Effect of melatonin on glucose tolerance and blood glucose circadian rhythm in rabbits

Experimental studies on pinealectomized animals and in vitro studies using pancreatic tissue, have indicated that the pineal gland has a suppressive effect on the pancreatic B cells which secrete insulin. In this study, melatonin, was injected into rabbits and a statistically significant decrease in glucose tolerance was noted. The effect of melatonin in influencing the circadian rhythm of blood glucose was also studied in rabbits. Results showed that melatonin influences the circadian rhythm leading to a shift in the occurrence of minimum levels from 16.00 hr to 04.00 hr (next day) during fasting and from 16.00 hr to 20.00 hr during feeding. Also melatonin treatment lead to a statistically significant rise in blood glucose levels. It is probable that melatonin administration reduces glucose tolerance and influences the blood glucose circadian rhythm mainly through its effects on insulin release by pancreatic B cells.     

Effect of Tinospora cordifolia on blood glucose and total lipid levels of normal and alloxan-diabetic rabbits.

The aqueous, alcoholic, and chloroform extracts of the leaves of Tinospora cordifolia were administered in doses of 50, 100, 150 and 200 mg/kg body weight to normal and alloxan-diabetic rabbits. The blood glucose and total lipid levels were estimated before and 2, 4, 6, and 8 hours after administration of the extract. The extract exerted a significant (P less than 0.5) hypoglycaemic effect in normal as well as in alloxan-treated rabbits. The extracts, however, had no significant (P greater than 0.05) effect on total lipid levels in normal as well as in alloxan-treated diabetic rabbits. The doses used did not show acute toxicity or result in behavioural changes. From this study, it may be concluded that extracts of the leaves of Tinospora cordifolia have an insulin-like action and can significantly reduce the blood glucose but not the total lipid levels in normal rabbits and in alloxan-induced diabetic rabbits.     

一种新型胰岛素直肠栓剂对健康兔和糖尿病兔血糖的影响

我们曾发现甲硝唑（MN）和葡聚糖凝胶G10（DGG－10）对水杨酸钠（SS）促进胰岛素（IN）在兔直肠中吸收具有协同作用．本试验首次利用AUC等各项指标研究了由此制成的胰岛素直肠栓剂（INS）在一定剂量范围内对健康兔和糖尿病兔的降血糖的情况。结果证实该INS在0．5～1．5IU/kg剂量范围内剂量与效应间都成很好的线性关系。通过以上直线回归方程计算得出本试验INS的降血糖效率无论是健康兔还是糖尿病免都接近40％。相同剂量的本试验中INS对于糖尿病兔比正常兔造成的Cmax稍小,糖尿病兔tmax于1．5IU/kg剂量下比正常兔提前。     

Effect of caesalpina bonducella seeds on blood glucose in rabbits

The seeds of Caesalpinia bonducella (L.) Flem. (Caesalpiniaceae) are sold in shops in Dar es Salaam, Tanzania, for the treatment of diabetes mellitus. A suspension of the powdered seed kernel in 0.5% carboxymethylcellulose (CMC) was tested for ability to lower blood glucose in fasted and glucose-fed normal albino rabbits. Following administration of 0.2, 0.4 and 0.8 g/kg body weight of the powder there was no difference in areas under the fasting blood glucose and oral glucose tolerance test (OGTT) curves as compared to controls given CMC (P > 0.05). Similarly, 0.2 g/kg body weight of the powder administered for 7 consecutive days had no effect on either fasting blood glucose or the clearance of a glucose load from the blood. However, 0.1 g/kg body weight chlorpropamide significantly decreased the area under the fasting blood glucose and OGTT curves as compared to controls given CMC (P = 0.05). Thus, contrary to a previous report, we could not detect any hypoglycaemic activity in the seeds of Caesalpinia bonducella growing in Dar es Salaam.     

Calcium antagonists: effects on cerebral blood flow and blood-brain barrier permeability in the rat

1 Because they affect isolated cerebral arteries, some calcium antagonists have been studied on the intact cerebral circulation of the rat.

2 Global cerebral blood flow (¹³³Xe clearance technique) was measured in anaesthetized rats. Neither perhexiline (0.1 μg/kg to 1.0 mg/kg, i.v.) nor diltiazem (0.06-0.6 mg/kg, i.v.) had any significant effect on resting cerebral blood flow when measured 5 min after each dose. A high dose of nifedipine (1.0 mg/kg, i.v.) was administered during induced hypocapnia. Nifedipine failed to modify the hypocapnic vasoconstriction of the cerebral vasculature when compared to vehicle-treated rats.

3 The possibility of discrete changes in regional cerebral blood flow was investigated. Local cerebral blood flow was measured in a number of brain regions by the [¹⁴C]-ethanol technique 15 min after the administration of nifedipine (20 or 100 μg/kg, i.v.). Nifedipine had no apparent effect on regional blood flow in the rat brain.

