshold shifts of each group were higher after exposure.There was difference between ABRs of the experiment groups before and after exposure (P<0.05).IF showed that the inner hair cells (IHCs) missing was the main damage in the basal turn of weightlessness group, the hair cells in the middle turn were swell and in the top turn, the hair cells were not clear.In noise group, the main loss happened in the outer hair cells (OHCs) of the outermost layer.In weightlessness+noise group, the nuclear missing in the basal turn was apparent, and mainly happened at the outermost layer.Meanwhile, the missing of hair cells in the middle turn and top turn was seen at the innermost layer.SEM showed that the cilia in the basal turn of weightlessness group were serious lodging, and occasional absence.Furthermore, the basal cilia in noise group became lodged and absent, and the other two turns were seriously missing.And in weightlessness+noise group, the cilia missing in the basal turn was apparently seen.The damage degree of the four groups: weightlessness+noise group>noise group>weightlessness group>control group and the damage degree of the four turns of hair cells: basal turn>mid turn>top turn.Conclusion: The rats exposed to the above environment for 2 weeks displayed obvious changes in cochlea morphology, and the weightlessness+noise group had the most obvious damage.

Objective To investigate the synergistic effects of simulated microgravity and noise on the audito‐ry functions and corti organs in rats .Methods A total of 48 healthy rats were randomly divided into 4 groups (n=12):control group (Group A) ,microgravity only group (Group B) ,noise only group (Group C) and microgravity+noise group (Group D) .The microgravity environment was simulated by suspending the posterior limb using Morey-Holton method .The noise exposure was the simulation of the noise environment in spaceship including steady -state noise (72 ± 2) dB SPL and impulse noise up to 160 dB SPL .The control group was kept in normal conditions without any exposure .Auditory brainstem responses (ABRs) ,HE stainings ,immunofluorescence stainings and scanning electron microscopes (SEMs) were tested after 1week and 2 weeks exposure respectively (n=6) .Results The average of ABR threshold shifts of 2 weeks exposure were higher than those of 1 week in each group .Group D showed the highest ABRs (P<0 .01) .The HE stainings showed different degrees of injury in corti organs in all experimental groups ;which Group D being the most serious ,followed by Group C .The results of immunefluorescence in hair cells showed that swelling necrosis was the main damage of cochlear hair cell after 1 week's exposure .The swelling rate of Group D was the highest ,followed by Group C .Nucleus missing in hair cells was observed after 2 weeks'exposure . Group D had the highest missing rate and the main missing of Group B happened in the inner hair cells .SEM showed that the most serious damage of stereociliums in Group D ,followed by Group C ,then Group B .Conclusion The synergistic effects of simulated microgravity and noise lead to significant damage of the auditory function and cochlea Corti organs in rat .

Objective To investigate the effects of intense low frequency noise on expression of caspase -3 in bama pigs ,and observe the death of cochlea hair cell .Methods 8 bama pigs were randomly divided into a normal control group(2 pigs) and experimental groups(6 pigs) .Auditory brainstem responses(ABR) were tested before the experiment .The control group was the same as the experimental groups except noise exposure .The experimental group was randomly divided into immediate group ,36 h group ,and 84 h group(2 pigs per group) .They were ex-posed to intense low frequency noise at 142 dB of 50 Hz for 5 min according to the three time points .ABR were test-ed again before the cochlea were collected at different time points .The expression of caspase -3 was studied through immunohistochemistry and immunofluorescence ,hair cell loss rate by counting to determine cell death .Results The average ABR threshold of 8 bama pigs(16 ears) before the exposure was 61 .25 ± 10 .72 dB nHL .ABR thresh-olds were not elicited after exposure to the noise .Different parts of bama pigs showed positive expression of caspase -3 in two ways .As time prolonged after exposure ,the positive expression of caspase -3 gradually weakened .The im-mediate group and 36 h group ,compared with the control group ,showed the apparent misplace of three out hair cells in the arrangement and levels .The 84 h group through immunofluorescence lost out hair cells ,and only inner hair cells were visible .Conclusion ABR thresholds were elevated after noise exposure .The procedure of hair cell nucleus damage and caspase-3 expression is different ,and the noise can induce opening apoptotic program of spiral ganglion .

Objective: To investigate the adrenocortical function changes of patients with advanced solid tumors who received the anti- programmed cell death protein-1 (PD-1) antibody, SHR-1210 therapy. Methods: The clinical data of 98 patients with advanced solid tumors who were enrolled in a prospective phase I trial of SHR-1210 therapy at our institution between April 27, 2016 and June 8, 2017 were collected. The levels of plasma adrenocorticotropic hormone (ACTH) and cortisol were evaluated in 96 patients. The clinical manifestations, laboratory tests and radiologic data were collected to define the immune-related adrenal insufficiency. Results: Until December 14th, 2018, no SHR-1210 related primary adrenal insufficiency occurred, and the incidence of immune-related secondary adrenal insufficiency was 1.0% among the 96 patients, which was identified as grade 2. No patient developed grade 3-4 adrenal insufficiency. The main clinical manifestations of the patient who was diagnosed as secondary adrenal insufficiency were grade 2 fatigue, anorexia and headache.The patient developed fatigue and anorexia at the 267th day after receiving the first dose of SHR-1210, the hypocortisolism occurred on the 279th day, and the headache emerged on the 291th day. The anorexia of patient who treated by physiological replacement doses of glucocorticoid since the 457th day was attenuated.The patient whose cortisol level was still below the normal limit continued to accept the hormone replacement therapy up to 776 days after the initial administration of SHR-1210. Conclusions The incidence of SHR-1210 related adrenal insufficiency of patients with advanced solid tumors is low, and the symptoms can be effectively ameliorated by hormone replacement therapy. The potential adverse outcome of adrenal insufficiency following immunotherapy should be noticed by clinicians to avoid the occurrence of adrenal crisis.

