Association of beta-agonists with corresponding beta 2- and beta 1-adrenergic pentapeptide sequences

Synthesized beta 1- and beta 2-pentapeptide sequences corresponding to published adrenoceptor transmembrane activation site subtypes were investigated in vitro for selectivity in association for drug ligands of known selectivity. Both nuclear magnetic resonance spectroscopy and molecular mechanics demonstrated that structural differences among the corresponding pentapeptide activation-site sequences can explain agonist selectivity. Results suggest the agonists bind across the activation site loop on the second transmembrane alpha-helix by dipole/dipole interactions between a ligand and the peptide. Since electrostatic interactions within the membrane may determine the rate of intercellular ion flux, agonist association across the activation site sequence could thereby decrease electrostatic resistance to positive ion flux into the cell. Interactions between the peptides and the ligands may provide insight into the structures and mechanisms involved in association of ligands for the identical sequences on the beta-adrenoreceptors.     

Treatment of diabetes mellitus with long-acting biguanides

The paper discusses of the results of treatment with preparations of phenylethylbiguanide (dibotin, meltrol, dipar, dibophen-retard), of butylbiguanide (silubin-retard, buforming-retard) and of dimethyl-biguanide (glucophage-retard). All these preparations were of prolonged action. The treatment was carried out in 242 patients. The saccharolytic action of the active agent contained in one tablet of each type of biguanide was approximately the same. Biguanides of prolonged action were highly effective in obese patients with diabetes mellitus of moderate severity. The best results were obtained in complex treatment with biguanides of prolonged action together with sulfonylurea preparations of the second generation. There were noted almost no toxic reactions from the use of biguanides up to 2 tablets a day.     

Pergolide, a potent long-acting dopamine-receptor agonist

After single doses (100 to 400 microgram orally), pergolide, a synthetic ergot, reduced basal plasma prolactin levels in normal subjects in a dose-related manner. This effect persisted for more than 24 hr. Multiple doses of pergolide (150 to 250 microgram daily for 7 days) resulted in a plasma prolactin decrease of more than 80%. A single dose of pergolide (150 microgram orally) suppressed plasma prolactin and abolished the plasma prolactin diurnal rhythm, i.e., suppression of sleep-induced elevation in plasma prolactin during a 40-hr period. Perphenazine (5 mg intramuscularly)-induced plasma prolactin elevation was inhibited by pergolide; the effect was dose dependent. After single or multiple doses, pergolide had no effect on plasma follicle-stimulating hormone, luteinizing hormone, cortisol, growth hormone, and thyroid-stimulating hormone. Pergolide appears to have specificity at the pituitary level for the dopamine receptors that mediate prolactin secretion.     

Salmeterol: a novel, long-acting beta 2-agonist

OBJECTIVE: The clinical pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of the long-acting beta 2-agonist salmeterol are reviewed. DATA SOURCES: A MEDLINE search was performed to identify English-language publications pertaining to salmeterol. STUDY SELECTION: Open and controlled trials were reviewed in assessing clinical efficacy. Only the results of controlled, randomized trials were considered in the effectiveness evaluation. DATA EXTRACTION: The primary measures of effectiveness in the clinical trials were bronchodilator activity and reduction of hyperresponsiveness that may reflect antiinflammatory activity. Bronchodilator activity was measured as changes in pulmonary function; reduction of hyperresponsiveness was evaluated using respiratory challenge with methacholine, histamine, allergen, or cold air. Secondary measures included symptom scores, need for rescue doses, and patient preference. DATA SYNTHESIS: Salmeterol is a selective, beta 2-agonist that has been studied in the treatment of exercise-induced, nocturnal, and allergen-induced asthma. Salmeterol interacts with the traditional beta-receptor in a similar manner as other beta-agonists, and it exhibits potent in vitro antiinflammatory effects as an inhibitor of inflammatory mediator release. Less evidence exists for its in vivo antiinflammatory activity. Salmeterol demonstrates prolonged receptor occupancy, which is thought to contribute to its long duration of action. The recommended dose is 50 micrograms via metered-dose inhaler or dry-powdered inhalation. In the published clinical trials, salmeterol was more effective than albuterol in treating asthma, including exercise and allergen-induced asthma. Salmeterol's major advantage over other inhaled beta-agonists is its long duration of action (12 hours), making it an excellent choice for treatment of nocturnal asthma. A potential disadvantage is delayed onset of action. Tachyphylaxis to salmeterol's bronchodilator effects has not been shown, but tolerance to its protective effects against methacholine-induced bronchoconstriction has occurred. Adverse effects reported have been mild and have included headache, tremor, and palpitations. CONCLUSIONS: Salmeterol is an effective beta 2-agonist in the treatment of asthma. However, several issues require further investigation regarding its long-term effects on disease control, significance of antiinflammatory activity, and role as a rescue medication.     

