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PubMed1987

Vasoconstrictor effects of endogenous digitalis-like factors extracted from urine of hypertensive patients.

The vascular effects of endogenous digitalis-like factors (EDLFs) extracted from the urine of hypertensive patients were investigated in isolated and perfused intermediate auricular and mesenteric arterial preparations of dogs. EDLFs produced a transient vasoconstriction in a dose-related manner in intermediate auricular arteries but only a slight constriction in mesenteric arteries. Ouabain induced a long-lasting vasoconstriction with tachyphylaxis in intermediate auricular arteries, but it did not constrict mesenteric arteries. EDLF-induced vasoconstrictions were reproducible and were not modified by alpha-adrenoceptor blockade. They were slightly suppressed by a potent calcium entry blocker, verapamil, in doses which markedly suppressed KCl-induced vasoconstrictions. Noradrenaline- and KCl-induced vasoconstrictions were not significantly modified by either EDLF or ouabain. From these results, it is concluded that EDLF has clear vasoconstrictor properties which are not due to adrenergic or calcium entry mechanisms and that there are differences in the vasoconstrictor effects of EDLFs with respect to different vascular beds. This is similar to what was found with ouabain.

Animals↗
PubMed1999

Effects of nifedipine on anorectal smooth muscle in vitro.

INTRODUCTION: Glyceryl trinitrate reduces anal resting pressure and aids the healing of anal fissures. However, some patients develop tachyphylaxis and the fissure fails to heal, suggesting that other agents are needed. This study assesses the effects of nifedipine (a calcium channel antagonist) in modulating resting tone and agonist-induced contractions in human internal anal sphincter (IAS) and rectal circular muscle. METHODS: Smooth muscle strips from the IAS and rectal circular muscle from ten patients undergoing surgical resection were mounted for isometric tension recording in a superfusion organ bath. The effects of noradrenaline and carbachol were assessed in the presence of various perfusates. RESULTS: LAS strips developed tone and spontaneous activity. Noradrenaline produced dose-dependent contractions. In calcium-free Krebs solution, tone and activity were abolished and no contractions were elicited in response to noradrenaline. Nifedipine also abolished tone and spontaneous activity, but contractions to noradrenaline were only slightly attenuated. In contrast, rectal smooth muscle strips developed spontaneous activity but no resting tone and contracted in response to carbachol. In calcium-free Krebs solution, the spontaneous activity and carbachol contractions were abolished. Addition of nifedipine to the perfusate abolished spontaneous activity and greatly reduced contractions. DISCUSSION: These data suggest that spontaneous activity and resting tone are dependent on extracellular calcium and flux across the cells. Agonist-induced contraction in the IAS is attributable mainly to the release of calcium from intracellular stores, whereas rectal circular smooth muscle depends principally on extracellular calcium entering the cell for contraction. The attenuation of contractions in both tissues and the abolition of resting tone in the IAS suggest that nifedipine may be useful in the management of patients with anorectal disorders.

Adult↗
PubMed1991

Acute tolerance to the locomotor stimulant effects of nicotine in the rat.

Studies of peripheral nicotinic receptors have revealed that, after an initial agonist action, the receptors remain inhibited either through continued depolarization blockade due to continued presence of the agonist or through a brief inactivation of the receptor following its activation. If a similar phenomenon occurs at central nervous system nicotinic receptors, then behavioral responses to nicotine should exhibit an acute tolerance (tachyphylaxis). Groups of rats were given either saline or 0.2 mg/kg nicotine injections at 20-min intervals in photocell activity cages. A progressive decline in the locomotor responsiveness to nicotine was observed. The time course of this acute tolerance was observed in other rats given initial 0.2 mg/kg nicotine injections followed at differing time intervals by second 0.2 mg/kg nicotine test injections. The secondary antagonism to nicotine's locomotor stimulant effects was maximal at 45-60 min and recovered by 90-120 min. The locomotor response to 0.2 mg/kg nicotine test injections was observed in other rats following exposure to 1.8 mg/kg nicotine, and the behavioral response was attenuated for more than 5 h.

Animals↗
PubMed1978

Metoprolol eye drops in the treatment of glaucoma. A double-blind single-dose trial of a beta1-adrenergic blocking drug.

