Development of sustained-release lipophilic calcium stearate pellets via hot melt extrusion

The objective of this study was the development of retarded release pellets using vegetable calcium stearate (CaSt) as a thermoplastic excipient. The matrix carrier was hot melt extruded and pelletized with a hot-strand cutter in a one step continuous process. Vegetable CaSt was extruded at temperatures between 100 and 130 °C, since at these temperatures cutable extrudates with a suitable melt viscosity may be obtained. Pellets with a drug loading of 20% paracetamol released 11.54% of the drug after 8 h due to the great densification of the pellets. As expected, the drug release was influenced by the pellet size and the drug loading. To increase the release rate, functional additives were necessary. Therefore, two plasticizers including glyceryl monostearate (GMS) and tributyl citrate (TBC) were investigated for plasticization efficiency and impact on the in vitro drug release. GMS increased the release rate due to the formation of pores at the surface (after dissolution) and showed no influence on the process parameters. The addition of TBC increased the drug release to a higher extent. After dissolving, the pellets exhibited pores at the surface and in the inner layer. Small- and Wide-Angle X-ray Scattering (SWAXS) revealed no major change in crystalline peaks. The results demonstrated that (nearly) spherical CaSt pellets could be successfully prepared by hot melt extrusion using a hot-strand cutter as downstreaming system. Paracetamol did not melt during the process indicating a solid suspension. Due to the addition of plasticizers, the in vitro release rate could be tailored as desired.     

Combining Cariporide with Glyceryl Trinitrate Optimizes Cardiac Preservation During Porcine Heart Transplantation

Sodium–hydrogen exchange inhibitors, such as cariporide, are potent cardioprotective agents, however, safety concerns have been raised about intravenously (i.v.) administered cariporide in humans. The aim of this study was to develop a preservation strategy that maintained cariporide's cardioprotective efficacy during heart transplantation while minimizing recipient exposure. We utilized a porcine model of orthotopic heart transplantation that incorporated donor brain death and 14 h static heart storage. Five groups were studied: control (CON), hearts stored in Celsior; CAR1, hearts stored in Celsior with donors and recipients receiving cariporide (2 mg/kg i.v.) prior to explantation and reperfusion, respectively; CAR2, hearts stored in Celsior supplemented with cariporide (10 μmol/L); GTN, hearts stored in Celsior supplemented with glyceryl trinitrate (GTN) (100 mg/L); and COMB, hearts stored in Celsior supplemented with cariporide (10 μmol/L) plus GTN (100 mg/L). A total of 5/5 CAR1 and 5/6 COMB recipients were weaned from cardiopulmonary bypass compared with 1/5 CON, 1/5 CAR2 and 0/5 GTN animals (p = 0.001). Hearts from the CAR1 and COMB groups demonstrated similar cardiac function and troponin release after transplantation. Supplementation of Celsior with cariporide plus GTN provided superior donor heart preservation to supplementation with either agent alone and equivalent preservation to that observed with systemic administration of cariporide to the donor and recipient.     

Prednisolone reduces nitric oxide-induced migraine

Background and purpose Glyceryl trinitrate (GTN) induces delayed migraine attacks in migraine patients. The purpose of this study was to investigate whether pre‐treatment with prednisolon could decrease this effect of GTN. Methods In this double‐blind, randomized and placebo‐controlled, crossover study 15 migraineurs with migraine without aura were pre‐treated with 150 mg of prednisolone or placebo followed by a 20‐min infusion of GTN (0.5 ug/kg/min). One hour after the GTN‐infusion, the participants were sent home, but continued to rate headache and possible associated symptoms by filling out a headache diary every hour for 12 h. There were two equal primary efficacy end‐points: frequency of delayed migraine and intensity of delayed headache. Results Nine patients experienced a GTN headache fulfilling the diagnostic criteria for migraine without aura on the placebo day compared with four patients on the prednisolone day (P = 0.14). Prednisolone pre‐treatment did not alter the summed or peak immediate headache responses to GTN significantly (P = 0.08, P = 0.07), whereas the peak headache scores during the following 12 h were significantly lower after prednisolone pre‐treatment (median peak score = 1, range 0–8) compared with placebo (median = 4, range 0–8) (P < 0.01). There was no difference between the two treatment days in the effect of GTN on blood flow velocity of the middle cerebral artery (a decrease) or on the dilation of the superficial temporal artery or the radial artery. Conclusion Pre‐treatment with prednisolone did not reduce the immediate GTN‐induced headache, did not inhibit the frequency of delayed headache but significantly decreased the intensity of delayed GTN‐induced headache. These findings suggest that GTN causes induction of inflammatory mediators, and that this is the mechanism of delayed GTN‐induced migraine. They also support a role of inflammatory mediators in spontaneous migraine attacks.     

