Interactions between imidazoline compounds and sulphonylureas in the regulation of insulin secretion

1. Imidazoline α₂-antagonist drugs such as efaroxan have been shown to increase the insulin secretory response to sulphonylureas from rat pancreatic B-cells. We have investigated whether this reflects binding to an islet imidazoline receptor or whether α₂-adrenoceptor antagonism is involved.
2. Administration of (±)-efaroxan or glibenclamide to Wistar rats was associated with a transient increase in plasma insulin. When both drugs were administered together, the resultant increase in insulin levels was much greater than that obtained with either drug alone.
3. Use of the resolved enantiomers of efaroxan revealed that the ability of the compound to enhance the insulin secretory response to glibenclamide resided only in the α₂-selective-(+)-enantiomer; the imidazoline receptor-selective-(−)-enantiomer was ineffective.
4. In vitro, (+)-efaroxan increased the insulin secretory response to glibenclamide in rat freshly isolated and cultured islets of Langerhans, whereas (−)-efaroxan was inactive. By contrast, (+)-efaroxan did not potentiate glucose-induced insulin secretion but (−)-efaroxan induced a marked increase in insulin secretion from islets incubated in the presence of 6 mM glucose.
5. Incubation of rat islets under conditions designed to minimize the extent of α₂-adrenoceptor signalling (by receptor blockade with phenoxybenzamine; receptor down-regulation or treatment with pertussis toxin) abolished the capacity of (+)-and (±)-efaroxan to enhance the insulin secretory response to glibenclamide. However, these manoeuvres did not alter the ability of (±)-efaroxan to potentiate glucose-induced insulin secretion.
6. The results indicate that the enantiomers of efaroxan exert differential effects on insulin secretion which may result from binding to effector sites having opposite stereoselectivity. Binding of (−)-efaroxan (presumably to imidazoline receptors) results in potentiation of glucose-induced insulin secretion, whereas interaction of (+)-efaroxan with a second site leads to selective enhancement of sulphonylurea-induced insulin release.

     

Solute Absorption from the Airways of the Isolated Rat Lung. IV. Mechanisms of Absorption of Fluorophore-Labeled Poly-α,β-[N(2-Hydroxyethyl)-DL-Aspartamide]

The pulmonary absorption kinetics of a single molecular weight distribution (MWD) of fluorophore-labeled poly-,-[N(2-hydroxyethyl)-DL-aspartamide] (F-PHEA), a hydrophilic and biocompatible synthetic polypeptide, were studied in the isolated, perfused rat lung (iprl) as functions of administered polymer concentration, dose, vehicle, and presence and absence of fluorophore. The MWD was characterized before and after absorption by measurement of weight- and number-averaged molecular weights (M _wand M _n, respectively) using high-performance gel-permeation chromatography. Values for M _w and M _n were 8.6 and 5.3 kD before, and 6.7 and 4.7 kD after, absorption into the perfusate; there was no significant metabolism and the MWD of the absorbed polymer was independent of both dose and sampling time over a 3-hr period. F-PHEA failed to show any evidence of aggregation in solution or changes in dose distribution within the airways as functions of increasing polymer concentration and dose. A concentration ranging study indicated the presence of a saturable, carrier-mediated transport process for F-PHEA with a maximum absorption rate, V _max, of approximately 180 µg or 0.027 µmol/hr. Coadministration of fluorophore-free PHEA was capable of depressing the absorption of F-PHEA. The transport process for F-PHEA appeared to have a molecular weight limit of about 7 kD for this hydrophilic polymer.     

Effect of Perfusate pH on Reduction of Quinidine Capillary Permeability by Albumin in Isolated Perfused Rat Heart

It has been suggested that albumin reduces quinidine capillary permeability (PS) in the single-pass perfused heart preparation by reducing paracellular transport of quinidine ions. Using this preparation, we examined the effect of albumin (0.1 per cent) on quinidine PS at perfusate pHs of 7.1 and 7.9 during uptake of quinidine (19 µM) and also during washout of the drug using a randomized design. Quinidine PS was approximately 16 ml/min/g heart at pH 7.9 and was not altered by the presence of albumin in perfusate. At pH 7.1, in the absence of albumin, quinidine PS was also 16 ml/min/g, but in the presence of albumin (0.1 per cent) PS was reduced significantly to approximately 5 ml/min/g (P < 0.001). In the absence of albumin PS was the same at pH 7.1 and 7.9 in spite of a greater degree of ionisation of quinidine at pH 7.1. This suggests that there is significant uptake of ionised quinidine at pH 7.1. The greater effect of albumin on PS at pH 7.1 supports the hypothesis that albumin reduces paracellular transport of quinidine ions.     