A double-blind single-dose trial was performed on 13 patients with primary open-angle glaucoma. Metoprolol 1%, 2%, and 4% produced a median fall in IOP of 5.6, 5.4, and 6.8 mm Hg, respectively, in the treated eye. The differences in effect between the 1%, 2%, and 4% solutions were not statistically significant. There was no significant fall in IOP in the untreated eyes. There were no significant changes in blood pressure, pulse rate, or pupillary diameter. We could not detect any local objective or subjective side effects during the single-dose study. The clinical usefulness of metoprolol may be limited due to local toxic reactions after treatment with multiple doses. Furthermore, there is the problem of tachyphylaxis that could limit extended treatment with topical beta-adrenergic blocking drugs.

Adult↗
PubMed1990

Bronchial asthma and the role of beta 2-agonists.

Asthma is defined as reversible airflow obstruction; the mechanism for this airflow obstruction is considered to be caused by a combination of an inflammatory process leading to a thickened edematous airway lining and bronchial smooth muscle constriction. The identification of specific beta-receptors in the autonomic system led to the development in the early 1960s of selective beta 2-agonists with their precise effects on the bronchial smooth muscle without direct action on cardiac muscle. The early beta 2-agonists such as salbutamol have a comparatively short bronchodilator action but a rapid onset of action, making them useful as "rescue" bronchodilators. Regular beta 2-agonists alone may mask the underlying pathogenesis of asthma and may be associated with tachyphylaxis or rebound bronchial hyperreactivity. The observation that a thickened airway lining may lead to disproportionate increases in airways resistance with small changes in bronchial muscle shortening suggests beta 2-agonists should be given in conjunction with anti-inflammatory therapy. With their long duration of action but slow onset the new beta 2-agonists may have a role in prophylaxis of asthma rather than rescue bronchodilation.

Adrenergic beta-Agonists↗
PubMed1990

The current place of beta 2-agonists in the management of asthma.

Inhaled beta 2-stimulants are the most effective drugs for acute asthma attacks. This is probably due to the functional antagonism against a large variety of possible asthma mediators. A slight rebound increase of bronchial hyperreactivity 12 to 23 h after stopping regular treatment has been proposed. This finding is not well documented and must be further studied. There is no convincing evidence that tachyphylaxis of clinical importance to the bronchodilating effect occurs in asthmatics receiving normal doses of beta 2-receptor stimulants but cannot be totally excluded. Candidates for regular inhaled beta 2-agonist treatment always have inflammation in their airways and should be given inhaled steroids. Steroids not only seem to reduce airway inflammation and hyperreactivity but they also reverse beta 2-receptor subsensitivity in experimental studies. Patients on purely prophylactic antiasthmatic drugs should be instructed always to carry their beta 2-stimulants inhalers.

Administration, Inhalation↗
PubMed1990

Acute and long-term effectiveness of tulobuterol inhaler, a new beta 2-agonist, in the treatment of asthma.

Two separate studies were conducted to evaluate the efficacy and safety of tulobuterol and the development of tachyphylaxis, if any, after prolonged use. The first, a double blind, crossover study, compared the efficacy and safety of tulobuterol aerosol 400 micrograms tid and salbutamol aerosol 200 micrograms tid in 38 patients with reversible obstructive airways disease. Each study period lasted 4 weeks, separated by a one week washout period. Evaluation of efficacy was performed on day 1 by monitoring spirometric values up to 6 hours postdosing. Additionally, changes in baseline pulmonary function were evaluated by measuring FEV1, FVC and PEFR at each weekly visit. Twenty-nine patients were evaluable. Tulobuterol was shown to be as effective as salbutamol in onset, peak, and duration of response. Mean increases in FEV1 after tulobuterol ranged from 22% at 5 minutes postdose to 30% at 1 hour postdose; a clinically significant mean increase of 24% was recorded after 3 hours. In comparison, mean increases for salbutamol were 24% at 5 minutes postdose and 31% at 1 hour postdose; after 3 hours the mean increase was 21%. Statistically significantly greater increases in mean baseline FEV1 were recorded in favor of tulobuterol. Following 2 weeks of each treatment, tulobuterol showed a mean increase of 14%, compared to a mean postsalbutamol increase of 12%. After 4 weeks, differences were again statistically significant, with tulobuterol showing a mean increase in baseline FEV1 of 17% compared to 3% for salbutamol. Tulobuterol treatment was associated with smaller changes in blood pressure and pulse rate than salbutamol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Studies on secretion of catecholamine evoked by caffeine from the isolated perfused rat adrenal gland.

