A wealth of evidence has suggested that gastrointestinal dysfunction is associated with the onset and progression of Parkinson's disease (PD). However, the mechanisms underlying these links remain to be defined. Here, we investigated the impact of deregulation of intestinal dopamine D2 receptor (DRD2) signaling in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration. Dopamine/dopamine signaling in the mouse colon decreased with ageing. Selective ablation of Drd2, but not Drd4, in the intestinal epithelium, caused a more severe loss of dopaminergic neurons in the substantia nigra following MPTP challenge, and this was accompanied by a reduced abundance of succinate-producing Alleoprevotella in the gut microbiota. Administration of succinate markedly attenuated dopaminergic neuronal loss in MPTP-treated mice by elevating the mitochondrial membrane potential. This study suggests that intestinal epithelial DRD2 activity and succinate from the gut microbiome contribute to the maintenance of nigral DA neuron survival. These findings provide a potential strategy targeting neuroinflammation-related neurological disorders such as PD.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/adverse effects* ; Animals ; Disease Models, Animal ; Dopamine ; Dopaminergic Neurons/metabolism* ; Gastrointestinal Microbiome ; Mice ; Mice, Inbred C57BL ; Neuroprotection ; Parkinson Disease ; Pyrrolidines ; Receptors, Dopamine D2/metabolism* ; Substantia Nigra ; Succinates

INTRODUCTION: GUARD (vildaGliptin clinical Use in reAl woRlD) was  a  multinational,  prospective,  observational  study that assessed the effectiveness,safety  and  tolerability of vildagliptin and vildagliptin+metformin in patients with type 2 diabetes mellitus (T2DM) under real-world conditions across four  geographical  regions  (Asia,  the  Middle  East,  Central  America and Africa). The current paper discusses the results of patients with T2DM enrolled in the Philippines.
METHODS: Patients  with  T2DM  who  were  prescribed vildagliptin or vildagliptin+metformin combination therapy were enrolled and followed as per routine clinical practice for 24 ± six weeks. Primary endpoint was the change in HbA1c from  baseline  to  study  end  (week  24±6).  Key  secondary endpoints included proportion of patients reaching target HbA1c ?7.0%, incidence of hypoglycemic events, adverse events (AEs) and serious AEs (SAEs).
RESULTS: A total of 1,117 patients were included in the final analysis, 280 on vildagliptin (of these, eight patients received additional oral antidiabetes medications) and 837 on vildagliptin+metformin. At baseline, the mean (±SD) age of the enrolled population was 54.1±11.5 years, BMI 26.3±4.7 kg/m2, HbA1c 8.0±1.2% and T2DM duration 2.3±4.0 years.At  study  end,  significant  mean  (±SE)  reductions  in  HbA1c of -1.2±0.1% (p<0.0001) and -1.5±0.1% (p<0.0001) from a baseline of 7.6±1.1% and 8.1±1.2% were observed for the vildagliptin and vildagliptin+metformin group, respectively.A similar proportion of patients achieved HbA1c ?7.0% in the vildagliptin (66.1%) and vildagliptin+metformin group(62.7%). Changes in body weight and BMI from baseline to week 24±6 were statistically significant (p<0.0001) in both the vildagliptin (-1.5±0.3 kg; -0.6±0.1 kg/m2) and the vildagliptin+metformin group (-1.4±0.2 kg; -0.5±0.1 kg/m2).The incidence of hypoglycemia was low--six patients reported hypoglycemia in the vildaglipti metformin group and  none  in  the  vildagliptin  group.  Incidence  of  adverse events was also low in both the groups (vildagliptin, 8.6% and vildagliptin+metformin, 5.3%).
CONCLUSION: Vildagliptin  and  vildagliptin+metformin significantly  reduced  HbA1c  with  good  weight  control and low incidence of hypoglycemia in patients with T2DM under real-world conditions in Philippines

Human ; Male ; Female ; Aged ; Middle Aged ; Adult ; Metformin ; Vildagliptin ; Diabetes Mellitus, Type 2 ; Adamantane ; Pyrrolidines ; Hypoglycemic Agents ; Nitriles ; Hypoglycemia ; Body Weight ; Asia ; Africa ; Central America