Towards safer treatments for benign anorectal disease: the pharmacological manipulation of the internal anal sphincter

INTRODUCTION

The internal anal sphincter (IAS) is an important structure that is responsible for the majority of resting tone of the sphincter complex. It has a central role in continence and damage to the muscle has serious implications. Injury is most frequently from obstetric trauma though iatrogenic injury from proctological surgery is also common. This review expands on how developments in understanding of the pharmacology of IAS might identify drug treatments as alternatives for proctological conditions such as anal fissure, avoiding the risk of sphincter injury. It also examines the role of pharmacology in treatment of those patients with established incontinence.

RESULTS

Much of the basic physiology and pharmacology of the IAS has been established through in vitro analysis, particularly in the superfusion organ bath. Further analysis has been undertaken using animal models such the pig. Clinical trials have established the efficacy of a number of agents for reducing IAS tone including glyceryl trinitrate and botulinum toxin. These drugs are probably safer, but less effective, than surgery for sphincter spasm, as is seen in anal fissure, though surgery alone or in combination with drug treatment may be appropriate for some patients. In vitro analysis and small-scale clinical trials suggest that phenylephrine and methoxamine may have a role in treating patients with incontinence primarily attributable to inadequate IAS function.

CONCLUSIONS

The pharmacology of IAS has been extensively studied in the laboratory, both in vitro and in animal models. In a short time, this laboratory work has been applied to clinical problems after testing in clinical trials. It is likely, however, that the best drugs and the optimal targets for manipulation have not yet been identified.     

直立倾斜试验对不明原因头晕与晕厥患者诊断比较

目的探讨直立倾斜试验(HUTT)对不明原因头晕与晕厥患者诊断上的差异。方法对头晕组(n=35)进行HUTT检查,并选择同期晕厥组(n=303)的HUTT结果为对照,HUTT采用基础直立倾斜试验(BHUT)及舌下含服硝酸甘油倾斜试验(SNHUT)。结果①头晕组与晕厥组患者在BHUT、SNHUT时收缩压、舒张压、心率比较差异无显著性意义(P>0.05),阳性结果反应类型比较差异亦无显著性意义(P>0.05)。②阳性率:HUTT时头晕组31.43%(11/35),晕厥组42.90%(130/303)。其中BHUT时头晕组28.57%(8/28),晕厥组33.82%(70/207);SNHUT时头晕组42.86%(3/7),晕厥组62.50%(60/96)。阳性率在头晕组和晕厥组比较差异无显著性意义(P>0.05)。两组SNHUT阳性率较BHUT均明显提高(P<0.05)。③出现阳性结果时间:BHUT时头晕组(29.13±11.01 min)仅比晕厥组(23.52±12.80 min)稍长,SNHUT时在舌下含服硝酸甘油后也是头晕组(6.00±3.61 min)比晕厥组(4.98±3.51 min)稍长(P均>0.05)。结论临床上部分不明原因头晕患者由VVS所致,但并不出现晕厥发作,这类患者应重视倾斜试验检查。     

Combined examination of glyceryl trinitrate‐mediated vascular dilation with flow‐mediated vascular dilation is essential for assessment of vascular function in type 2 diabetes

Aims/Introduction

In order to characterize the impaired vascular function in type 2 diabetes (DM) patients, we evaluated the flow‐mediated vascular dilation (FMD) with glyceryl trinitrate‐mediated vascular dilation (NMD) using ultrasonography.

Materials and Methods

A total of 111 DM patients and 42 healthy control participants were studied. The maximal dilatation of FMD and NMD (%FMD and %NMD, respectively), the beginning time (T) of dilatation after stimulation and the velocity (V) of the vascular dilatation were also measured.

Results

Among DM patients, 49% had impaired %NMD, which affects the results of %FMD. In DM patients with normal %NMD, the %FMD was also significantly lower than that in control participants, although the T and the V were not impaired. In contrast, both the T and the V were disturbed in the DM patients with low %NMD. Multiple linear regression analysis showed that %NMD was independently correlated with albuminuria. Our results indicate that the impaired FMD in DM is be affected by low NMD, and impaired endothelial function already exists even in DM patients whose vascular smooth muscle function is still retained, and also albuminuria is the clinical feature of DM with low %NMD.

Conclusions

Examination of NMD, not only FMD, should be carried out as it offers the possibility of clarifying vascular function in DM patients.     