Ba 679 BR, a novel long-acting anticholinergic bronchodilator

The use of anticholinergics in antiobstructive therapy is well established in pulmonary medicine. We sought to improve the duration of action of inhaled antimuscarinics. A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range. Assessment of the dissociation rate of complexes of labelled Ba 679 and human muscarinic receptors revealed very slow dissociation in comparison to ipratropium. The half-lives in hours were: Ba 679-Hm3: 34.7, -Hm1: 14.6, -Hm2: 3.6; ipratropium-Hm3: 0.26, -Hm1: 0.11, -Hm2: 0.035. The duration of action in vivo was determined by means of acetylcholine-induced bronchospasms in dogs following inhalation of the drugs. Ba 679 demonstrated a significantly longer duration of protection than an equipotent dose of ipratropium. The plasma levels following inhalation in dogs declined rapidly and are unlikely to reflect the duration of the pharmacological activity. In summary, Ba 679 represents a novel type of antimuscarinic bronchodilator with a long duration of action, most likely due to its slow dissociation from Hm3-receptors. In addition, the drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors.     

Catamenial insulin reactions treated with a long-acting gonadotropin releasing hormone agonist

Exacerbation of a variety of symptoms during the menstrual cycle is a well-described phenomenon. The exact causes of these changes are poorly understood, and no specific and efficacious therapy has been described. We successfully treated a patient with severe catamenial insulin reactions with a long-acting gonadotropin releasing hormone agonist to suppress menstrual function and added a combination of estrogen and progestin to offset any adverse effect of the resultant hypoestrogenemia for 1 year.     

Pharmacology of Bay g 2821, a long-acting, high-ceiling diuretic

Bay g 2821 is a diuretic, from a new class of chemical substances, with both the efficacy of diuretics with a high-ceiling activity, such as furosemide, bumetanide and ethacrynic acid, and the prolonged duration of action of thiazides. Pharmacological investigations showed that Bay g 2821 was more potent than furosemide in dogs but less potent in rats. Bay g 2821 did not differ from furosemide in excretion of electrolytes. Further studies showed that Bay g 2821 had an antihypertensive effect in dogs, spontaneously hpertensive rats, and in rats with artificially-induced renal hypertension. Other pharmacological studies did not reveal any other significant effects.     

Analysis of beta-agonists in urine and tissues by capillary gas chromatography-mass spectrometry: in vivo study of salbutamol disposition in calves

The fate of salbutamol sulphate given orally has been investigated in calves. The urinary excretion rate and the tissue distribution of this beta-agonistic drug were studied by capillary gas chromatography coupled to low resolution mass spectrometry (GC-LRMS) under electron impact (EI) ionization mode, using an hexadeuterated salbutamol analogue as the internal standard. The parent drug and metabolites were extracted via solid phase extraction (SPE) mixed-phase-containing disposable columns and analysed as their trimethylsilyl derivatives. A more efficient clean-up had to be carried out for tissue samples. An acidic precipitation followed by a liquid-liquid extraction were therefore performed before the SPE. Moreover, the problem of tissue digestion was elucidated by means of an ultrasonic probe. Samples were also analysed before and after enzymic hydrolysis using purified beta-glucuronidase and a mixture of beta-glucuronidase and arylsulphatase, to obtain evidence of phase II conjugation mechanisms. Both free salbutamol and conjugated metabolites were detected in urine and tissue samples. Except for liver or kidney, salbutamol was rapidly cleared from most tissues after a withdrawal period. The possible excretion of some phase I metabolites was also investigated, using further analyses under positive chemical ionization LRMS and high resolution mass spectrometry (HRMS).     

