Soft drugs. 17: Quantitative structure-activity relationships of soft anticholinergics based on methatropine and methscopolamine.
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Animals↗
Biomedical subjects
R Hammer
Publications and source records attributed to R Hammer.
Interferon therapy for atopic dermatitis reduces basophil histamine release, but does not reduce serum IgE or eosinophilic proteins.
Nine adult patients suffering from severe atopic dermatitis (AD) and increased total serum IgE were treated with recombinant human interferon-alpha 2A (Roferon-AR; IFN-alpha-2A) 3 x 10(6) units daily for 21 d to study the effect upon serum IgE, basophil histamine release (HR), eosinophil-derived proteins in serum, and clinical symptoms. The skin disease was so severe that all patients needed topical treatment with glucocorticosteroid cream. Changes were not observed in total serum IgE or in eosinophil-derived proteins, the latter being increased in six of nine patients. A significant reduction in basophil HR was found in six of nine patients after anti-IgE and concanavalin A (Con A) stimulation, but not after A23187 stimulation. The clinical skin score was reduced in eight of nine patients at the end of therapy, but disease activity returned to pretreatment levels within 3 weeks despite continued topical treatment. rIFN-alpha-2A was well tolerated with few clinical side-effects, and all patients completed the study. The short-term therapy using IFN-alpha-2A neither brought a sustained clinical remission nor reduced total serum IgE or eosinophil-derived proteins. However, a significant reduction in IgE-receptor-mediated basophil HR was observed in six of nine patients.
Adolescent↗
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.
Animals↗
Novel potent inhibitor of receptor-activated nonselective cation currents in HL-60 cells.
A pharmacological classification of receptor-activated nonselective cation channels has not been possible because of the lack of specific and potent pharmacological blockers. In dibutyryl-cAMP-differentiated HL-60 cells, we recently identified ATP- and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-stimulated cation currents that were blocked by an organic inhibitor of receptor-mediated Ca2+ entry, 1-beta-[3-(4-methoxyphenyl)-propoxy]-4-methoxyphenethyl-1H-imidazole hydrochloride (SK&F 96365), with an IC50 of about 3 microM. Here, we describe a new compound, (RS)-(3,4-dihydro-6,7-dimethoxyisoquinoline-1-gamma 1)-2-phenyl-N, N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]acetamide (LOE 908), that fully blocked these currents at 3 microM. Half-maximal inhibition of agonist-activated nonselective inward currents was seen at 40 nM LOE 908, whereas voltage-dependent K+ currents in undifferentiated HL-60 cells were blocked with an IC50 of 620 nM. fMLP-induced single-channel currents of 4-5-pS conductance were abolished when the excised inside-out patch was exposed to 3 microM LOE 908. The rank order of potency of cations blocking ATP- and fMLP-induced inward currents was Gd3+ > Ni2+ > Cd2+.
Acetamides↗
Atropine poisoning in children during the Persian Gulf crisis. A national survey in Israel.
OBJECTIVE: To evaluate the effects of high doses of atropine in children accidentally injected with automatic atropine injectors. These were distributed in Israel during the Persian Gulf Crisis as an antidote for chemical warfare agents. DESIGN AND SETTING: A national survey in pediatric emergency departments in Israel, involving 22 medical centers, with prospective data collection in 14 centers. PATIENTS: Children (n = 268) presenting to emergency departments following misuse of automatic atropine injectors. MAIN OUTCOME MEASURES: Documentation of atropine dose and clinical manifestations; determination of a clinical severity score and its correlation with atropine dose; measurements of serum atropine levels in six patients. RESULTS: Over a period of 4 months, 268 cases were reported, of which 240 were clinically evaluated. The most common site of injection (75%) was the finger or palm. Doses were up to 17-fold higher than standard doses for age. In 116 children (48%), systemic effects of atropine were observed, and 20 (8%) had severe atropinization. Seizures and life-threatening arrhythmias were not reported, and there were no fatalities. The severity of atropinization was correlated with the dose following a classic nonlinear, dose-response relationship. Serum atropine levels (6.2 to 61.0 ng/mL) were much higher than those observed after administration of therapeutic doses. CONCLUSIONS: The high incidence of injection in the hand implies accidental use of automatic atropine injectors among children. The lack of mortality or life-threatening complications from injection of large doses of atropine attests to its relative safety in children. The low risk from atropine injections weighed against expected benefit as a lifesaving antidote justifies the distribution of personal atropine injectors to children at risk of organophosphorus nerve agent attack.
Accidents↗
Team approach to tibial fracture. 37 consecutive type III cases reviewed after 2-10 years.
