The objective of this work is to evaluate the effect of polyamidoamine (PAMAM) dendrimers on electroosmotic flow (EOF) through skin. The effect of size and concentration of dendrimer was studied, using generation 1, 4 and 7 dendrimer (G1, G4 and G7, respectively). As a marker molecule for the direction and magnitude of EOF, a neutral molecule, acetoaminophen (AAP) was used. The visualization of dendrimer permeation into the current conducting pore (CCP) of skin was made using G4–fluorescein isothiocyanate (FITC) conjugate and confocal microscopy. Without dendrimer, anodal flux of AAP was much higher than cathodal or passive flux. When G1 dendrimer was added, anodal flux decreased, presumably due to the decrease in EOF by the association of G1 dendrimer with net negative charge in CCP. As the generation increased, larger decrease in anodal flux was observed, and the direction of EOF was reversed. Small amount of methanol used for the preparation of dendrimer solution also contributed to the decrease in anodal flux of AAP. Cross-sectional view perpendicular to the skin surface by confocal laser scanning microscope (CLSM) study showed that G4 dendrimer-FITC conjugate (G4-FITC) can penetrate into the viable epidermis and dermis under anodal current. The permeation route seemed to be localized on hair follicle region. These results suggest that PAMAM dendrimers can permeate into CCP and change the magnitude and direction of EOF. Overall, we obtained a better understanding on the mechanistic insights into the electroosmosis phenomena and its role on flux during iontophoresis.
Acetaminophen ; Dendrimers* ; Dermis ; Electroosmosis* ; Epidermis ; Fluorescein-5-isothiocyanate ; Hair Follicle ; Iontophoresis ; Methanol ; Microscopy, Confocal ; Skin*

INTRODUCTIONWe aimed to evaluate the effectiveness and safety of canagliflozin as compared to sitagliptin in a real-world setting among multiethnic patients with Type 2 diabetes mellitus (T2DM) in Singapore.

METHODSThis was a new-user, active-comparator, single-centre retrospective cohort study. Patients aged 18-69 years with T2DM and estimated glomerular filtration rate ≥ 60 mL/min/1.73 m were eligible for inclusion if they were initiated and maintained on a steady daily dose of canagliflozin 300 mg or sitagliptin 100 mg between 1 May and 31 December 2014, and followed up for 24 weeks.

RESULTSIn total, 57 patients (canagliflozin 300 mg, n = 22; sitagliptin 100 mg, n = 35) were included. The baseline patient characteristics in the two groups were similar, with overall mean glycated haemoglobin (HbA1c) of 9.4% ± 1.4%. The use of canagliflozin 300 mg was associated with greater reductions in HbA1c (least squares [LS] mean change -1.6% vs. -0.4%; p < 0.001), body weight (LS mean change -3.0 kg vs. 0.2 kg; p < 0.001) and systolic blood pressure (LS mean change: -9.7 mmHg vs. 0.4 mmHg; p < 0.001), as compared with sitagliptin 100 mg. About half of the patients on canagliflozin 300 mg reported mild osmotic diuresis-related side effects that did not lead to drug discontinuation.

CONCLUSIONOur findings suggest that canagliflozin was more effective than sitagliptin in reducing HbA1c, body weight and systolic blood pressure in patients with T2DM, although its use was associated with an increased incidence of mild osmotic diuresis-related side effects.

Adolescent ; Adult ; Aged ; Blood Glucose ; drug effects ; Blood Pressure ; Body Mass Index ; Body Weight ; Canagliflozin ; administration & dosage ; Diabetes Mellitus, Type 2 ; drug therapy ; Female ; Glomerular Filtration Rate ; Hemoglobins ; analysis ; Humans ; Hypoglycemic Agents ; administration & dosage ; Least-Squares Analysis ; Male ; Middle Aged ; Osmosis ; Retrospective Studies ; Singapore ; Sitagliptin Phosphate ; administration & dosage ; Systole ; Treatment Outcome ; Young Adult

OBJECTIVETo study the role of RpoE and RpoS on the influence of the metabolism and growth of bacterial under hyperosmotic stress.

