Biodegradable bromocryptine mesylate microspheres prepared by a solvent evaporation technique. I: Evaluation of formulation variables on microspheres characteristics for brain delivery

The aim of this study was to formulate biodegradable microspheres containing an anti-parkinsonian agent, bromocryptine mesylate, for brain delivery. The effect of formulation parameters (e.g. polymer, emulsifying agent type and concentration) on the characteristics of the microspheres produced, the efficiency of drug encapsulation, the particle size distribution and in vitro drug release rates from the bromocryptine mesylate microspheres were investigated using a 3 2 factorial design. Bromocryptine mesylate was encapsulated into biodegradable polymers using the following three different polymers; poly(L-lactide), poly(D,L-lactide) and poly(D,L-lactide-co-glycolide). The SEM photomicrographs showed that the morphology of the microspheres greatly depended on the polymer and emulsifying agent. The results indicate that, regardless of the polymer type, increase in emulsifying agent concentration from 0.25-0.75% w/v markedly decreases the particle size of the microspheres. Determination of particle size revealed that the use of 0.75% w/v of emulsifying agent concentration and a polymer solution concentration of 10% w/v resulted in optimum particle size. In order to prepare biodegradable microspheres with high drug content and small particle size, selection of polymer concentration as well as emulsifying agent concentration is critical. Polymer type has a less pronounced effect on the percentage encapsulation efficiency and particle size of microspheres than on the t 50% . The microspheres prepared by all three polymers, at a polymer concentration of 10% w/v and an emulsifying agent concentration of 0.75% w/v with NaCMC:SO (4:1, w/v) mixture was as the optimum formulation.     

Low Attenuation Area Is Associated with Airflow Limitation and Airway Hyperresponsiveness

Background. Asthma is a chronic inflammatory disorder of the airways characterized by airflow limitation and airway hyperresponsiveness. Lung density indices on quantitative computed tomography (QCT) are assumed to reflect the degree of air trapping originated from airflow limitation in airway diseases. Purpose. The present study investigated the availability of lung density indices on QCT in clinical evaluation of asthma. Methods. Eleven asthmatic patients and 48 healthy control subjects were prospectively evaluated by QCT, pulmonary function testing, and a methacholine challenge test. High-resolution computed tomography scans were performed at full-inspiratory and full-expiratory phases, and percentage of lung field occupied by low attenuation area (LAA%) and mean lung density (MLD) at both inspiratory and expiratory phases were measured. Results. MLD values at inspiratory phase were significantly increased in asthmatic patients compared with those in healthy control subjects. Inspiratory LAA% values were significantly decreased in asthmatics compared with the values in control subjects. On expiratory scans, MLD values of asthmatics were significantly lower than the values of control subjects. Expiratory LAA% values of asthmatics were significantly higher than the values of control subjects. The LAA% in the expiratory phase showed significant negative correlation with forced expiratory volume in 1 second (FEV₁), FEV₁/forced vital capacity, and the provocative dose of methacholine causing a 20% decrease in FEV₁ in asthmatic patients. Conclusion. These results suggest that lung density indices on QCT may be useful for clinical evaluation of asthmatic patients and increased LAA% in the expiratory phase is associated with airflow limitation and airway hyperresponsiveness in asthma.     

PTU-induced ANCA-positive vasculitis: an innocent or a life-threatening adverse effect?

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides are rare, but they can be triggered by chemicals, infections and drugs; among them, antithyroid drugs are common. Autoimmune disorders, such as vasculitis, are unusual, but serious complications of antithyroid therapy. Both propylthiouracil (PTU) and methimazole may induce ANCA-associated vasculitis. PTU-induced vasculitides may have different organ involvement patterns. Herein, we report four cases with ANCA-associated vasculitis with different clinical manifestations.     