BACKGROUND/AIMS: To investigate the expression of Toll-like receptor 4 (TLR4) in the pancreases of rats with acute necrotizing pancreatitis (ANP) and any changes upon treatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor kappaB (NF-kappaB), as well as to determine the relationship between TLR4 and NF-kappaB in ANP pathogenesis. METHODS: A total of 72 SD rats were randomly divided into three groups, namely, the control (sham-operation), ANP, and ANP with PDTC pretreatment groups. The PDTC-pretreated group was intraperitoneally injected with PDTC at a dose of 100 mg/kg 1 hour before the induction of ANP. The expressions of TLR4 and NF-kappaB in pancreatic tissue were evaluated by immunohistochemistry and Western blot analysis. The mRNA levels of cytokines tumor necrosis factor alpha, interleukin (IL)-1beta, and IL-6 were measured by reverse transcription polymerase chain reaction. RESULTS: The expressions of TLR4, NF-kappaB, and cytokine (NF-kappaB target) genes in the pancreatic tissue increased more significantly in the ANP groups than in the sham-operation group at 3, 6, and 12 hours. Pretreatment with PDTC alleviated the inflammatory activation in the pancreas with ANP, causing a significant decrease in the expressions of TLR4, NF-kappaB, and cytokine genes in the pancreatic tissue. CONCLUSIONS: The expressions of TLR4 and NF-kappaB were increased in the pancreases of rats with ANP. PDTC not only inhibits NF-kappaB but also suppresses the expression of TLR4 and downregulates the expression of the related cytokine genes.
Animals ; Antioxidants/*pharmacology ; Interleukin-1beta/genetics/metabolism ; Interleukin-6/genetics/metabolism ; Male ; NF-kappa B/*drug effects/metabolism ; Pancreas/metabolism/pathology ; Pancreatitis, Acute Necrotizing/chemically induced/*drug therapy ; Pyrrolidines/*pharmacology ; RNA, Messenger/metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Thiocarbamates/*pharmacology ; Toll-Like Receptor 4/*drug effects/metabolism ; Tumor Necrosis Factor-alpha/genetics/metabolism

BACKGROUND/AIMS: To investigate the expression of Toll-like receptor 4 (TLR4) in the pancreases of rats with acute necrotizing pancreatitis (ANP) and any changes upon treatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor kappaB (NF-kappaB), as well as to determine the relationship between TLR4 and NF-kappaB in ANP pathogenesis. METHODS: A total of 72 SD rats were randomly divided into three groups, namely, the control (sham-operation), ANP, and ANP with PDTC pretreatment groups. The PDTC-pretreated group was intraperitoneally injected with PDTC at a dose of 100 mg/kg 1 hour before the induction of ANP. The expressions of TLR4 and NF-kappaB in pancreatic tissue were evaluated by immunohistochemistry and Western blot analysis. The mRNA levels of cytokines tumor necrosis factor alpha, interleukin (IL)-1beta, and IL-6 were measured by reverse transcription polymerase chain reaction. RESULTS: The expressions of TLR4, NF-kappaB, and cytokine (NF-kappaB target) genes in the pancreatic tissue increased more significantly in the ANP groups than in the sham-operation group at 3, 6, and 12 hours. Pretreatment with PDTC alleviated the inflammatory activation in the pancreas with ANP, causing a significant decrease in the expressions of TLR4, NF-kappaB, and cytokine genes in the pancreatic tissue. CONCLUSIONS: The expressions of TLR4 and NF-kappaB were increased in the pancreases of rats with ANP. PDTC not only inhibits NF-kappaB but also suppresses the expression of TLR4 and downregulates the expression of the related cytokine genes.
Animals ; Antioxidants/*pharmacology ; Interleukin-1beta/genetics/metabolism ; Interleukin-6/genetics/metabolism ; Male ; NF-kappa B/*drug effects/metabolism ; Pancreas/metabolism/pathology ; Pancreatitis, Acute Necrotizing/chemically induced/*drug therapy ; Pyrrolidines/*pharmacology ; RNA, Messenger/metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Thiocarbamates/*pharmacology ; Toll-Like Receptor 4/*drug effects/metabolism ; Tumor Necrosis Factor-alpha/genetics/metabolism

OBJECTIVETo investigate the effect of paraquat (PQ) on reactive oxygen species (ROS) and neutrophil apoptosis and its possible signal transduction pathways.

METHODSCultured neutrophils were treated with different concentrations of PQ for 6-24 h. The apoptosis rate of neutrophils and ROS content were determined by flow cytometry. The exoressions of nuclear factor kappa B (NF-κB) and Caspase 3 were detected by Western blot. These parameters were checked again after NF-κB and Caspase 3 antagonist were applied.

RESULTSPQ could boost ROS generation and depress neutrophil apoptosis significantly. At the same time PQ could enhance the expression of NF-κB and inhibit the expression of Caspase 3. These effects could be reversed by ROS inhibitor diphenyleneiodonium (DPI) and NF-κB inhibitor pyrrolidinedithiocarbamate (PDTC).

