The pharmacokinetics and pharmacodynamics of cefquinome against Streptococcus agalactiae in a murine mastitis model.

Cefquinome is a new generation cephalosporin that is effective in the treatment of mastitis in animals. In this study, we evaluated the associations between the specific pharmacokinetics and pharmacodynamics (PK/PD) of cefquinome and its antibacterial activity against Streptococcus agalactiae in a mouse model of mastitis. After a single intramammary dose of cefquinome (30, 60, 120, and 240 µg/mammary gland), the concentration of cefquinome in plasma was analysed by liquid chromatography with tandem mass spectrometry (HPLC/MS-MS). The PK parameters were calculated using a one-compartment first-order absorption model. Antibacterial activity was defined as the maximum change in the S. agalactiae population after each dose. An inhibitory sigmoid Emax model was used to evaluate the relationships between the PK/PD index values and antibacterial effects. The duration for which the concentration of the antibiotic (%T) remained above the minimum inhibitory concentration (MIC) was defined as the optimal PK/PD index for assessing antibacterial activity. The values of %T > MIC to reach 0.5-log10CFU/MG, 1-log10 CFU/MG and 2-log10 CFU/MG reductions were 31, 47, and 81%, respectively. When the PK/PD index %T > MIC of cefquinome was >81% in vivo, the density of the Streptococcus agalactiae was reduced by 2-log10. These findings provide a valuable understanding to optimise the dose regimens of cefquinome in the treatment of S. agalactiae infections.

Pharmacokinetics and Pharmacodynamics of Gamithromycin Treatment of Pasteurella multocida in a Murine Lung Infection Model.

Gamithromycin is approved for the treatment and prevention of bovine respiratory disease (BRD), which is caused mainly by Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma species. In this study, multiple dosage regimens were administered to the neutropenic mouse lung infection model in order to investigate the pharmacokinetic/pharmacodynamic (PK/PD) parameters of gamithromycin treatment of P. multocida and to further define the PK/PD parameter that best correlates with the efficacy of gamithromycin against P. multocida. The PK characteristics of gamithromycin were analyzed after a single subcutaneous (s.c.) injection (1, 3, 6, and 9 mg/kg). The concentration-time profiles of unbound (f) gamithromycin in plasma samples were analyzed by non-compartmental analysis. The main PK parameters of gamithromycin for the area under the concentration-time curve from 0 to 24 h (f AUC0-24) and the peak drug concentration (f C max) values ranged from 0.86 to 8.42 µg·h/ml and from 0.55 to 5.69 µg/ml, respectively. The PD values were calculated based on multiple s.c. injections over 24 h (1, 3, 6, and 9 mg/kg at 6, 8, 12, and 24 h, respectively; total dosage 1-36 mg/ kg). The minimum inhibitory concentration (MIC) of gamithromycin against P. multocida in mice serum was 0.15 µg/ml. Analysis of PK/PD indices using the inhibitory effect E max model indicated a strong correlation (R 2 = 0.9624) between the f AUC0-24/MIC ratio and various antibacterial effects. The area under the unbound concentration-time curve over 24 h to MIC (f AUC0-24/MIC) predicted for bacteriostatic action, 1-log10 reduction, 2-log10 reduction, and 3-log10 reduction were 56.77, 90.18, 143.06, and 239.44 h, respectively. These in vivo data may facilitate gamithromycin dosage optimization against P. multocida in veterinary medicine.

Prevalence of cardiovascular risk factors in non-menopausal and postmenopausal inpatients with type 2 diabetes mellitus in China.

BACKGROUND: To investigate the prevalence of cardiovascular disease (CVD) risk factors and assess the 10-year risk of CVD in non-menopausal and postmenopausal women with type 2 diabetes mellitus (T2DM). METHODS: A total of 569 patients with T2DM at a Chinese tertiary hospital were investigated using the Framingham Risk Score (FRS). We evaluated the 10-year risk of CVD, clinical and menopause characteristics in all subjects. RESULTS: Among the 569 diabetic patients, the incidence of smoking, dyslipidemia, hypertension, overweight or obesity, and nonalcoholic fatty liver disease (NAFLD) was 0.7, 36.2, 38.1 56.6 and 58.2%, respectively. The usage rate of hypoglycemic agents, antihypertensive agents, lipid modulators and antithrombotic drugs was 88.6, 78.3, 50.0 and 27.1%, respectively. However, only 1.2% of inpatients achieved the three target goals for the control of blood glucose (HbA1c < 7%), blood pressure (systolic blood pressure < 130 mmHg, diastolic blood pressure < 80 mmHg), and blood lipids (total cholesterol < 174 mg/dL). The 10-year risk of CVD was (1.6 ± 1.5%) and tended to increase along with age (F = 27.726, P <  0.001). For all subjects (n = 569), multiple linear regression analysis showed that menopause (ß = 0.275, P <  0.001), low-density lipoprotein cholesterol (LDL-C) (ß = 0.212, P <  0.001), fasting plasma glucose (FPG) (ß = 0.093, P = 0.018) and waist-to-hip-ratio (ß = - 0.078, P = 0.047) were risk factors of 10-year risk of CVD, which may explain the variance of 14.3%. In the postmenopausal group (n = 397), LDL-C (ß = 0.227, P <  0.001), FPG (ß = 0.139, P = 0.003) and time since menopause (ß = 0.230, P <  0.001) were found to be associated with CVD, which may explain the variance of 14.6%. CONCLUSION: The incidence of dyslipidmia, hypertension, overweight or obesity and NAFLD is high. The level of control of blood glucose, blood pressure, and blood lipids was found to be extremely low and the treatment status was not ideal. Besides menopause, LDL-C, FPG and time since menopause were found to be independent risk factors for the 10-year risk of CVD. Therefore, it is necessary to focus on comprehensive control of multiple risk factors, such as plasma glucose, blood pressure and serum lipid.

