Pharmacokinetics and safety of bromotetrandrine (BrTet, W198) after single-dose intravenous administration in healthy Chinese volunteers

Objective: To investigate the safety and pharmacokinetics of bromotetrandrine (BrTet, W198), a novel inhibitor of P‐glycoprotein (P‐gp), after single‐dose i.v. infusion in healthy Chinese volunteers. Methods: We conducted a randomized, dose‐escalating, phase I clinical study for that purpose. Thirty healthy subjects received BrTet at the doses of 10, 20 or 30 mg/m² by i.v. infusion. Plasma and urine concentrations of bromotetrandrine were determined by using a liquid chromatography–tandem mass spectrometric (LC/MS/MS) method. AUC was calculated by the trapezoidal rule extrapolation method. C_max, T_max, t_1/2α, t_1/2β, Cl and V_d were compiled from the plasma concentration–time data. Results: Bromotetrandrine was generally well tolerated at all doses. No serious or severe adverse events were found in the study. The pharmacokinetic parameters of BrTet after single i.v. infusion doses of BrTet 10, 20 and 30 mg/m² were as follows: T_max were 1·5 h in three groups, C_max were 24·79, 39·59 and 64·31 μg/L, t_1/2α were 0·37, 0·29 and 0·30 h, t_1/2β were 62·88, 56·45 and 52·20 h. AUC_0–194h were 345·83, 688·15 and 1096·28 μg h/L, Cl were 23·68, 25·69 and 25·66 L h/m², V_d were 157·73,156·96 and 140·73 L/m². In urine, the total eliminate rate of originate compound was 0·61 ± 0·19%. Conclusions: This study suggested that bromotetrandrine was well tolerated in healthy volunteers within the dose range evaluated. The pharmacokinetics parameters of bromotetrandrine indicated that the compound was rapidly distributed and accumulated in the tissues, and slowly cleared from plasma, which supported the use of BrTet for a once or twice dosing per chemotherapy cycle.     

Synchronous Bilateral Breast Carcinoma in a Patient with Cowden Syndrome: A Case Report with Morphologic,Immunohistochemical and Genetic Analysis

Abstract: Synchronous bilateral breast carcinoma (SBBC) and early onset are important characteristics of hereditary cases. The lifetime risk for breast carcinoma in Cowden syndrome (CS) is estimated to be 25–50%. We reported a 44‐year‐old woman presenting SBBC and characteristic mucocutaneous lesions of CS, confirmed by PTEN gene mutation analysis. Bilateral modified mastectomy and axillary dissection were performed. Histopathologic examination revealed a moderate‐differentiated invasive ductal carcinoma with mixed features of luminal A immunophenotype (Estrogen and/or Progesterone Receptors >50% and/or Ki67 < 30% of positive cells). The skin lesions showed the characteristic findings of tricholemmoma. Lack of PTEN expression was observed in all specimens. Sequencing analysis confirmed the presence of PTEN splice‐acceptor site mutation in intron 8 (c.1027‐2A>G), a germline mutation which had not been previously reported in CS. The patient received adjuvant chemotherapy and tamoxifen for 5 years. After 5 years of follow‐up, she persists recurrence‐free. SBBC with early onset suggests a hereditary predisposition. Thus, analysis of PTEN expression abnormality, easily assessed by immunohistochemistry, may be of clinical value to screen those patients with CS.     

The effect of different cement insertion techniques on the bone-cement interface

Since the introduction of cemented total hip arthroplasty, the method of cement usage has evolved through several generations. These changes may have been responsible for an improvement in femoral component longevity. The nature of the bone-cement interface in first-generation cementing techniques has been described, but the bone-cement interface in more recent cementing techniques has not. This article describes the bone-cement interface after 2 different cementing techniques in a canine total hip arthroplasty model.     

Comparison of the basal ganglia in rats, marmosets, macaques, baboons, and humans: volume and neuronal number for the output, internal relay, and striatal modulating nuclei

This study compares the basal ganglia of rats, marmosets, macaques, baboons, and humans. It uses established protocols to estimate the volume and number of neurons within the output nuclei (internal globus pallidus, IGP; and nondopaminergic substantia nigra, SNND), two internal relay and modulating nuclei (subthalamic nucleus, STh; and external globus pallidus, EGP), and a modulator of the striatum (dopaminergic substantia nigra, SND). Nuclear boundaries were defined by using immunohistochemistry for striatal afferents. Total numbers of Nissl-stained and parvalbumin-immunoreactive neurons were calculated by using the fractionator technique. Comparisons between species were standardized relative to brain mass (rats < marmosets < macaques < baboons < humans). The EGP consistently had more neurons relative to the IGP, STh, and SND, which had similar neuronal numbers within each species. The SNND had proportionally more neurons in rats than in primates (especially humans). The distribution of SND neurons varied substantially between rats and primates (very few ventrally located neurons in rats) with humans containing fewer SND neurons than other primates. The reduction in SND neurons in humans suggests less dopaminergic regulation of the basal ganglia system compared with other species. The consistency in the number of IGP neurons across all species, combined with the reduction in SNND neurons in humans, suggests a greater emphasis on output pathways through the IGP and that there are proportionally more STh and EGP neurons in humans.     