METHODSThe rpoS/rpoE double deletion mutant of Salmonella enterica serovar typhi (S. typhi) was prepared by homologous recombination through the suicide plasmid mediated. The recombination was visualized by PCR. Growth curves were drawn by using photometric value A600 as the ordinate and cultivation time as abscissa. The survival abilities of bacterial were compared under hyperosmotic stress. Statistical differences of early logarithmic growth stage (4 h) and laters logarithmic growth stage (12 h) were analyzed by one-way ANOVA. The expression difference of metabolism related genes of wild-type and mutant strains of S. Typhi incubated under hyperosmotic stress were investigated by Salmonella genomic DNA microarray. Real-time quantitative PCR (qRT-PCR) was performed to validate the results of microarray assay in some selected genes.

RESULTSThe rpoS/rpoE double deletion mutant of S. Typhi was successfully generated. The analysis of growth curve showed that the 4-hour and 12-hour A600 values were separately 0.503 ± 0.018 and 2.060 ± 0.112 in rpoS deletion mutant strains, 0.293 ± 0.053 and 1.933 ± 0.115 in rpoE deletion mutant strains, and 0.051 ± 0.007 and 0.963 ± 0.111 in rpoS/rpoE double deletion mutant strains; all of which were lower than the values of wild-type strains, who were 0.725 ± 0.097 and 2.496 ± 0.171, respectively. The difference were statistically significant (P < 0.05). The genomic DNA microarray revealed that 42 genes relevant with bacterial metabolism were influenced by RpoE and RpoS. Results of qRT-PCR showed that the expression values of rpsE, rbsK, nusG and etuB in rpoS deletion mutant strains were (1.86 ± 0.14)×10(6), (1.37 ± 0.11)×10(6), (2.72 ± 0.58)×10(6) and (8.27 ± 1.01)×10(6) copies/µg, respectively; while those in rpoE deletion mutant strains were (2.19 ± 0.17)×10(6), (1.51 ± 0.12)×10(6), (2.73 ± 0.57)×10(6) and (9.63 ± 1.42)×10(6) copies/µg, respectively. Compared with the values in wild-type strains, which were separately (1.94 ± 0.10)×10(6), (1.52 ± 0.11)×10(6), (2.39 ± 0.52)×10(6) and (10.83 ± 1.52)×10(6) copies/µg, the differences was not statistical significance (P > 0.05). However, compared with the values in rpoS/rpoE double mutant strains, which were separately (5.64 ± 0.59)×10(6), (4.17 ± 0.40)×10(6), (9.44 ± 1.22)×10(6) and (2.95 ± 0.88)×10(6) copies/µg, the difference was significant (P < 0.05).

CONCLUSIONRpoE and RpoS could influence the expression of lots of metabolism genes. Together, they regulated the metabolism and growth of S. Typhi under hyperosmotic stress.

Bacterial Proteins ; genetics ; Gene Deletion ; Osmosis ; Salmonella typhi ; genetics ; growth & development ; metabolism ; Sigma Factor ; genetics ; Stress, Physiological

The purpose of this study is to investigate the applicability of a natural swelling matrix derived from boat-fruited sterculia seed (SMS) as the propellant of osmotic pump tablets. The sugar components, static swelling, water uptake and viscosity of SMS were determined and compared with that of polythylene oxide (WSR-N10 and WSR-303). Both ribavirin and glipizide were used as water-soluble and water-insoluble model drugs. Then, the monolayer osmotic pump tablets of ribavirin and the bilayer osmotic pump tablets of glipizide were prepared using SMS as the osmotically active substance and propellant. SMS was mainly composed of rhamnose, arabinose, xylose and galactose and exhibited relatively high swelling ability. The area of the disintegrated matrix tablet was 20.1 times as that at initial after swelling for 600 s. SMS swelled rapidly and was fully swelled (0.5%) in aqueous solution with relative low viscosity (3.66 +/- 0.03) mPa x s at 25 degrees C. The monolayer osmotic pump tablets of ribavirin and the bilayer osmotic pump tablets of glipizide using SMS as propellant exhibited typical drug release features of osmotic pumps. In conclusion, the swelling matrix derived from boat-fruited sterculia seed, with low viscosity and high swelling, is a potential propellant in the application of osmotic pump tablets.
Arabinose ; chemistry ; isolation & purification ; Chemistry, Pharmaceutical ; Delayed-Action Preparations ; Drug Carriers ; Galactose ; chemistry ; isolation & purification ; Glipizide ; administration & dosage ; chemistry ; Osmosis ; Plants, Medicinal ; chemistry ; Rhamnose ; chemistry ; isolation & purification ; Ribavirin ; administration & dosage ; chemistry ; Seeds ; chemistry ; Solubility ; Sterculiaceae ; chemistry ; Tablets ; Technology, Pharmaceutical ; methods ; Viscosity ; Water ; Xylose ; chemistry ; isolation & purification

