Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations.

Buprenorphine is an effective new treatment for opiate dependence. This study compared the bioavailability of buprenorphine from a tablet to that from a reference solution. Six men experienced with, but not dependent on, opiates (DSM-III-R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in tablet form 1 week apart in a balanced crossover design. Plasma levels were measured by electron capture capillary gas chromatography (GC), and concentration-time curves were constructed. Pharmacokinetic data were analyzed by analysis of variance. The bioavailability from the tablet was approximately 50% that from the liquid and was not affected by saliva pH. Lower bioavailability from the tablet may be due to slow dissolution.     

Compatibility and stability of bryostatin 1 in infusion devices

Bryostatin 1 is currently in phase II clinical trial sponsored by the National Cancer Institute as an anticancer chemotherapeutic agent. Bryostatin 1 for injection was supplied in a dual pack containing a drug vial and a diluent vial and was manufactured by Ben Venue Laboratories, Inc (Bedford, OH). The stability and compatibility of the bryostatin 1-PET formulation, diluted to 1 and 10 ug/mL in saline and benzyl alcohol preserved saline, with polypropylene (PP) and polyvinyl chloride (PVC) bags at room temperature (27°C) were studied. All experiments were conducted in triplicate and analyses were performed using a validated, stability-indicating, high performance liquid chromatography (HPLC) assay.Bryostatin 1 solutions were compatible with PP bags. At both concentrations and with both salines, the bryostatin content remained unchanged during the 28-day storage period, benzyl alcohol concentration in the preserved saline solutions also remained relatively constant. In PVC bags, however, a decrease in bryostatin 1 concentrations without generation of decomposition products was observed at both dilutions and with both salines during the 28-day storage. A decrease in benzyl alcohol concentration in the preserved saline was also observed. While no diethylhexylphthalate (DEHP) leakage into the solution was observed in PP bags, DEHP leakage in PVC infusion bags was observed on day 2 of storage which increased with storage time and leveled off on day 6. The amount of DEHP leached into drug solution is dependent on the drug concentration. This study suggests bryostatin-PET formulation diluted with preserved saline can be used for long-term (4 week) intravenous administration using PP infusion bags, but not with PVC bags.     

Clinical pathologic findings of Propionibacterium acnes endophthalmitis

The autors presented two typical cases of patients who were infected with Propionibacterium acnes (P. acnes) after intraocular lens implantation. The patients were treated successfully by the removal of the intraocular lens and the residual lens capsule, and the administration of intravitreal vacomycin. The histopathology illustrated numerous prokaryote bacilli surrounding the lens material without inflammatory reaction. The thickened bacterial cell wall structure may relate to the resistance of P. acnes killing and degradation by the host neutrophils and macrophages. Complete removal of the lens material which may sequester the bacterial growth in the eye is important to eradicate P. acnes endophthalmitis.     

CT and DSA appearances of a ruptured congenital arteriovenous malformation of the posterior mediastinal aorta

A case of symptomatic congenital arteriovenous malformation detected in an adult patient is presented. The diagnosis was not suspected clinically but was demonstrated by CT and digital subtraction angiography. Although very rare, a congenital arteriovenous malformation of the posterior mediastinal aorta could present as a catastrophic event if it ruptures. Serpiginous vascular channels in the retro-oesophageal posterior mediastinum on CT and angiography should raise the possibility of an arteriovenous malformation.     

Phase II study of neoadjuvant carboplatin and paclitaxel followed by radiotherapy and concurrent cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: therapeutic monitoring with plasma Epstein-Barr virus DNA.