Objective To investigate the adrenocortical function changes of patients with advanced solid tumors who received the anti?programmed cell death protein?1 ( PD?1) antibody, SHR?1210 therapy. Methods The clinical data of 98 patients with advanced solid tumors who were enrolled in a prospective phase I trial of SHR?1210 therapy at our institution between April 27, 2016 and June 8, 2017 were collected. The levels of plasma adrenocorticotropic hormone ( ACTH) and cortisol were evaluated in 96 patients. The clinical manifestations, laboratory tests and radiologic data were collected to define the immune?related adrenal insufficiency. Results Until December 14th, 2018, no SHR?1210 related primary adrenal insufficiency occurred, and the incidence of immune?related secondary adrenal insufficiency was 1.0% among the 96 patients, which was identified as grade 2. No patient developed grade 3?4 adrenal insufficiency. The main clinical manifestations of the patient who was diagnosed as secondary adrenal insufficiency were grade 2 fatigue, anorexia and headache.The patient developed fatigue and anorexia at the 267th day after receiving the first dose of SHR?1210, the hypocortisolism occurred on the 279th day, and the headache emerged on the 291th day. The anorexia of patient who treated by physiological replacement doses of glucocorticoid since the 457th day was attenuated.The patient whose cortisol level was still below the normal limit continued to accept the hormone replacement therapy up to 776 days after the initial administration of SHR?1210. Conclusions The incidence of SHR?1210 related adrenal insufficiency of patients with advanced solid tumors is low, and the symptoms can be effectively ameliorated by hormone replacement therapy. The potential adverse outcome of adrenal insufficiency following immunotherapy should be noticed by clinicians to avoid the occurrence of adrenal crisis.

Objective To investigate the adrenocortical function changes of patients with advanced solid tumors who received the anti?programmed cell death protein?1 ( PD?1) antibody, SHR?1210 therapy. Methods The clinical data of 98 patients with advanced solid tumors who were enrolled in a prospective phase I trial of SHR?1210 therapy at our institution between April 27, 2016 and June 8, 2017 were collected. The levels of plasma adrenocorticotropic hormone ( ACTH) and cortisol were evaluated in 96 patients. The clinical manifestations, laboratory tests and radiologic data were collected to define the immune?related adrenal insufficiency. Results Until December 14th, 2018, no SHR?1210 related primary adrenal insufficiency occurred, and the incidence of immune?related secondary adrenal insufficiency was 1.0% among the 96 patients, which was identified as grade 2. No patient developed grade 3?4 adrenal insufficiency. The main clinical manifestations of the patient who was diagnosed as secondary adrenal insufficiency were grade 2 fatigue, anorexia and headache.The patient developed fatigue and anorexia at the 267th day after receiving the first dose of SHR?1210, the hypocortisolism occurred on the 279th day, and the headache emerged on the 291th day. The anorexia of patient who treated by physiological replacement doses of glucocorticoid since the 457th day was attenuated.The patient whose cortisol level was still below the normal limit continued to accept the hormone replacement therapy up to 776 days after the initial administration of SHR?1210. Conclusions The incidence of SHR?1210 related adrenal insufficiency of patients with advanced solid tumors is low, and the symptoms can be effectively ameliorated by hormone replacement therapy. The potential adverse outcome of adrenal insufficiency following immunotherapy should be noticed by clinicians to avoid the occurrence of adrenal crisis.

Objective: To assess the incidence and characteristics of thyroid dysfunction during anti-Programmed cell death 1 receptor (PD-1) antibody SHR-1210 therapy in patients with advanced solid tumor. Methods: The medical records of 98 patients who initiated SHR-1210 treatment between April 27, 2016 and June 8, 2017 in the phase 1 trial to evaluate the safety, efficacy, and pharmacokinetics of SHR-1210 in patients with advanced solid tumors were retrospectively reviewed. Serological tests of thyroid stimulating hormone (TSH) and free thyroxine (fT4) were measured at baseline and prior to each SHR-1210 administration. Results: A total of 86 patients had normal thyroid function before the first dose of SHR-1210 treatment. Nine out of 86 (10.5%) patients developed new onset hypothyroidism from euthyroid state. 12 patients presented thyroid dysfunction at baseline, 10 of whom were subclinical hypothyroid and 2 were hypothyroidism. Four out of 10 patients developed hypothyroidism from subclinical hypothyroid. Most patients with hypothyroidism were asymptomatic. Thyroid dysfunction occurred early (median, 55days) after the initiation of SHR-1210. The severity of hypothyroidism were all grade 1-2. No grade 3-4 hypothyroidism occurred. No patients discontinue the treatment of SHR-1210 due to clinical impact of the thyroid dysfunctions. Conclusions: Thyroid-related adverse events were common during anti-PD-1 antibody SHR-1210 treatment . The incidence of hypothyroidism is lower in patients with euthyroid state than in patients with thyroid dysfunction at baseline during SHR-1210 treatment . Thyroid function can be improved after thyroid hormone replacement. During SHR-1210 treatment, it is necessary to pay attention to monitor the thyroid function, especially in the patients with thyroid dysfunction at baseline. Trial registration Chinese Clinical Trial Registry, 2016L01455