The influence of caffeine on secretion of catecholamines (CA) was examined in the isolated perfused rat adrenal gland. Caffeine (0.3 mM) perfused into an adrenal vein of the gland produced a marked increase in secretion of CA. This secretory effect of CA evoked by perfusion of caffeine for one minute was considerably prolonged, lasting for more than 90 minutes. The tachyphylaxis to releasing effect of CA induced by caffeine was observed by repeated perfusion of this drug. The caffeine-evoked CA secretion was markedly inhibited by pretreatment with ouabain, trifluoperazine, TMB-8 and perfusion with calcium-free Krebs solution containing 5 mM EGTA, but was not affected by perfusion of calcium-free Krebs solution without other addition. CA secretion evoked by caffeine was not reduced significantly by pretreatment with chlorisondamine but after the first collection of perfusate for 3 min was clearly inhibited. Interestingly, the caffeine-evoked CA secretion was considerably potentiated by pretreatment with atropine or pirenzepine, but after the first collection for 3 min it was markedly decreased. These experimental results suggest that caffeine causes a marked increase in secretion of CA from the isolated perfused rat adrenal gland by an extracellular calcium-independent exocytotic mechanism. The secretory effect of caffeine may be mainly due to mobilization of calcium from an intracellular calcium pool in the rat chromaffin cells and partly due to stimulation of both muscarinic and nicotinic receptors.

Adrenal Glands↗
PubMed2002

Influence of cytisine on catecholamine release in isolated perfused rat adrenal glands.

The aim of the present study was to determine the characteristics of cytisine on the secretion of catecholamines (CA) in isolated perfused rat adrenal glands, and to clarify its mechanism of action. The release of CA evoked by the continuous infusion of cytisine (1.5 x 10(-5) M) was time-dependently reduced from 15 min following the initiation of cytisine infusion. Furthermore, upon the repeated injection of cytisine (5 x 10(-5) M), at 30 min intervals into an adrenal vein, the secretion of CA was rapidly decreased following the second injection. Tachyphylaxis to the release of CA was observed by the repeated administration of cytisine. The cytisine-induced secretion of CA was markedly inhibited by pretreatment with chlorisondamine, nicardipine, TMB-8, and the perfusion of Ca2+-free Krebs solution, while it was not affected by pirenzepine or diphenhydramine. Moreover, the secretion of CA evoked by ACh was time-dependently inhibited by the prior perfusion of cytisine (5 x 10(-6) M). Taken together, these experimental data suggest that cytisine causes secretion of catecholamines from the perfused rat adrenal glands in a calcium-dependent fashion through the activation of neuronal nicotinic ACh receptors located in adrenomedullary chromaffin cells. It also seems that the cytisine-evoked release of catecholamine is not relevant to the activation of cholinergic M1-muscarinic or histaminergic receptors.

Adrenal Glands↗
PubMed1978

Nitroprusside, its metabolites and red cell function.

The effects on metabolism and red cell function of blood levels of thiocyanate (SCN-) and cyanide (CN-) were studied in 42 patients undergoing surgery under controlled hypotension (CH) induced by sodium nitroprusside (SNP). The mean dosage of SNP administered was 21.38 mg (SD = 12). The durating of perfusion was 121 minutes (SD = 11). All operations were performed under neuroleptanalgesia without complications. No tachyphylaxis was encountered. Under SNP a slight increase of blood SCN- (from 13.9 mg/l +/- 1.1 to 23 mg/l +/- 2.6) was found. Blood levels of CN- are increased mostly in the red cell, the mean value being 0.300 mg/l +/- 0.10 for whole blood after two hours of perfusion. This value decreased when perfusion was stopped. All blood samples were negative for methaemoglobin and cyanmethaemoglobin. Carbonic anhydrase activity was not modified, CN- toxicity levels for this enzyme being 50 times higher than those found during our study. 2,3-DPG levels did not vary. Blood gases, acid-base balance and Davo2 did not change significantly, although a slight increase in blood lactate was measured. As shown by this study, appreciable amounts of CN- are detected in blood during SNP perfusion while SCN- stays at relatively low levels. Fortunately most of the CN- released from SNP moves into the red cell and does not alter its functions at clinical concentrations. The low plasma concentration of CN- is not sufficient to cause important metabolic disturbances. However, dosages of SNP higher than those administered during this study could increase the blood and tissue CN- to toxic levels. A toxicity study shows that, during a relatively short period of time, SNP dosage should not exceed 1.16 mg/kg or a maximum of 10 microgram/kg/min for a period of two hours.