During a 10-year period, we managed 35 patients with 37 cases of Type III open tibial fractures, 15 cases within 1 week and 22 as late referrals. In all cases, simultaneous assessment and management by a microvascular and an orthopedic surgeon were mandatory throughout the treatment period. 6 of the 15 acute cases had a primary amputation. Of the remaining 31 cases, limb salvage was possible in 27. 31 flaps, pedicle and microvascular free flaps were used. Major complications occurred in 6 cases, but in 27 cases infection-free solid union was obtained. At long-term follow-up, average 5 years, the function was good or acceptable in 23 cases. We conclude that: (1) patients with Type III tibial injuries should preferably be transferred within a week after injury to a hospital where major reconstructive procedures are commonly performed, (2) early soft tissue coverage is essential in the management of these injuries, (3) unilateral external fixation should be the preferred technique of stabilization, and, finally, (4) plastic surgery expertise is important in management of severe tibial fractures.
Adolescent↗
Fenoterol and its bromide.
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Administration, Inhalation↗
Misonidazole combined with split-course radiotherapy in the treatment of invasive carcinoma of larynx and pharynx: report from the DAHANCA 2 study.
Between October 1979 and May 1985, 626 patients with pharynx and larynx carcinoma were randomized to two different split-course radiation regimens and given either misonidazole (MISO; 11 g/m2) or placebo during the initial 4 weeks of treatment. Patients in the different treatment groups were evenly distributed among stages. The small number of females (136) gave an uneven distribution, thus making analysis difficult. The results show that females had a statistically better loco-regional control (45 vs. 33%; 5-year actuarial value). Overall, the MISO treated group did not have a significantly better control rate than the placebo groups (37 vs. 34%). However, a difference was found in patients with pharynx carcinomas (38 vs. 27%; p less than 0.05). The pre-irradiation hemoglobin (Hb) concentration was found to be a prognostic parameter. In females, loco-regional control for IIb values below or above 8 mmol/l were 37 and 47%, respectively. In males, the same values were below or above 9 mmol/l 26 and 38%. Hb influence on local control was only seen in supraglottic and pharynx tumors. This effect was independent of tumor size, which also was of prognostic value. In addition Hb concentration and MISO had an apparent additive effect. Thus in the male pharynx group, placebo patients with low Hb had a 14% disease rate compared to 40% in MISO treated patients with Hb above 9 mmol/l. MISO induced significant peripheral neuropathy in 26% of the treated patients, whereas other drug related side effects were minimal and tolerable.
Carcinoma, Squamous Cell↗
Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics.
On the basis of the cardioselective muscarinic receptor antagonist AF-DX 116 (2), a series of 11-substituted pyridobenzodiazepinones (9-35) was prepared and screened for their binding affinity to muscarinic receptors located in cardiac (M2) and glandular (M3) tissue. The ratio of IC50 values of the test compounds in the two different tissues was taken as a measure of cardiac (M2) receptor selectivity. Qualitative structure-selectivity relationships point to the fact that it is the spatial orientation of the protonated side-chain nitrogen atom in relation to the tricycle that is the main determinant for receptor subtype recognition and hence is important for the achievement of cardiac (M2) selectivity.
Animals↗
Tricyclic compounds as selective antimuscarinics. 2. Structure-activity relationships of M1-selective antimuscarinics related to pirenzepine.
In order to gain some insight into those structural features that control M1 selectivity, a selected set of pirenzepine analogues has been studied in which both the tricyclic ring system and the basic side chain have been varied. Binding studies were conducted in rat tissue homogenates from cerebral cortex (M1) and gastric fundus (M2). The ratio of IC50 values of the test compounds in the two different tissues was taken as a measure of M1 receptor selectivity. Several derivatives, especially those with flexible side chains, i.e. high degree of freedom of rotation around single bonds, proved to be nonselective. Among semirigid compounds only those containing 6-membered ring systems (11, 13, 14, and 15) showed significant M1 selectivity. Principles of structure-activity and structure-selectivity are discussed.
Animals↗
Treatment of mycosis fungoides with recombinant interferon-alpha 2a2 alone and in combination with etretinate.
Eleven patients with mycosis fungoides (MF) were treated with recombinant alpha-interferon (rIFN-alpha 2a2) in combination with etretinate (seven patients) or alone. One patient, who also received etretinate, went into complete remission and remained without signs of MF after 18 months. Six patients experienced partial remission; one of these was treated with rIFN-alpha 2a alone and was clinically in complete remission, but had still a pleomorphic skin infiltrate. Two patients were non-evaluable, and two stopped therapy due to progressive disease. Five patients discontinued therapy due to side-effects although three had partial remission of their disease. Only four patients received 12 months therapy. The study shows that rIFN-alpha 2a in combination with etretinate or alone can induce remission of MF.
Aged↗
A new device for external fixation.