OBJECTIVE: To detect the impact of artificial cerebrospinal fluid lavage time on the edema of traumatic brain injury. METHODS: A total of 240 SD rats were randomly divided into a sham group, a traumatic brain injury model group, 3 artificial cerebrospinal fluid lavage groups (3 h, 6 h and 9 h). Each group was divided into 4 sub-groups by time of sacrifice namely 12 h, 1 d, 3 d and 7 d postoperatively. We detected the content of brain water, sodium, and potassium, and the VEGF expression to confirm whether the duration of lavage could reduce the traumatic brain edema. RESULTS: Compared with the sham group and the traumatic brain injury model group, brain water content and sodium content were decreased, while the potassium content and the VEGF levels were increased in the artificial cerebrospinal fluid lavage groups. Significant difference was found at 12 h, 1 d, and 3 d after the injury (P<0.05). With the increase of artificial cerebrospinal fluid lavage time, the difference was more obvious. CONCLUSION Artificial cerebrospinal fluid lavage can reduce the brain edema after traumatic brain injury. The longer the lavage, the more obvious the effect.
Animals ; Brain Edema ; etiology ; prevention & control ; Brain Injuries ; complications ; Cerebrospinal Fluid ; Male ; Osmosis ; Pharmaceutical Solutions ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Therapeutic Irrigation ; methods

The purpose of this study is to develop glipizide push-pull osmotic pump (PPOP) tablets by using a formulation design expert system and an artificial neural network (ANN). Firstly, the expert system for the formulation design of osmotic pump of poor water-soluble drug was employed to design the formulation of glipizide PPOP, taking the dissolution test results of Glucotrol XL as the goal. Then glipizide PPOP was prepared according to the designed formulations and the in vitro dissolution was carried out. And in vivo evaluation was carried out between the samples which were similar to Glucotrol XL and the Glucotrol XL in Beagle dogs. The range of the factors of formulation and procedure, which could influence the drug release, was optimized using artificial neural network. Finally, the design space was found. It was found that the target formulation which was similar to Glucotrol XL in dissolution test could be obtained in a short period by using the expert system. The samples which were similar to Glucotrol XL were bio-equivalent to the Glucotrol XL in Beagle dogs. The design space of the key parameter coating weight gain was 9.5%-12.0%. It could be concluded that a well controlled product of glipizide PPOP was developed since the dissolution test standard of our product was more strict than that of Glucotrol XL.
Animals ; Area Under Curve ; Delayed-Action Preparations ; Dogs ; Drug Compounding ; methods ; Drug Delivery Systems ; Drug Design ; Expert Systems ; Female ; Glipizide ; administration & dosage ; chemistry ; pharmacokinetics ; Hypoglycemic Agents ; administration & dosage ; chemistry ; pharmacokinetics ; Male ; Neural Networks (Computer) ; Osmosis ; Polyethylene Glycols ; chemistry ; Random Allocation ; Sodium Chloride ; chemistry ; Solubility ; Tablets

OBJECTIVETo study the variation in plasma concentration after oral administration of Danshen multi-component osmotic pump tablets in Beagle dogs with conventional Danshen tablets as the control preparation, in order to assess the sustained release of Danshen multi-component osmotic pump tablets.

METHODHPLC was adopted for determination, with Shimadzu's ODS-SP column (4.6 mm x 150 mm, 5 microm), flow rate of 1 mL x min(-1), and column temperature of 30 degrees C. Protein in plasma samples of tanshinone II(A) and salvianolic acid B was removed by ethyl acetate extract and acetone precipitation method respectively. Their pharmacokinetic parameters were calculated based on determination results.