Adolescent↗
PubMed1982

Effect of enflurane and fentanyl on the clinical characteristics of long-term succinylcholine infusion.

The characteristics of the neuromuscular block produced by prolonged succinylcholine infusion were compared in 40 patients anaesthetized with either nitrous oxide with enflurane (1-2 per cent inspired) or nitrous oxide and fentanyl. Neuromuscular transmission was monitored using train-of-four stimulation and the infusion rate was adjusted to keep the first twitch at 10-15 per cent of its control value. Initially, all patients, exhibited a depolarizing-type block all twitches of the train-of-four being roughly the same size, and the infusion rates were similar in the enflurane (54 microgram X kg-1/min) and the fentanyl (58 microgram X kg-1/min) groups. Tachyphylaxis developed later in both groups and correlated well with the onset of phase II block (dual block). This occurred sooner and at a lower cumulative dose in the enflurane group. Fourth to first twitch ratios decreased to 50, 25 and 0 per cent in 31, 46 and 59 minutes in the enflurane group, at cumulative succinylcholine doses of 2.2, 3.2 and 4.2 mg X kg-1 respectively. Corresponding figures for the fentanyl group were 52, 73 and 86 minutes, with dose of 3.4, 5.0 and 5.9 mg X kg-1. Infusion rates increased markedly after establishment of dual block, but were similar with enflurane (0.99 mg X kg-1/min) and fentanyl (1.12 mg X kg-1/min). Ten minutes after stopping the infusion fourth to first twitch ratios failed to reach 50 per cent in most patients given enflurane who had received more than 6 mg X kg-1 succinylcholine over more than 90 minutes. Corresponding figures for fentanyl patients were 13 mg x kg-1 and 150 minutes. The block in all 15 patients (9 enflurane, 6 fentanyl) who did not recover spontaneously was successfully antagonized with atropine and neostigmine.

Adult↗
PubMed2006

Anesthetic management of a labouring parturient with urticaria pigmentosa.

PURPOSE: To report the anesthetic management of labour pain and Cesarean section in a patient with urticaria pigmentosa at risk for systemic mastocytosis. CLINICAL: A 37-yr-old patient with a history of urticaria pigmentosa and an allergic reaction to a local anesthetic agent was seen in consultation at 36 weeks gestation. She previously tested negative for an allergy test to lidocaine. Recommendations to avoid systemic mastocytosis included: avoidance of histamine-releasing drugs, using lidocaine for labour epidural, and regional anesthesia in case of a Cesarean section. The patient presented at term in labour. Intravenous fentanyl was used for early labour, followed by a combined spinal-epidural. The spinal contained lidocaine and fentanyl, but because of pruritus, the epidural infusion contained lidocaine only. Most likely because of tachyphylaxis to lidocaine, an epidural bolus of lidocaine with epinephrine failed to provide adequate anesthesia for a Cesarean section. The block was supplemented with nitrous oxide by mask, with fentanyl postdelivery. Postoperative pain control was managed with an epidural infusion of lidocaine and fentanyl for three days. The patient was discharged without complications four days postsurgery. CONCLUSION: Proper allergy testing prior to pregnancy is important to help the management of labour pain and anesthesia for Cesarean section in a patient at risk for systemic mastocytosis.

Adult↗
PubMed2002

Beta2-agonist eutomers: a rational option for the treatment of asthma?