Risk and predictors of arterial thrombosis in lupus and non-lupus primary glomerulonephritis: a comparative study

We conducted the current study to compare the incidence and risk factors of arterial thrombosis in lupus and non-lupus primary glomerulonephritis. We identified patients in whom lupus nephritis and non-lupus primary glomerulonephritis were diagnosed between 1993 and 2003 using our lupus cohort database and pathology registry. We analyzed the cumulative incidence of new arterial thromboembolic events since diagnosis by Kaplan-Meier plot, and studied risk factors by multivariate analysis. We studied 162 patients with lupus and 181 patients with non-lupus primary glomerulonephritis. After a mean observation of 8.1 years, 47 (14%) patients died, 23 (7%) were lost to follow-up, and 38 (11%) developed 42 arterial events (incidence, 15.1/1000 patient-years). Although patients with lupus nephritis were younger and had a significantly lower frequency of smoking, hypertension, obesity, and renal dysfunction, their cumulative risk of arterial event at 5 years was not significantly lower than that of patients with primary non-lupus glomerulonephritis (6.3% vs. 6.6%, p = 0.96). In a Cox regression model, lupus was found to be an independent risk factor for arterial thrombosis (hazard ratio 3.57 [1.07-11.9]; p = 0.04), in addition to increasing age (hazard ratio 1.04 per year; p = 0.02), low-density lipoprotein > or =2.6 mmol/L (hazard ratio 4.46; p = 0.002), and glomerular filtration rate <30 mL/min (hazard ratio 2.67; p = 0.04). We concluded that in immune-mediated glomerulonephritis, having systemic lupus increased the risk of arterial thromboembolism after adjustment for age, renal insufficiency, and other traditional risk factors.     

Can daclizumab reduce acute rejection and improve long‐term renal function in tacrolimus‐based primary renal transplant recipients?

SUMMARY: Aims: To evaluate the efficacy and safety of a tacrolimus‐based immunosuppressive regimen with and without induction therapy using daclizumab in first cadaveric renal transplant recipients. Methods: Since January 2001, we studied the effect of daclizumab in a non‐randomized and prospective study of 36 sequential first cadaveric renal transplant recipients. They were compared with a historical control group of 21 sequential first cadaveric renal transplant recipients without induction therapy. All patients received tacrolimus, azathioprine and corticosteroids as concomitant immunosuppressive therapy. Daclizumab was given at 1 mg/kg infusion 2 h before transplantation and then every 14 days for four more doses. Outcomes measured included incidence of acute rejection, patient survival, graft survival, annualized change in creatinine clearance (CrCl), cardiovascular risk profile, infection and malignancy. Results: Fewer biopsy proven acute rejections were observed in the induction treatment group: 11.1% (4/36) versus 19% (4/21) but the rejection free survival was similar (P = 0.37). The patient survival and graft survival were comparable. The renal function was similar in both groups. There were also no significant difference in infection, malignancy and cardiovascular risk profile in both groups. Conclusion: Adding daclizumab to a tacrolimus‐based therapy is safe but cannot further improve clinical efficacy.     

Renal allograft C4d deposition in Chinese: Hong Kong perspective

Background: Acute rejection constitutes a significant proportion of renal allograft loss. Peritubular capillary deposition of C4d has been recognized as the footprint of humoral alloimmunity and proven to be a sensitive and specific marker for humoral rejection in the appropriate clinical context. Its presence in indication biopsies is the most important independent risk factor for graft failure. Data are, however, scarce among Chinese subjects. Methods: We retrospectively reviewed all renal graft biopsies performed from 1 April 2002 to 31 March 2006 for unexplained acute renal dysfunction or delayed graft function. Renal outcomes were assessed at the time of renal biopsy and at 1 month, 3 months, 6 months and 1 year afterwards. Survival was assessed by Kaplan–Meier analysis. Multivariate analysis was used to determine if C4d positivity is an independent risk factor for poor renal outcome. Results: Fifty‐two biopsies were included, of which 16 were positive for peritubular capillary C4d. Peritubular capillary C4d was associated with lower glomerular filtration rate and higher serum creatinine at 6 and 12 months after renal biopsies. The C4d‐positive group fares worse in terms of death‐censored graft failure, doubling of serum creatinine and reaching 50% of glomerular filtration rate at the end of the study. Peritubular capillary C4d deposition was the only significant risk factor that predicts graft failure in multivariate analysis. Conclusion: Our findings confirmed the independent prognostic value of peritubular capillary C4d staining on renal allograft survival in Chinese.     