Expression of QK/QR/RRRAA or DERAA motifs at the third hypervariable region of HLA-DRB1 and disease severity in rheumatoid arthritis

OBJECTIVE: To examine the relationship between disease severity in patients with confirmed rheumatoid arthritis (RA) and the carriage of alleles expressing the high risk epitope (HRE) QK/QR/RRRAA or the low risk epitope (LRE) DERAA at positions 70-74 of the third hypervariable region of HLA-DRB1. METHODS: A case-control design to compare allele carriage rates in 204 Caucasian subjects with severe RA and mild RA and healthy controls. Patients had a mean disease duration of 12-18 years and severity of RA was defined using clinical and therapeutic criteria. Molecular typing at the HLA-DRB1 locus was performed using a polymerase chain reaction method. RESULTS: Eighty-seven percent of patients (52/60) with severe RA had one or more of the alleles bearing the QK/QR/RRRAA motif or HRE, compared with 54% (21/39) with mild RA (OR 5.57, p = 0.0007) and 39% (41/105) of controls (OR 10.15, p < 0.0001). Twenty-five percent of patients (15/60) with severe disease expressed 2 disease associated HRE DRB1 alleles, compared with 13% of patients (5/39) with mild disease (OR 2.3, p = NS) and 5% (5/105) of controls (OR 6.67, p = 0.0003). In contrast, only 5% of patients (3/60) with severe RA expressed one of the LRE alleles that carry the DERAA motif at positions 70-74, compared with 31% of patients (12/39) with mild RA (OR 0.12, p = 0.0013) and 22% of controls (23/105) (OR 0.19, p = 0.0082). No patient or control was homozygous for LRE alleles. Eighty-three percent (50/60) of patients with severe RA expressed the HRE without the LRE, compared with 44% (17/39) of those with mild disease (OR 6.47, p < 0.0001) and 35% (37/105) of controls (OR 9.19, p < 0.0001). In contrast, only one patient (2%) with severe disease expressed the LRE without the HRE, compared with 20% (8/39) of those with mild disease (OR 0.07, p = 0.0047) and 16% (17/105) of controls (OR 0.09, p = 0.009). There was no significant difference between the 3 groups in the frequency of patients who expressed both or neither epitope. Logistic regression showed that age at disease onset (p = 0.0009), duration of disease (p = 0.007), positive rheumatoid factor status (p = 0.003), and presence of the HRE or LRE (p = 0.00005) were significantly associated with the presence of severe disease. CONCLUSION: HLA-DRB1 alleles appear to confer an important bidirectional influence on the risk of disease severity in RA, with 20-fold difference in OR between those associated with the highest (HLA-DRB1*0401) and lowest (HLA-DRB1*1301/02) risk. The HRE and LRE exhibit diametrically opposed effects, which may be mutually antagonistic. These data support a multistep pathogenesis in which MHC class II genes are one component of a coordinate genetic and environmental interaction leading to immunological injury and joint destruction.     

Proximal femoral osteotomy for the treatment of hip arthritis in young adults

Background : The outcome of proximal femoral osteotomy for hip arthritis in young adults performed at the Wellington Hospital (Wellington, New Zealand) was reviewed. Methods : Seventeen patients underwent 21 proximal femoral osteotomies for the treatment of hip arthritis at Wellington Hospital between 1992 and 1999. Thirteen patients (17 hips) were contacted and were able to complete a questionnaire form specific for hip pain and function. Results : There was a response rate of 76.5% (13 out of a possible 17 patients undergoing proximal femoral osteotomy) at a mean 3 years 4 months postoperatively. Of these, one patient has had a total hip joint replacement and one patient is currently on the waiting list for a total hip joint replacement. Three other patients (three hips) report moderate or severe hip pain. The remaining eight patients (12 hips) report having mild or no hip pain. Questionnaire results show a postoperative decrease in hip pain in most patients. Hip function as assessed by the questionnaire was essentially unchanged. Conclusions : Proximal femoral osteotomy is a satisfactory option for young patients with degenerative hip arthritis. The operation is only likely to be useful in the treatment of pain.