Beta2-adrenoceptor agonists (beta2-agonists) such as albuterol (salbutamol) and terbutaline and their long-acting analogs salmeterol and formoterol are widely used as bronchodilators in the treatment of asthma. They are chiral drugs historically marketed as racemic mixtures of an active (eutomer) and essentially inactive (distomer) stereoisomer. Despite their obvious therapeutic value and widespread use, beta2-agonists have been implicated, somewhat controversially, in causing an increase in asthma mortality and a deterioration of asthma control by a mechanism that remains elusive. Inherent toxicity of the distomers has been widely touted as an explanation and has given rise to pressure for the replacement of the racemates with pure eutomer formulations (the so-called chiral or racemic switch). This has culminated in the recent introduction into clinical practice of the single active stereoisomer of albuterol (levalbuterol) and the promise of other pure beta2-agonist eutomer formulations to follow. This article examines the evidence on which these chiral switches are based. Clinical studies designed to reveal negative effects of beta2-agonists have searched for reductions in lung function, increases in airway responsiveness to bronchoconstrictor mediators and worsening of asthma control. Crossover studies administering the pure stereoisomers and racemate of albuterol have not shown a clear superiority of the pure eutomer formulation over the racemate in terms of either bronchial hyperresponsiveness, tachyphylaxis to bronchoprotective effects or improvements in lung function. Clinical toxicity of beta2-agonist distomers on any aspect of asthmatic lung function has also not been demonstrated in the relatively short-term inhalational studies (single dose or repeated dose studies <1 week) that have been carried out. In animal studies, the administration of beta2-agonist racemates and distomers has been shown to enhance bronchial hyperresponsiveness but only in ovalbumin-sensitized animals where the relevance to humans is questionable. The pharmacokinetics and metabolism of beta(2)-agonist stereoisomers appear to be essentially similar whether administered as single stereoisomers or as racemates. Levalbuterol may be slightly more potent than an equivalent dose given as racemate, but there is some evidence that it forms a small amount of the distomer in vivo which detracts somewhat from its purported benefits over use of the racemate. Whilst there remains a clear need for studies of longer duration with sensitive clinical endpoints to evaluate the benefits of beta2-agonist eutomers and to investigate distomer toxicity, the chiral switch for beta2-agonists in general, and for albuterol in particular, does not appear to be justified on the basis of the evidence available to date.

Adrenergic beta-2 Receptor Agonists↗
PubMed2003

Distinct features of recombinant rat vanilloid receptor-1 expressed in various expression systems.

In this study, we expressed rat vanilloid receptor 1 (VR1) in various heterologous expression systems using different VR1-encoding vectors, and examined how the VR1 agonists capsaicin and resiniferatoxin affected intracellular calcium. Our results clearly show that the magnitude and kinetics of response as well as the extent of tachyphylaxis differ markedly between systems. Using green fluorescent protein-tagged VR1, we show that much of the VR1 is localized to intracellular membranes. Consistent with this localization, VR1 agonists are able to liberate calcium from intracellular stores in the absence of extracellular calcium. As with other parameters of response, the three expression systems differ in the degree to which, in the absence of extracellular calcium, capsaicin and resiniferatoxin can liberate calcium from the intracellular stores. Our findings emphasize the influence of the expression system on characteristics of the response of VR1 to its ligands and the need for caution in extrapolating such results to other settings.

Animals↗
PubMed1995

[Controlled hypotension].

Induced hypotension is defined as a reduction in mean arterial blood pressure to 50-60 mm Hg in normotensive subjects. The aim of induced hypotension is to decrease intraoperative blood loss, decrease the need for blood transfusions and improve operating conditions. Most studies indicate that induced hypotension can decrease intraoperative blood loss by 50% in many surgical procedures; however, some studies report that blood loss is not significantly reduced. Current methods of induced hypotension are based on the use of rapid and short-acting vasodilators as primary agents (nitroprusside, nitroglycerine, urapidil), supplemented by volatile anesthetics (isoflurane) and/or beta-blockers (esmolol) to improve effect, reduce dosage and prevent side effects (reflex tachycardia, tachyphylaxis, rebound hypertension). Proper positioning of the patient and controlled ventilation aid in reducing blood loss. Major risks of induced hypotension are a reduction in blood flow (i.e. ischaemia) of vital organs (brain, myocardium) and elevation of intracranial pressure in neurosurgical patients. Thus, major contraindications of induced hypotension are severe coronary artery disease, hypertension combined with arteriosclerosis of cerebral vessels and increased intracranial pressure in patients with cerebral disease. Complications are rare in otherwise healthy patients, but may be higher in elderly patients and those with underlying organ dysfunction. Therefore, careful assessment and selection of patients, together with consideration of the potential complications, appropriate choice of drugs and invasive beat-by-beat monitoring, are essential for the safe practice of induced hypotension.