CONCLUSIONPQ is a potent inducer of ROS and can inhibit neutrophil apoptosis by activating NF-κB and surpressing Caspase 3 activity.

Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Cells, Cultured ; NF-kappa B ; antagonists & inhibitors ; metabolism ; Neutrophils ; cytology ; drug effects ; Paraquat ; toxicity ; Pyrrolidines ; pharmacology ; Reactive Oxygen Species ; metabolism ; Signal Transduction ; Thiocarbamates ; pharmacology

OBJECTIVETo observe the therapeutic effect and safety of vildagliptin combined with insulin aspart injection in elderly patients with type 2 diabetes.

METHODSSixty-six elderly patients with type 2 diabetes who had poor blood glucose control with insulin aspart injection were divided into two groups to have additional Vildagliptin (50 mg, twice daily, n=36, observation group) or Acarbose (50 mg, three times a day, n=30, control group). Blood glucose (including FBG and 2hPG), HbA1C, fasting c-peptide, postprandial c-peptide, BMI and GFR were observed after 12 weeks.

RESULTSIn the observation group, FBG, 2hPG and HbA1C decreased significantly (P<0.05), fasting and postprandial c-peptide increased (P<0.05), and BMI and GFR showed no obvious changes (P>0.05). In the control group, 2hPG and HbA1C were significant lowered (P<0.05) but FBG, fasting and postprandial c-peptide, BMI or GFR showed no changes (P>0.05). Compared with those in the control group, FBG in the observation group showed a significant reduction (P<0.05), but no significant differences were found in 2hPG, HbA1C, BMI or GFR (P>0.05). No hypoglycemia occurred in the two groups during the treatment.

CONCLUSIONVildagliptin with insulin aapart injection has equivalent effect with Acarbose combined with insulin aspart injection in decreasing 2hPG and HbA1C without increasing the body weight or the risk to hypoglycemia or causing lowered GFR. Vildagliptin has better effect in decreasing FBG and improving the function of the islet cells.

Adamantane ; analogs & derivatives ; therapeutic use ; Aged ; Blood Glucose ; Diabetes Mellitus, Type 2 ; drug therapy ; Glycated Hemoglobin A ; metabolism ; Humans ; Hypoglycemic Agents ; therapeutic use ; Injections ; Insulin Aspart ; therapeutic use ; Nitriles ; therapeutic use ; Pyrrolidines ; therapeutic use

BACKGROUND: Vildagliptin is believed to improve glucose variability by restoring the physiologic pattern of insulin secretion and improving beta and alpha cells' sensitivity to glucose but with less increase in insulin secretion compared to sulfonylureas resulting in similar glucose levels but with less risk of hypoglycemia.
OBJECTIVE: To compare the effect of vildagliptin and glimepiride on glucose variability among Type 2 diabetic patients not controlled on metformin alone.
METHODS: This investigation is a prospective, interventional, open-labeled, active control, parallel assignment, efficacy study that included patients with inadequate glycemic control on monotherapy with metformin, randomly assigned either to vildagliptin or glimeparide. For one month, one group took vildagliptin 50mg/tablet one tablet twice a day while the other group took glimepiride 1 mg/tablet one tablet once a day. Subjects were asked to monitor their capillary blood glucose at seven points throughout the day for 35 days.
RESULTS: A total of 18 patients were recruited for the study and randomly assigned to either of the two treatment arms. However, only 16 patients completed the study. The vildagliptin and glimepiride groups had comparable blood sugars at baseline and at the end of the study although the glimepiride group showed a steeper decline in the blood sugar levels. Subjects in both groups showed a downward trend in the blood glucose values from day one to the 35th day with comparable mean glucose values between treatments and across combinations of day and treatment. Likewise, mean postprandial incremental area under the curve (AUCpp)and mean amplitude of glycemic excursions (MAGE) were comparable across treatments and across combinations of day and treatment, although the Glimepiride group showed relatively higher MAGE values.
CONCLUSION: Vildaglipitin and glimepiride both improved glycemia of patients with uncontrolled blood sugar on monotherapy with metformin as both groups showed downward glucose trend, although vildagliptin showed relatively less abrupt glucose lowering effect suggesting lesser risk of hypoglycemia. Mean postprandial glucose excursions of the two groups were also comparable but the vildagliptin arm had lower MAGE and may suggest an improvement in both ?- and ?-cell function.