Nalmefene: a long-acting opioid antagonist. Clinical applications in emergency medicine

The use of the opioid antagonist naloxone is well known to the experienced health care provider. The availability of the longer acting opioid antagonist nalmefene has several potential benefits in clinical practice. Nalmefene has a plasma half-life of almost 11 h, compared to 60-90 min for naloxone. Nalmefene has been shown to reverse opioid intoxication for as long as 8 h, reducing the need for continuous monitoring of intoxicated patients and repeated dosing of naloxone. Single dose administration has also been used effectively in the reversal of opiate-assisted conscious sedation. In addition, this agent has been used in the treatment of diseases as diverse as interstitial cystitis and chronic alcohol dependence. However, the long duration of action enables extended withdrawal reactions in the chronically opioid-dependent patient. The prolonged opioid antagonism of nalmefene has several applications in the clinical practice of emergency medicine, and is a useful addition in certain situations to the pharmacologic armamentarium of the practicing emergency physician.     

Prevention of Eimeria alabamensis coccidiosis by a long-acting baquiloprim/sulphadimidine bolus

Twelve calves aged 6-10 months, and 12 calves aged 10-16 months were turned out onto a permanent pasture known to have been contaminated with oocysts of Eimeria alabamensis during the previous year. Two days after turnout, six of the older calves and six of the younger were each treated with one bolus per 200 kg bodyweight containing 1.6 g baquiloprim and 14.4 g sulphadimidine. The other 12 calves were left untreated. The excretion of Eimeria oocysts, the faecal dry matter and the weight gain of treated and untreated calves within each age group were compared during the first 3 weeks on pasture to assess the efficacy of the bolus in preventing E. alabamensis coccidiosis. All the older of the untreated calves and four of the younger developed gruel-like to watery diarrhoea 4-7 days after turnout. The faecal consistency of the treated calves remained firm and they lost significantly less weight than the control calves during the first 13 days on pasture. The treated calves also excreted significantly fewer oocysts during the first 20 days of grazing; their oocyst excretion remained low during days 8-10 when all but one of the diarrhoeic control calves excreted more than 850,000 oocysts per gram faeces (OPG). Starting on days 12 to 14 the oocyst excretion of 8 of the treated calves increased to 20,000-65,000 OPG and of 2 calves to 210,000-240,000 OPG. There was no difference in oocyst output between treated and untreated calves from the fourth week of grazing and no difference in weight gain among the younger calves. In the older calves there was a tendency for the untreated calves to gain more weight than treated calves.     

Pharmacokinetics of L-749,345, a long-acting carbapenem antibiotic, in primates

L-749,345 is a carbapenem antibiotic, currently in phase II clinical trials, which possesses a broad antibacterial spectrum and extended half-life. The time courses of levels of the drugs in plasma and urinary recovery were evaluated for L-749,345, imipenem-cilastatin (IPM), and ceftriaxone (CTX) in male rhesus monkeys (Macaca mulatta) and a chimpanzee (Pan troglodytes). The chimpanzee pharmacokinetics was predictive of human results and indicated a compound that was superior to IPM and approached CTX in its ability to persist in the circulation. Levels of binding to protein, in the range of clinically relevant concentrations in serum, are virtually equivalent for L-749,345 and CTX in humans. Results of a crossover bioassay versus those of a high-pressure liquid chromatography assay of 1-g human samples showed that there were no bioactive metabolites of L-749,345. The extended half-life at elimination phase of L-749,345 allows consideration of single daily dosing. In contrast to results with IPM, the improved stability of L-749,345 with respect to hydrolysis by the renal dehydropeptidase I (0.25 times the rate of IPM) results in urinary recovery sufficient for the drug's use as a single agent.     

Successful treatment of an advanced hepatocellular carcinoma with the long-acting somatostatin analog lanreotide

Treatment options for hepatocellular cancer apart from surgical resection are limited because of the drug-refractory nature of this disease. Little is known about the role of somatostatin-receptors in hepatocellular cancer, and somatostatin analogs have not been investigated for treatment of this malignancy. We present the case of a 68-yr-old male, who was successfully treated with the long-acting somatostatin analog lanreotide.     

Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide

SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the "synthetic pentasaccharide" (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 +/- 0.3 v 48 +/- 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 +/- 15 anti-factor Xa U/mg v 850 +/- 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti-factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti-factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50 values = 40.0 +/- 3.4 and 105.0 +/- 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti-factor Xa activity. SANORG 34006 enhanced rt-PA-induced thrombolysis and inhibited accretion of 125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.     

Airway subsensitivity with long-acting beta 2-agonists. Is there cause for concern?

Regular treatment with both long- and short-acting beta 2-agonists results in tolerance to their bronchoprotective effects, although the relevance of this phenomenon in terms of long term asthma control remains unclear. However, there appears to be no appreciable difference between the 2 long-active beta 2-agonists, salmeterol and formoterol, in their propensity to induce beta 2-adrenoceptor down-regulation and subsensitivity. The degree of subsensitivity appears to be somewhat greater with indirect stimuli such as exercise and allergen challenge, compared with direct stimuli such as histamine and methacholine. This loss of functional antagonism with long-acting beta 2-agonist therapy is partial and is not prevented by concomitant inhaled corticosteroid therapy. However, the protective effects of inhaled corticosteroids on their own appear to be additive to those of long-acting beta 2-agonists when both drugs are concomitantly administered in the long term. The subsensitivity to bronchoprotection may be of clinical relevance in terms of patients who are inadvertently exposed to indirect bronchoconstrictor stimuli such as allergens or exercise, suggesting that long-acting beta 2-agonists should not be taken on a regular basis for this particular indication. There is a greater tendency for bronchodilator subsensitivity to develop with longer-acting, than with shorter-acting beta 2-agonists, and this may reflect the longer duration of beta 2-adrenoceptor occupancy and consequent downregulation. As with the bronchoprotective effects of long-acting beta 2-agonists, the development of bronchodilator subsensitivity is only partial and occurs regardless of whether patients are taking concomitant inhaled corticosteroid therapy. The long-term bronchodilator action of the long-acting beta 2-agonist itself is maintained within the twice daily administration interval. However, subsensitivity occurs in relation to a blunted response to repeated doses of short-acting beta 2-agonists, as in the setting of an acute asthma attack. There is considerable inter-individual variability in the propensity for downregulation and subsensitivity, which is determined by genetic polymorphism of the beta 2-adrenoceptor. Current international asthma management guidelines suggest that long-acting beta 2-agonists should be used on a regular basis in patients who ware inadequately controlled on inhaled corticosteroid therapy, so the addition of long-acting beta 2-agonist therapy is an alternative to using higher doses of inhaled corticosteroids. There are, however, concerns that regular long-acting beta 2-agonists might result in masking of inadequately treated inflammation in patients receiving suboptimal inhaled corticosteroid therapy. Physicians should be aware of the airway subsensitivity that develops with long-acting beta 2-agonist therapy, and patients should be warned that they may have to use higher than conventional dosages of short-acting beta 2-agonists to relieve acute bronchoconstriction in order to overcome this effect. In patients receiving an optimised maintenance dose of inhaled corticosteroid, if long-acting beta 2-agonists are to be used on an as required basis, it would seem rational to use formoterol for this purpose, due to its faster onset of action than salmeterol.     

A super long-acting LH-RH analogue induces regression of hypothalamic hamartoma associated with precocious puberty

We treated a 1-year-old female with a hypothalamic hamartoma and precocious puberty with leuprolide acetate depot, a super long-acting hormone-releasing hormone analogue (Tap-144-SR; [D-Leu6-[des-Gly10-NH2] LH-RH ethylamide acetate). The infant's major symptoms were genital bleeding and gynaecomastia. The LH-RH analogue (30 micrograms/kg) was injected subcutaneously once every 4 weeks. Clinical and laboratory manifestations of precocious puberty showed marked improvement. A follow-up after 16 months of treatment, the size of the tumour decreased significantly and remained unchanged for 2 years of further follow-up. To the best of our knowledge, this is the first hypothalamic hamartoma case in whom a decrease of tumour size under treatment with LH-RH analogue has been documented. But, because diagnosis of hamartoma is only based on neuroradiological and not on histological examinations, the possibility of a gangliocytoma cannot be excluded with certainty.