RESULTThe methodology study on the two constituents with different polarity showed conformity to the requirements. Compared with conventional Danshen tablets, Danshen multi-component osmotic pump tablets showed decrease in Cmax and extension in Tmax after oral administration in Beagle dogs.

CONCLUSIONDanshen multi-component osmotic pump tablet has a good sustained-release effect compared with conventional Danshen tablets.

Animals ; Dogs ; Drugs, Chinese Herbal ; pharmacokinetics ; Male ; Osmosis ; Salvia miltiorrhiza ; chemistry ; Tablets ; Time Factors

This paper reported that a new type of floating osmotic pump of ambroxol hydrochloride was designed. Third method apparatus (Chinese Pharmacopeia 2010, appendix XD) was employed to simultaneously evaluate the release and floating behavior in vitro. The system was optimized using central composite design-response surface methodology. Similar factor (f2) between the release profile of self-made formulation and the target release profile was chosen as dependent factor. The amount of glucose (A, mg), pore former (B, %) and weight of coating (C, %) were employed as independent factors. Optimized formulation was: A (100.99 mg), B (1.70%), C (4.21%). The value of f2 (89.14) was higher than that of market capsules (69.02) and self-made tablets (72.15). It was showed that self-made capsules possessed character of zero-order release (r = 0.994 4) and drug release completely (>90%). It was showed in result of in vivo study that tmax and Cmax of self-made capsules were significantly lower than that of market capsules and self-made tablets. The correlation coefficient between the fraction of absorption in vivo and the release rate in vitro was 0.985 1, and relative bioequivalence of self-made capsules was 110.77%. Accordingly, self-made capsules displayed obviously characteristics of controlled release both in vivo and in vitro.
Absorption ; Administration, Oral ; Ambroxol ; administration & dosage ; chemistry ; pharmacokinetics ; Animals ; Area Under Curve ; Capsules ; Delayed-Action Preparations ; Dogs ; Drug Compounding ; methods ; Drug Delivery Systems ; Excipients ; Female ; Glucose ; chemistry ; Male ; Osmosis ; Osmotic Pressure ; Porosity ; Random Allocation ; Solubility ; Therapeutic Equivalency

The purpose of this study is to design push-pull osmotic pump (PPOP) tablets of famotidine using the expert system for the formulation design of osmotic pump of poor water-soluble drug which had been established by the authors. Firstly, the parameters which were requisite of the system input were obtained from literatures and experimental tests. Then the parameters were input into the system, and the program was run. The system displayed the designed formulations sequential. Finally, famotidine PPOP was prepared according to the designed formulations and the in vitro dissolution was carried out. It was found out that the target formulation of famotidine PPOP which could release for 24 hours was obtained in a very short period. Meanwhile, the practicability of the established expert system was proved.
Delayed-Action Preparations ; Drug Delivery Systems ; methods ; Excipients ; chemistry ; Expert Systems ; Famotidine ; administration & dosage ; chemistry ; Osmosis ; Solubility ; Tablets ; Water

OBJECTIVETo develop a sensitive and specific LC-MS/MS method for determination of Yizhi osmotic pump tablets active ingredient in Beagle dog plasma.

METHODBeagle dog plasma pre-treatment methods were established. Geniposide, notoginsenoside R1, ginsenoside Rg1 and Rb1 notoginsenoside molecular ions and fragment ions peaks were separated well and detected synchronously by LC-MS/MS with digoxin as internal standard.

RESULTUnder the selected LC-MS/MS conditions, the characteristic fragment ions of the four components could be well separated and quantified, and the calibration curves showed good linearity within a certain concentration range of each component; extraction recoveries of those four compounds in plasma were higher than 75%, method recoveries were higher than 90%; day precision (RSD <10%) and inter-day precision (RSD <15%) were generally fine; freeze-thaw and room temperature experiments showed good stability (RSD <15%).

CONCLUSIONThe method is proved to be suitable for pharmacokinetic studies of Yizhi active ingredients in Beagle dog plasma.

Animals ; Blood Chemical Analysis ; methods ; Calibration ; Chromatography, Liquid ; methods ; Dogs ; Drug Stability ; Drugs, Chinese Herbal ; analysis ; pharmacokinetics ; Male ; Osmosis ; Tablets ; Tandem Mass Spectrometry ; methods ; Temperature ; Time Factors