PURPOSE: To assess the efficacy of neoadjuvant paclitaxel and carboplatin (TC) followed by concurrent cisplatin and radiotherapy (RT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and to monitor treatment response with plasma Epstein-Barr virus (EBV) DNA. PATIENTS AND METHODS: Thirty-one patients with International Union Against Cancer stages III and IV undifferentiated NPC had two cycles of paclitaxel (70 mg/m2 on days 1, 8, and 15) and carboplatin (area under the curve 6 mg/mL/min on day 1) on a 3-weekly cycle, followed by 6 to 8 weeks of cisplatin (40 mg/m2 weekly) and RT at 66 Gy in 2-Gy fractions. Plasma EBV DNA was measured serially using the real-time quantitative polymerase chain reaction method. Results All patients completed planned treatment. Response to neoadjuvant TC was as follows: 12 patients (39%) achieved partial response (PR) and 18 achieved (58%) complete response (CR) in regional nodes; five patients (16%) achieved PR and no patients achieved CR in nasopharynx. At 6 weeks after RT, one patient (3%) achieved PR and 30 patients (97%) achieved CR in regional nodes, and 31 patients (100%) achieved CR in nasopharynx; 29 patients (93%) had EBV DNA level of less than 500 copies/mL. Neoadjuvant TC was well tolerated, and the most common acute toxicity of cisplatin plus RT was grade 3 mucositis (55%). At median follow-up of 33.7 months (range, 7 to 39.3 months), six distant and three locoregional failures occurred. Plasma EBV DNA level increased significantly in eight of nine patients who experienced treatment failure but did not increase in those who did not. The 2-year overall and progression-free survival rates were 91.8% and 78.5%, respectively. CONCLUSION This strategy was feasible and resulted in excellent local tumor control. Serial plasma EBV DNA provides a noninvasive method of monitoring response in NPC.     

2. Survival Impact of HER-2/Neu, Cox-2, Urokinase Plasminogen Activator (upa), Cytokeratin 17/5,6 and other Markers with Long-Term Outcome of Early Breast Cancer. Report from the British Columbia Tissue Micro-Array Project (BCTMAP)

Tumor samples are available from over 19,600 Stage I-III breast cancer patients treated according to evolving British Columbia guidelines from 1978 to 1990. A tissue mico-array (TMA) was constructed from 930 of these patients, all of whom participated in randomized or phase II studies. Outcome was defined as 20-year Breast Cancer specific Survival (BrCaSS), with events defined as Breast Ca death. Follow up was median 17.8 years (ranges 11–28). Multiple tumor markers were tested, and results correlated with 20-year BrCaSS for markers expressed versus non-expressed. No difference in BrCaSS was found for aromatase, integrin-linked kinase (ILK), IGF-1 and Topo-isomerase-2. The negative predictive value of IHC versus FISH and ACIS-IHC versus FISH was 96 and 97%, respectively. The positive predictive value of IHC versus FISH and ACIS-IHC versus FISH was 84 and 84%, respectively. All tests, with the exception of HER-2 FISH were done by IHC. Results of other markers (VEGF, ER/PgR, hypoxia markers, etc.), and an interactive multivariate analysis adjusting for conventional prognostic factors and for all above markers, are in progress. Conclusions 1. The TMA is a technique which provides opportunity for rapid screening of multiple genetic markers.2. Expression of Her-2/Neu, uPA, Cox-2 and Cytokeratin 17/5,6 (but not of Aromatase, ILK, TOPO-II and IGF-1) is associated with inferior BrCaSS.3. HER-2 determination by ACIS-IHC provides comparable results to IHC done manually (with a potential for more uniform reporting), and both provide comparable results to Her-2 assessment by FISH. ^** ACIS-IHC:IHC red by Automated Cell Image System (M.L.)     

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. BACKGROUND: In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 +/- 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients. METHODS: After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (beta-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine). RESULTS: In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the beta-1/Cr (0.65 +/- 4.29 vs. -1.93 +/- 2.35 1/micromol x 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 +/- 24.1 vs. 63.5 +/- 21.3 vs. 41.9 +/- 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0. 001). On multivariate analysis, beta-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (beta = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (beta = 2.426, P = 0.018), high-density lipoprotein cholesterol (beta = -8.797, P = 0.03), baseline UAE (beta = 0.002, P = 0.04), and mean CCr during treatment (beta = -0.211, P = 0.006). CONCLUSION: In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.