Effects of sucrose on plasma concentrations and urinary excretion of purine bases

To determine whether an increase in the plasma concentration of uric acid by sucrose intake is ascribable to enhanced purine degradation and/or decreased urinary excretion of uric acid, we measured the plasma concentrations of purine bases (uric acid, hypoxanthine, and xanthine) and uridine, as well as the urinary excretion of purine bases in 7 healthy subjects before and after administering sucrose at 1.5 g/kg of body weight in 2 related experiments, with and without an administration of 300 mg of allopurinol. In addition, in the control experiment without an administration of sugar and with an administration of 300 mg of allopurinol, we measured the same parameters in those 7 subjects. Without added allopurinol, sucrose increased the plasma concentration of uric acid by 11% (P<.01) as well as that of uridine, although it did not significantly increase the plasma concentrations of hypoxanthine and xanthine or the urinary excretion of uric acid. On the other hand, the plasma concentration and urinary excretion of hypoxanthine were increased by 2.4-fold (P<.05) and 3.42-fold (P<.05), respectively, and the plasma concentration of xanthine was increased by 1.2-fold (P<.05) together with an increase in the plasma concentration of uridine in the experiment with allopurinol administration. In contrast, the plasma concentration and urinary excretion of uric acid and the urinary excretion of xanthine were not increased. In addition, in the control experiment, all parameters did not change significantly. These results indicate that purine degradation enhanced by sucrose plays a major role in the increased plasma concentration of uric acid.     

Prognostic factors for Korean patients with anaplastic thyroid carcinoma

BACKGROUND: Anaplastic thyroid carcinoma (ATC), although rare, is one of the most aggressive human cancers, and patients with ATC have extremely poor prognoses despite various therapeutic measures. We wished to determine the prognostic factors of survival and effect of treatment on survival rate in patients with ATC. METHODS: We retrospectively reviewed the medical records of the 121 patients (41 men and 80 women) diagnosed with ATC from January 1995 to June 2004 at 5 major referral centers in Korea. RESULTS: Mean patient age at diagnosis was 64 +/- 11 years (range, 17-84 years). Of the 121 patients, 11 (9%) had intrathyroidal tumors, 69 (57%) had extrathyroidal tumors or lymph node involvement, 29 (24%) had distant metastases, and 12 had no data about staging (9%). The mean tumor diameter was 5.5 +/- 2.5 cm (range, 0.5-17.0 cm). At a median follow-up of 41 months (range, 26-122 months), 8 patients were alive. Median survival time was 5.1 months. The disease-specific survival rates were 42% at 6 months, 16% at 12 months, and 9% at 24 months. Sixteen patients (13%) received only supportive care, 25 (21%) received surgery alone, 20 (16%) received radiation treatment or chemotherapy without surgery, and 60 (50%) received surgery plus radiation treatment or chemotherapy. Multivariate analysis showed that age less than 60 years, tumor size less than 7 cm, and lesser extent of disease were independent predictors of lower disease-specific mortality. CONCLUSIONS: Long-term survival is possible for ATC patients less than 60 years old and with small localized tumors. Although aggressive multimodal therapy, including surgery, radiation treatment, and chemotherapy, was not significantly associated with improved survival, we advocate aggressive multimodal therapy in selected ATC patients with good prognostic factors.     

The carina is not a landmark for central venous catheter placement in neonates

BACKGROUND: Cardiac tamponade is rare but one of the most serious complications in relation to central venous catheters (CVC). The tip of the CVC should be placed outside the pericardium to avoid tamponade. In adults, the carina is always located above the pericardium; therefore, the carina is a reliable landmark for CVC placement. We examined whether the carina could also be an adequate landmark for CVC placement in neonates. METHODS: The study was conducted using nine fresh neonatal cadavers. The longitudinal distance between the carina and the pericardium as it transverses the superior vena cava (the pericardial reflection: PR) was measured. RESULTS: The median postconceptional age (gestational age in weeks + weeks after delivery) at autopsy was 35 (range: 23-42) weeks. The PR was located at a distance of 4 mm above to 5 mm below the carina. Unlike in adults, the position of the PR varies in relation to the carina in neonates. In seven of the nine subjects, the location of the PR was above the carina. CONCLUSIONS: In neonates, the carina is not always located above the pericardium, as it is in adults; therefore, the carina is not an appropriate landmark for CVC placement.