Effect of Systemic Vasodilators on Internal Mammary Flow During Coronary Bypass Grafting

Background. The effect of vasodilators on acute flow in the internal mammary (IMA) is unclear. Topical vasodilators show no effect on acute flow when the distal segment of the IMA is resected. The purpose of this study was to evaluate the effect of systemic vasodilators when this segment is resected.

Methods. We studied 60 patients with proximal anterior descending coronary artery lesions in whom the left IMA was harvested for grafting to the left anterior descending coronary artery. The patients were divided into six groups (n = 10), based on which of the following agents were studied: normal saline solution, nitroglycerin, nitroprusside, dobutamine, dopexamine, and amrinone. After harvesting, the IMA was trimmed as proximally as possible (and at least 3 cm proximal to the bifurcation), and free flow was measured before any pharmacologic intervention (flow 1). Systemic infusion of one of the six agents commenced. A mean of 17 ± 3.4 minutes after infusion began, with a comparable cardiac index, a second measurement of IMA flow was taken (flow 2). Hemodynamic measurements for each flow, including blood pressure, heart rate, and cardiac output, were taken.

Results. A significant increase in IMA flow was noted for those patients receiving nitroglycerin (93.5 versus 106.8 mL/min; p = 0.025), and a significant decrease in flow was noted for those receiving nitroprusside (91.0 versus 78.2 mL/min; p = 0.042). The effects remained significant when corrected for cardiac index and compared with the normal saline solution group. No other systemic agents tested significantly affected the IMA flow (dobutamine, 83.8 versus 85.0 mL/min; dopexamine, 101.8 versus 91.4 mL/min; amrinone, 75.4 versus 79 mL/min; normal saline solution, 85.8 versus 84.6 mL/min).

Conclusions. Resection of the distal segment of the IMA and the use of intravenous nitroglycerin optimizes the flow in IMA grafts.     

Renal sodium handling in experimental diabetes: role of NO

Recent studies have suggested that diabetes is a state of increasedrenal nitric oxide (NO) activity as assessed by urinary excretionof nitrites and nitrates (NO_x), and that NO synthase inhibitorsreverse the increased glomerular filtration rate (GFR) observedin experimental diabetes. In addition to being a potent vasodilatorin the renal vasculature, NO also plays a role in modulationof renal sodium excretion. To explore the role of NO in diabetes-associatedalterations in renal excretory function, renal haemodynamicand sodium handling parameters were evaluated in conscious control(C) and streptozotocin diabetic rats (D) and correlated to therenal activity of NO, as assessed by urinary excretion of itsmetabolites NO_x. To further explore this issue, the changesin renal haemodynamics and sodium handling were also assessedafter NO synthase inhibition with a non-pressor dose of L-nitro-arginine-methyl-ester(L-NAME) and after administration of the NO donor, glyceryltrinitrate (GTN). Systolic blood pressure was not differentbetween C and D rats. D rats exhibited marked hyperglycaemia(P<0.001), and increases in GFR (P<0.001), renal plasmaflow, filtration fraction, urinary sodium excretion (U_NaV, P<0.001),filtered load of sodium (FL_Na, P<0.01), and a decrease infractional reabsorption of sodium (FR_Na, P<0.0001). In contrast,total reabsorption of sodium (TR_Na) was increased in D ratscompared to C rats (P<0.0001). The urinary excretion of NOwas markedly increased in D rats (P<0.01). Regression analysesperformed in D rats revealed a close relationship between U_NaVand GFR and a weaker correlation with urinary NO_x. AlthoughFR_Na correlated only with urinary excretion of NO_x, there wasa strong relationship between TR_Na and GFR. In contrast to Drats, control rats demonstrated only a relationship betweenTR_Na and GFR and no other correlations were found, in D rats,NO inhibition with L-NAME (1 mg/kg body weight) resulted ina marked decrease in GFR and urinary NO_x associated with decreasesin FL_Na and TR_Na but did not influence FR_Na. In contrast, inC rats the post-L-NAME decrease in NO_x was not associated withsignificant changes in GFR and renal sodium handling. GTN-treatedC rats exhibited a renal vasodilatory response and an increasein natriuresis and urinary NO_x whereas no renal changes wereobserved in D rats during GTN administration. The present dataindicate that changes in renal sodium handling before and afterNO modulation in experimental diabetes are related to changesin GFR rather than to the renal activity of NO. Therefore, incontrast to the effects on renal haemodynamics, NO does notplay an important role in the altered renal sodium handlingobserved in experimental diabetes.