4 Acute arterial hypertension increases protein leakage into the brain, a phenomenon susceptible to drugs that act on endothelial pinocytosis which is known to be calcium-dependent. The increase in protein extravasation, induced by the intravenous administration of either angiotensin II or adrenaline, was unchanged in rats previously treated with either nimodipine (20 μg/kg, i.v.) or nifedipine (50 μg/kg, i.v.) when dissolved in ethanol alone. However, nifedipine (20 μg/kg, i.v.) when dissolved in a solution of polyethylene glycol and ethanol further enhanced the hypertension-induced increase in brain albumin permeability.

5 In conclusion, we have been unable to demonstrate any apparent effects of various calcium antagonists on the intact cerebral circulation of the rat, despite the number of different experimental models used.

     

Calcium antagonists as antiatherosclerotic drugs

The effects of calcium antagonists on mobilization of calcium stores critical for induction and development of atherosclerosis are only beginning to be delineated. The idea that these types of agents (by selectively altering either platelet function or smooth muscle proliferation and accumulation of lipids and calcium) can arrest or even reverse the course of atherosclerosis presents an attractive approach. Available experimental information on the actions of calcium antagonists in atherosclerosis is suggestive rather than definitive in this regard. A number of calcium-sensitive steps in platelet aggregation and secretion as well as in smooth muscle accumulation and deposition of calcium are identified. Related experimental findings in models of arteriosclerosis and hypertension also support the concept that blockade of calcium accumulation in vascular smooth muscle can retard or prevent subsequent interactions leading to enhanced disease states. Thus technical approaches to delineation of the actions of calcium antagonists are available, and, though the therapeutic value of these types of agents is not established, their potential as novel antiatherosclerotic agents is attractive.     

Calcium antagonists. Pharmacokinetic properties

An understanding of the pharmacokinetics of the calcium antagonists (slow-channel blocking drugs) is essential in order to design appropriate dosage regimens which will provide optimum therapeutic efficacy with these agents. This review summarises and evaluates the current state of knowledge of the absorption and disposition characteristics of the 3 most extensively used calcium antagonists in cardiovascular therapeutics: verapamil, diltiazem and nifedipine. While an extensive literature regarding the kinetics of verapamil exists, reports dealing with diltiazem and nifedipine are limited. This is, in part, due to difficulties in developing simple, specific and sensitive analytical procedures. All 3 drugs undergo extensive metabolism in the liver. Metabolites of verapamil (norverapamil) and diltiazem (desacetyldiltiazem) accumulate in the plasma of patients and have been shown to produce some effects similar to those of their parent compounds. The bioavailability of diltiazem and nifedipine has not been well studied, and no investigations of the absolute bioavailability of these compounds have been reported. However, the bioavailability of verapamil has been studied extensively; about 22% of an orally administered dose of verapamil is systemically available. Bioavailability is increased when liver function is impaired, such as in patients with hepatic cirrhosis. The high first-pass extraction of verapamil has been suggested to be stereoselective, with preferential elimination of the (-) isomer. The plasma concentration-time curves of verapamil and diltiazem have been studied following oral administration. The elimination half-lives of verapamil and diltiazem are about 8 and 5 hours, respectively. All 3 drugs are highly protein-bound in the plasma. Several other drugs have the ability to displace verapamil from plasma protein binding sites, but the clinical significance of this interaction is doubtful. Other drug interactions have been investigated with these agents. Verapamil causes digoxin plasma levels to rise during concomitant administration, but no drugs have been shown to alter the disposition of verapamil. Diazepam affects the plasma levels of diltiazem leading to a decrease. The mechanism of this interaction has not been reported, but an effect on bioavailability has been suggested. Age has been shown to be a factor in the disposition of both diltiazem and verapamil. Older patients tend to have lower clearances of these 2 drugs than do younger patients. It has also been shown that hepatic cirrhosis leads to a decreased clearance of verapamil. Plasma level monitoring may be helpful for adjusting doses of both verapamil and diltiazem, despite the absence of a definition of therapeutic plasma concentrations. These agents all have low, and highly variable, systemic availability, and plasma concentrations cannot be predicted after oral administration.     