[Middle and long-term results of total hip arthroplasties for secondary post-traumatic arthritis and femoral head necrosis after acetabular fractures].

OBJECTIVE: To evaluate middle and long-term results of total hip arthroplasties (THA) for the treatment of secondary hip traumatic osteoarthritis and femoral head necrosis after acetabular fractures. METHODS: From January 2000 to December 2005, 33 patients with secondary hip traumatic osteoarthritis and (or) femoral head necrosis after acetabular fractures were treated with THA. There were 21 males and 12 females, ranging in age from 27 to 69 years old, with an average of 52 years old. Twenty-three patients were performed with open reduction and internal fixation: 5 patients were treated with anterior approach; 12 patients, posterior approach; 6 patients, combined approaches; other 10 patients, conservative treatment in the early stage. All THA were performed with posterior-lateral approach. Bone union was achieved in the all acetabular fractures. Removal of all implants was necessary in 5 patients, and partial removal in 3 patients. Cemented cup was implanted in 6 patients and uncommented cup in 27 patients. Intraoperative and postoperative complications were observed, and Harris hip scores before surgery and 10 years after operation were compared. The prosthetic loosening, osteolysis or revision were used to evaluate 10 years survival rate of prosthesis. RESULTS: All the patients were followed up,and the duration ranged from 10 to 15 years, with a mean of 12 years. One patient died at the 10th year after operation. The Harris score at the 10th year was higher than the preoperative one. One and two patients were performed with revision total hip arthroplasty caused by aseptic loosening alone and aseptic loosening combined with osteolysis respectively. Osteolysis occurred in 1 patient; deep venous thrombosis in 4 patients; dislocation of prosthesis in 2 patients. One patient had infection of incision and one patient had infection around the prosthesis. Ten years survival rate of implant was 84.8% (28/133). CONCLUSION: THA is an effective method to treat secondary hip traumatic osteoarthritis and (or) femoral head necrosis after acetabular fractures in improving hip joint functions with high implant survival rate and good middle and long-term results.

Rhynchophylline Protects Against the Amyloid ß-Induced Increase of Spontaneous Discharges in the Hippocampal CA1 Region of Rats.

Accumulated soluble amyloid ß (Aß)-induced aberrant neuronal network activity has been recognized as a key causative factor leading to cognitive deficits which are the most outstanding characteristic of Alzheimer's disease (AD). As an important structure associated with learning and memory, the hippocampus is one of the brain regions that are impaired very early in AD, and the hippocampal CA1 region is selectively vulnerable to soluble Aß oligomers. Our recent study showed that soluble Aß1-42 oligomers induced hyperactivity and perturbed the firing patterns in hippocampal neurons. Rhynchophylline (RIN) is an important active tetracyclic oxindole alkaloid isolated from Uncaria rhynchophylla which is a traditional Chinese medicine and often used to treat central nervous system illnesses such as hypertension, convulsions, tremor, stroke etc. Previous evidence showed that RIN possessed neuroprotective effects of improving the cognitive function of mice with Alzheimer-like symptoms. In the present study, we aimed to investigate the protective effect of RIN against soluble Aß1-42 oligomers-induced hippocampal hyperactivity. The results showed that (1) the mean frequency of spontaneous discharge was increased by the local application of 3 µM soluble Aß1-42 oligomers; (2) 30 µM RIN did not exert any obvious effects on basal physiological discharges; and (3) treatment with RIN effectively inhibited the soluble Aß1-42 oligomers-induced enhancement of spontaneous discharge, in a concentration-dependent manner with an IC50 = 9.0 µM. These in vivo electrophysiological results indicate that RIN can remold the spontaneous discharges disturbed by Aß and counteract the deleterious effect of Aß1-42 on neural circuit. The experimental findings provide further evidence to affirm the potential of RIN as a worthy candidate for further development into a therapeutic agent for AD.