Anesthesia↗
PubMed1997

[Chronopharmacology. Time of day variations in the action of bupivacaine are not manifested in nerves].

UNLABELLED: To test the hypothesis that the efficacy of local anaesthetics to block nerve conduction is related the time of day (TOD) of drug application, we retrospectively analysed data from previous experiments on tachyphylaxis. During the course of these experiments, as a measure of drug efficacy we determined the minimal blocking concentration (c(m)) of bupivacaine in rabbit aortic nerves at several TODs. The special in situ preparation used permitted study of local anaesthetic pharmacodynamics without the influence of pharmacokinetics, making it possible to investigate the chronopharmacodynamics of these drugs by relating c(m)s to the respective TODs of their measurement. METHODS: In 43 New Zealand rabbits anaesthetised with urethane, the aortic nerve was dissected and partly placed in a double-lumen perfusion chamber (Fig. 1A), which was continuously perfused with tyrode solution or bupivacaine. Spike activity was continuously recorded by bipolar platinum-iridium electrodes caudad to the chamber for control and cephalad for registration of blocking effects. As a measure of drug efficacy, by increasing the bupivacaine concentration stepwise we determined the smallest concentration that blocks spike activity i.e., c(m). After each determination bupivacaine was rinsed off to confirm intact nerve function (Fig. 18). RESULTS: Forty-nine determinations of bupivacaine c(m) were performed between 12:25 p.m. and 2:35 a.m. Data were pooled into groups of 2 h (Fig. 2). There was no significant difference between groups (ANOVA). In particular, c(m) at 3:00 p.m. was not lower than at 11:00 p.m., times at which local anaesthetics have been found to be most and least effective, respectively. CONCLUSIONS: The c(m) of bupivacaine, and thus its efficacy to block nerve conduction, does not depend on TOD of drug application. Therefore, it is suggested that chronopharmacodynamics does not play an important role in the well-known circadian rhythm of the action of bupivacaine and probably of local anaesthetics in general.

Anesthetics, Local↗
PubMed2007

[Steroid-aggravated rosacea: successful therapy with pimecrolimus].

Steroid-induced erythema in rosacea is a therapeutic challenge because of its tendency to rebound and the local characteristics of the facial skin. We describe 3 cases of steroid-induced rosacea with the typical history of steroid abuse with tachyphylaxis. Steroids with increasing potency had to be used with increasing frequency in the course of treatment in order to achieve a response. Acute exacerbations followed any attempt at withdrawal. The steroid treatment was discontinued and therapy with pimecrolimus cream 1% twice daily initiated. This brought rapid and marked improvement within a few days. The cases show that the calcineurin antagonist pimecrolimus offers an effective and well-tolerated therapy option in the acute therapy of steroid-aggravated facial dermatoses.

Aged↗
PubMed1996

Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM.

Intravenous glucagon-like peptide (GLP)-1 [7-36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 +/- 7, 61 +/- 9, 50 +/- 11 years; BMI 29.5 +/- 2.5, 26.1 +/- 2.3, 28.0 +/- 4.2 kg/m2; HbA1c 11.3 +/- 1.5, 9.9 +/- 1.0, 10.6 +/- 0.7%) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7-36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8%, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30-60 min, then return to basal levels after 90-120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p < 0.0001, respectively) and inhibited glucagon secretion (p < 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 +/- 0.4 mmol/l after 240 min vs 8.2 +/- 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30-45 min (p < 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40% (p = 0.051). In conclusion, subcutaneous GLP-1 [7-36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7-36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia.

Adult↗