Human ; Male ; Female ; Aged 80 And Over ; Aged ; Middle Aged ; Adult ; Young Adult ; Adolescent ; Adamantane ; Blood Glucose ; Diabetes Mellitus, Type 2 ; Glucose ; Hypoglycemia ; Insulins ; Metformin ; Nitriles ; Prospective Studies ; Pyrrolidines ; Sulfonylurea Compounds

To study the application characteristics of copovidone (PVP-S630) in Xinyueshu extracts during the spray drying process, and its effect on such pharmaceutical properties as micromeritics and drug release behavior. PVP-S630 was added into Xinyueshu extracts to study on the spray drying, the effect of different dosages of PVP-S630 against the wall sticking effect of the spray drying, as well as the power property of Xinyueshu spray drying power and the dissolution in vitro behavior of the effective component of hyperoside. The results showed that PVP-S630 revealed a significant anti-wall sticking effect, with no notable change in the grain size of the spray drying power, increase in the fluidity, improvement in the moisture absorption and remarkable rise in the dissolution in vitro behavior of hyperoside. It was worth further studying the application of PVP-S630 in spray drying power of traditional Chinese medicine.
Absorption ; Desiccation ; methods ; Drug Compounding ; methods ; Drugs, Chinese Herbal ; chemistry ; Porosity ; Powders ; Pyrrolidines ; chemistry ; Vinyl Compounds ; chemistry ; Wettability

OBJECTIVETo apply PVP-S630 in the preparation of tanshinone II(A) (TS II(A)) solid dispersion, in order to improve its dissolution in vitro and reduce the moisture absorption of the solid dispersion.

METHODTanshinone II(A) solid dispersion was prepared by spray drying method. Such analytical methods as SEM, DSC, XRD were used to characterize their phases and detect their dissolution, moisture absorption and stability.

RESULTIn the solid dispersion prepared with tanshinone II(A) and copovidone with proportion of 1:10, tanshinone II(A) was scattered on the surface of the carrier in the amorphous form, with a dissolution in vitro up to 100% at 0.5 h and a lower moisture absorption than PVP-K30 solid dispersion prepared with the same proportion. After a three-month accelerated stability test, it showed no significant change in drug dissolution and content.

CONCLUSIONThe solid dispersion prepared with copovidone as the carrier can significantly improve the dissolution of tanshinone II(A), with a relatively low moisture absorption and high stability, thereby having a good prospect of application.

Biological Availability ; Calorimetry, Differential Scanning ; Chemistry, Pharmaceutical ; methods ; Diterpenes, Abietane ; chemistry ; Drug Carriers ; chemistry ; Drugs, Chinese Herbal ; chemistry ; Microscopy, Electron, Scanning ; Pharmaceutical Preparations ; chemistry ; Pyrrolidines ; chemistry ; Solubility ; Time Factors ; Vinyl Compounds ; chemistry ; Water ; chemistry

We investigated characteristics associated with the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4i) in Korean patients with type 2 diabetes. We reviewed medical records of 477 patients who had taken sitagliptin or vildagliptin longer than 40 weeks. Response to DPP4i was evaluated with HbA1c change after therapy (DeltaHbA1c). The Student's t-test between good responders (GR: DeltaHbA1c > 1.0%) and poor responders (PR: DeltaHbA1c < 0.5%), a correlation analysis among clinical parameters, and a linear multivariate regression analysis were performed. The mean age was 60 yr, duration of diabetes 11 yr and HbA1c was 8.1%. Baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and creatinine were significantly higher in the GR compared to the PR. Duration of diabetes, FPG, HbA1c, C-peptide and creatinine were significantly correlated with DeltaHbA1c. In the multivariate analysis, age (r2 = 0.006), duration of diabetes (r2 = 0.019), HbA1c (r2 = 0.296), and creatinine levels (r2 = 0.024) were independent predictors for the response to DPP4i. Body mass index and insulin resistance were not associated with the response to DPP4i. In conclusion, better response to DPP4i would be expected in Korean patients with type 2 diabetes who have higher baseline HbA1c and creatinine levels with shorter duration of diabetes.
Adamantane/*analogs & derivatives/therapeutic use ; Blood Glucose/analysis ; Body Mass Index ; C-Peptide/analysis ; Creatinine/blood ; Diabetes Mellitus, Type 2/*drug therapy/pathology ; Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use ; Hemoglobin A, Glycosylated/analysis ; Humans ; Insulin Resistance ; Male ; Middle Aged ; Multivariate Analysis ; Nitriles/*therapeutic use ; Pyrazines/*therapeutic use ; Pyrrolidines/*therapeutic use ; Retrospective Studies ; Triazoles/*therapeutic use