Evaluation of a high sodium-low potassium cold-storage solution by the isolated perfused rat kidney technique

The isolated perfused rat kidney (IPK) model was used to assessinitial renal function after 24 h preservation in 3 differentcold storage solutions: EuroCollins (EC), a solution preparedaccording to the formulation of Belzer's solution (High-K⁺ UW)and a high Na⁺-low K⁺ Belzer UW solution (High Na⁺ UW). GFR and FR_Na were measured after 24 h cold storage in each ofthe solutions during 60 min, and were compared to values obtainedin a control group in which renal function was measured immediatelyafter the kidneys had been harvested. ATP and CP were measuredin fresh renal tissue, in kidneys preserved for 24 h in eachsolution, in control IPK, and in reperfused IPK after they hadbeen preserved for 24 h. Main results showed that preservationin either solution caused a dramatic decrease in GFR and inFR_Na within the first 60 min following reperfusion of cold-storedkidneys. However FR_Na was significantly higher in the High-Na⁺UW group. ATP and CP content were decreased to 10% of basalvalues in all experimental groups after cold-storage. Normothermicreperfusion of IPK after cold-storage induced a restorationof ATP levels, but CP content decreased further. There was nosignificant difference in ATP and CP content between cold-storagesolutions, nor any correlation between metabolic and functionalparameters.     

HX-Ⅰ液作为腹部内多器官灌注液可行性研究

采用大鼠肝脏非循环离体灌注模型,观察HX-Ⅰ液对大鼠肝组织含水量、肝窦内皮细胞死亡率,Krebs－Henseleit液天门冬氨酸转移酶活性、分泌胆汁的肝脏数量;观察HX-Ⅰ液对糖尿病大鼠胰腺移植术后血糖（Pod＋2,7,14）、糖耐量、胰岛素变化;观察HX-Ⅰ液对狗肾移植术后血肌酐、存活率及肝、胰、肾脏的形态学。结果表明,HX-Ⅰ液保存大鼠肝脏达24h,胰腺48h,狗肾脏达72h。说明HX-Ⅰ液作为腹部内多器官灌注液是可行的。     

Vascular anatomy of the pancreaticoduodenal region: A review

Vascular anatomy of the pancreaticoduodenal region has been the subject of numerous studies. However, several essential areas of confusion remain in interpretation of the vascular configuration. We note and discuss three key points in relation to this confusion: (1) a missing vascular arcade, (2) a rearrangement of the arcade by collateral and/or transverse vessels, and (3) a solitary vessel without an accompanying comites vein or artery. In addition, we consider that different interpretations as well as varying reported incidences depend on different "thresholds" when observations are made. Consideration of new aspects of vascular anatomy of the pancreaticoduodenal region is required for further improvement of surgical procedures. In terms of the selection of lymph node resection procedure, we discuss mainly the inferior arterial origin. Special attention should be paid to the ligation of inferior arteries because of the high incidence of the common trunk formation of the upper jejunal and inferior pancreaticoduodenal arteries. With regard to duodenum-preserving pancreatic head resection for benign tumors, our observations are introduced in view of either arterial or venous configuration. First, a communicating artery between the anterior and posterior arterial arcades is noted because of its possible critical role in blood supply to the papilla of Vater. Second, a venous drainage route from the duodenum to the retroperitoneal space in "normal" specimens is described. Received for publication on June 17, 1998; accepted on July 27, 1998     

Phase II trial of fazarabine (arabinofuranosyl-5-azacytidine) in patients with advanced pancreatic adenocarcinoma

We conducted a phase II evaluation of fazarabine 1.75–2.0 mg/m²hr over 72 hours every 28 days in 14 previously untreated patients with advanced adenocarcinoma of the pancreas. The intial dose was 1.75 mg/m²/hr in 10 patients, and 2.0 mg/m²hr in 4 patients. The dose was escalated in 8 patients, including all 4 who started at the higher dose level. Toxicity was unexpectedly mild. The median WBC nadir was 4.4 (range: 2.4–15.8)×10³/l, the median absolute neutrophil nadir was 3.2 (range: 0.9–13.0)×10³/l, and the median platelet count was 134.0 (range: 48.0–291.0)×10³/l. Gastrointestinal toxicity was generally mild. No major responses were seen, excluding, with 95% confidence, a response rate in excess of 20%.     

Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma

We conducted a phase II evaluation of edatrexate in 17 previously untreated patients with advanced adenocarcinoma of the pancreas; 14 patients had at least one month of therapy. The initial dose was 80 mg/m²iv. Treatment was administered weekly for 5 weeks, then every other week. Toxicity was generally mild. The median WBC nadir was 5.4 (range 0.6–7.4)×10³/l, and the median platelet nadir was 164.0 (range 62.0–341.0)×10³/l. One patient died with sepsis and gastrointestinal bleeding associated with pancytopenia. Five patients had a mild rash. Nausea occurred in 6 patients, including 3 who had vomiting. In addition, 11 patients complained of vague malaise which seemed to begin within 24–48 hours after administration of edatrexate, and lasted for 2 to 3 days, resolving within 6 days of drug administration. Median survival was 85 days. Although 5 patients had stable disease, including one with relief of pain, no major responses were seen, excluding, with 95% confidence, a response rate in excess of 20%.     