Calcium antagonists in the post-myocardial infarction setting

At present, the use of calcium antagonists for the secondary prevention of cardiac events following an acute myocardial infarction (MI) is not recommended. This advice is based on several large mortality studies using short-acting calcium antagonists in the absence of coronary reperfusion therapy. Even in these studies, discrepancies between the different pharmacological classes of calcium antagonists were recognised. When separated from the dihydropyridine calcium antagonists, the rate-lowering calcium antagonists, verapamil and diltiazem, do appear to provide some benefit in reduction of recurrent MI. Three large trials using verapamil post-MI demonstrated a significant reduction in reinfarction with a favourable trend towards reducing death as well. Similarly, the effects of diltiazem post-MI have been evaluated in 3 large trials. In 2 earlier trials, diltiazem lessened cardiac events in patients with nonQ-wave infarctions and those without pulmonary congestion upon presentation. Overall, there was a significant benefit in lessening reinfarction with no effect on mortality. The recently completed Incomplete Infarction Trial of European Research Collaborators Evaluating Prognosis Post-Infarction (INTERCEPT) trial found that sustained-release diltiazem given after thrombolytic therapy for acute MI lessened cardiac events by 23% (a nonsignificant difference) without worsening congestive symptoms. Overall, there is adequate data to support the use of heart-rate-lowering calcium antagonists for secondary prevention post-MI provided the patient is intolerant of beta-blocker therapy. These trials are reviewed in detail, and suggestions for clinical practice are provided in this article.     

Effect of Aralia cachemirica Decne root extracts on blood glucose level in normal and glucose loaded rats

An aqueous and alcoholic extract of the roots of Aralia cachemirica (Araliaceae) were evaluated for hypoglycemic activity in normal fasted and glucose induced hyperglycemic rats. The aqueous and alcoholic extracts at a dose of 250 mg/kg showed statistically significant (p < 0.01) hypoglycemic activity in glucose loaded animals however no effect was observed in normal fasted rats.     

Qi盐对正常及糖尿病模型大鼠血糖的影响

目的观察Qi盐对正常小鼠和糖尿病模型大鼠的降血糖作用.方法尾静脉注射四氧嘧啶制作大鼠糖尿病模型,连续灌胃给Qi盐14 d,葡萄糖氧化酶法测血糖.结果Qi盐1.6,0.8,0.4 g·kg-1对正常小鼠血糖及糖耐量均无明显影响,但0.8,0.4 g·kg-1可降低四氧嘧啶模型大鼠血糖,改善糖耐量.结论Qi盐对糖尿病模型大鼠有降血糖作用.     

Reduction of blood glucose level by orexins in fasting normal and streptozotocin-diabetic mice

The influence of chronic arthritic pain on two endogenous opioid peptides, dynorphin B and [Met5]enkephalin-Arg6-Phe7, and multiple opioid receptors in discrete brain, lumbar spinal cord and pituitary pools was investigated. Using radioimmunoassay and receptor binding assay, we examined the changes in regional opioid peptide levels and opioid receptor activity due to chronic inflammation in adjuvant arthritic rats. At 4 weeks post-inoculation, increased levels of immunoreactive dynorphin B and [Met5]enkephalin-Arg6-Phe7 were measured in tissues of arthritic rats compared with controls. No significant changes in mu-, delta- or kappa-opioid receptors were seen after chronic inflammation. Taken together, these results indicate that in chronic arthritis, opioid receptor changes do not follow the peptide alterations of pro-dynorphin and pro-enkephalin systems. Thus, dynamic modification and modulation of nociceptive information takes place during chronic inflammation. This supports the key role of the central nervous system in chronic inflammatory pain conditions.     

Calcium antagonists prevent cyclosporin a-Induced nephrotoxicity

Because of their favorable effects on renal haemodynamics, calcium antagonists (CATs) have a major role in preventing certain types of acute renal failure, including cyclosporin A (CSA) induced renal dysfunction. Verapamil (VP) given into the renal artery after revascularization significantly improved renal parenchymal blood flow velocity on the first post-transplant day and prevented CSA-induced decrease in renal blood flow. Kidney function was also improved and by post-transplant day 7, the majority or 77% of patients receiving VP had serum creatinine levels below 2.0 mg/100 ml versus 34% of controls. Glomerular filtration rates (GFR) increased with VP treatment between days 1 and 7 from 35±25 ml/min to 44±22 ml/min versus 19±19 ml/min to 28±22 ml/min for no VP. VP administration also decreased the need for post-transplant haemodialysis from 25% to 7%. The improved renal function occurred despite two times higher CSA blood levels in VP patients compared with controls. There were also fewer rejections in VP-treated patients (14%) than in controls (56%). Finally, graft survival at one year was 93% with VP treatment compared with 72% in control patients. The improved graft survival was most striking in repeat transplants, with 90% graft survival at one year for VP recipients versus 50% for controls. The combination of intraoperative VP and blood volume expansion acts synergistically resulting in larger urine volumes, improved renal function and decreased incidence of delayed function. The beneficial effects of CATs on post-transplant outcome may be related to cellular protection from ischaemia, preferential vasodilatation of the afferent arteriole, inherent immunosuppressive properties, and elevated CSA blood levels. CATs offer great potential to improve the outcome of solid organ transplantation.