Partial venous thrombosis of the pancreatic allografts after simultaneous pancreas-kidney transplantation

Despite new advances in transplantation, complete venous thrombosis (VT) of the pancreas after simultaneous pancreas kidney (SPK) transplantation usually results in graft loss. Data are limited regarding the outcome and treatment of partial VT of the pancreas allograft. From July 1994 to December 1999, 126 patients with IDDM/end-stage renal disease underwent SPK with systemic bladder drainage at the University of Miami. We retrospectively reviewed our experience regarding the outcome and treatment options of partial VT of the pancreas allografts. From July 1994 to April 1997, partial VT was not seen in the first 66 SPK patients induced with anti-CD3 rnAb and oral or intravenous (i.v.) tacrolimus (TAC) in the operating room. From May 1997 to June 1999, 14 (29%) out of 48 patients had VT. These cases were identified following the i.v. use of TAC with anti-IL-2R antibody-induction therapy (7/15) or without (7/33). Partial thrombosis of the splenic vein (PTSV) was documented in 10 patients, 2 had complete thrombosis of the splenic vein (CTSV), 1 had partial thrombosis of the superior mesenteric vein (PTSMV), and 1 patient had PTSV and PTSMV. These were identified incidentally during routine color Doppler ultrasonography (CDU). None of these SPK recipients demonstrates a change in clinical parameters. The first 8 patients were systemically heparinized, followed by oral anticoagulation, except 1 patient with CTSV. He progressed to complete thrombosis of the pancreas allograft and was treated with percutaneous thrombectomy and urokinase infusion, followed by heparinization and oral anticoagulation. One patient required exploration for bleeding. In an attempt to reduce the morbidity of heparinization, we treated the next 6 patients with PTSV with aspirin followed by serial CDU. All 14 patients had preservation of the endocrine and exocrine pancreatic functions. CDU showed resolution with recanalization of the thrombosed vein(s). From July 1999 to December 1999, 12 SPK recipients were administered TAC orally with or without induction therapy with anti-IL-2R antibody. So far, in this group, VT has not been identified. In summary, a total of 14 out of 126 patients (11%) had isolated VT with a mean follow-up of 36.4 months. Based on our experience, we suggest that extensive VT after pancreas transplantation, including splenic and superior mesenteric VT, be treated with heparin and subsequent oral anticoagulation for 3 months. For more limited, partial splenic VT, aspirin may be sufficient. Follow-up CDU is critical for a successful outcome. The i.v. use of TAC appears to be a risk factor for the increased incidence of VT. Currently, using IL-2rmAb as induction, TAC is started orally on postoperative days 3 or 4 and aspirin on postoperative day 2.     

Outcomes of simultaneous kidney-pancreas transplantation in African-American recipients: a case-control study

INTRODUCTION: Previous studies have suggested that African-American (AA) ethnicity is a risk factor for rejection and graft loss after kidney transplantation. However, little data is available regarding outcomes after simultaneous kidney pancreas transplantation (SKPT) in AA recipients. The objective of this study was to compare the outcomes of SKPT in AA patients to matched Caucasian patients as controls. METHODS: From January 1996 to September 1999, we performed 79 SKPTs, including 10 in AA recipients. Ten Caucasian controls were selected and matched for age, gender, weight, timing and technique of transplantation, and immunosuppressive regimen. Clinical outcomes were collected and compared between the two groups. RESULTS: The two groups were well matched for donor and recipient demographic, immunologic and transplant characteristics, including 2 patients in each group with type 2 diabetes. All patients received tacrolimus (TAC), mycophenolate mofetil (MMF) and steroids, and about half in each group received antibody induction therapy. Patient survival was 100% in both groups with a mean follow-up of 18 months (range 6 47). Kidney and pancreas graft survival rates were both 80% in the AA and 100% in the Caucasian groups, respectively (p = 0.14). All but one kidney (in the AA group) and all pancreas grafts experienced immediate function. There were two immunologic kidney and two immunologic pancreas graft losses in the AA group. No grafts were lost due to technical problems. The mean length of initial hospital stay was 16 d in the AA group compared to 10 d in the Caucasian group (p = 0.07). The AA group had a slight increase in the number of readmissions (mean 2.2 AA vs. 1.6 Caucasian, p = 0.08). The incidence of biopsy-proven pancreas acute rejection was significantly higher in the AA group (50%) compared to the Caucasian group (10%) (p = 0.05). The incidence of either kidney or pancreas acute rejection was also higher in the AA group (60% AA vs. 20% Caucasian, p = 0.06). TAC levels were comparable at specific times after transplantation, al-though there was a trend toward higher doses of TAC in the AA group to achieve therapeutic levels. The incidences of relaparotomy (30% AA vs. 20% Caucasian) and major infection (40% AA vs. 60% Caucasian) were similar between groups. Renal and pancreas allograft functions were comparable between groups at specific times after transplantation. CONCLUSIONS: These results suggest that SKPT in AA recipients may be associated with a higher incidence of rejection and immunologic graft loss compared to matched Caucasian controls.