Using a ball-and-socket joint model, the optimal mechanical design of a simple universal ball joint was established. The maximum resistive moment was 70-72 Nm for a tightening torque moment of 5 Nm, their ratio being 14. The corresponding ratios for the Hoffmann universal ball joint and Orthofix are 1.0-4.3 and 1.1-1.6, respectively. A complete unilateral frame consists of two ball joints and one square connecting tube. Full-frame behavior under external loads was tested in the three principal planes and in torsion. Compared with a Hoffman quadrilateral system, the new system was four times more rigid in the anteroposterior plane, similar in axial load and lateral bending, and 64 percent more rigid in torsion.
Biomechanical Phenomena↗
Muscarinic receptor heterogeneity in smooth muscle: binding and functional studies with AF-DX 116.
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Animals↗
Characterization of muscarinic receptors in guinea pig ileum longitudinal smooth muscle.
Heterogeneity in the muscarinic receptor population of guinea pig ileum longitudinal smooth muscle was found in competition binding experiments against N-methyl[3H]scopolamine using either a cardioselective (AF-DX 116) or a smooth muscle-selective (hexahydrosiladifenidol) antimuscarinic compound. AF-DX 116 recognized 65% of the total receptors with high affinity and 35% with low affinity. Hexahydrosiladifenidol distinguished 24% of the total receptors with high affinity and 76% with low affinity. The two affinity binding constants displayed in smooth muscle by the compounds were similar to those of heart and glands, suggesting that the muscarinic receptor population in the smooth muscle is formed of about 30% glandular type and 70% cardiac type of the M2 receptors. In dissociation experiments, the rate of breakdown of the N-methyl[3H]scopolamine receptor complex in the smooth muscle was rapid and similar to the dissociation of N-methyl[3H]scopolamine from muscarinic receptors in cardiac membranes, supporting the evidence for the presence of a large fraction of the cardiac receptor type in smooth muscle. To further characterize the population of the smooth muscle receptors recognized as glandular type, we performed protection experiments with hexahydrosiladifenidol, which binds to glandular M3 receptors with high affinity. Smooth muscle membranes were initially incubated with this compound and then phenoxybenzamine was added to irreversibly alkylate the remaining unprotected receptors. Data from competition and dissociation binding experiments showed that, under these conditions, this protected fraction of the total receptor population in ileum smooth muscle had all the characteristics of the glandular type, i.e., slow N-methyl[3H]scopolamine dissociation and affinity constants for a series of selective and nonselective muscarinic antagonists in the same order of magnitude as those found in the glandular tissue. These findings, together with the known observation that hexahydrosiladifenidol is more potent in inhibiting the functional activation of muscarinic receptors in smooth muscle relative to heart, lead to the hypothesis that smooth muscle contractility is mediated by a muscarinic receptor subtype similar to that found in glandular tissue.
Animals↗
Characterization of muscarinic receptors in salivary and lacrimal glands of the rat.
The binding characteristics of muscarinic receptors in rat salivary and lacrimal glands were studied by means of radioligand binding techniques. In competition experiments against [3H]N-methylscopolamine, classical muscarinic antagonists ipratropium bromide, N-methylscopolamine and N-methylatropine exhibited very similar KD values in all the glands and their binding behavior was well described by a one binding site model (nH congruent to 1). The novel cardioselective antimuscarinic compound, AF-DX 116, displayed an equally low affinity in all the tissues examined. Pirenzepine and dicyclomine, two other selective muscarinic antagonists, showed a similar behaviour in all but the sublingual gland, where their binding profile indicated the presence of a heterogeneous receptor population (nH = 0.74 and 0.84, respectively). Histological studies of the sublingual-submandibular glandular complex demonstrated the presence of ganglionic structures mainly located in the hilum of the sublingual-submandibular glandular complex connected with the sublingual gland. Binding studies carried out with pirenzepine on the hilum and on a synaptosomal preparation from this region again revealed the presence of two populations of muscarinic receptors with KD values of 22-25 and 270-463 nM. These results are best explained by the presence of M1 and M2 receptors located on neuronal and glandular structures.
Animals↗
Muscarinic receptor heterogeneity in guinea pig intestinal smooth muscle: binding studies with AF-DX 116.
Muscarinic receptor subtypes in longitudinal and circular smooth muscles of the guinea pig ileum were characterized with the use of the cardioselective antagonist AF-DX 116 in binding competition experiments against 0.3 nM [3H] N-methylscopolamine [( 3H]NMS). This compound recognized a heterogeneous receptor population in both smooth muscles, revealing the existence of different percentages of the cardiac (KD = 92-110 nM) and the glandular (KD = 1150-2541 nM) muscarinic receptor subtypes. These results, together with the low potency displayed by AF-DX 116 to inhibit the agonist-stimulated smooth muscle contraction and salivary secretion allow the suggestion that the glandular muscarinic receptor subtype, showing a low affinity for AF-DX 116, is involved in smooth muscle contraction.
Animals↗
Distribution of muscarinic receptor subtypes in rat brain as determined in binding studies with AF-DX 116 and pirenzepine.
In vitro competition binding experiments with the selective muscarinic antagonists AF-DX 116 and pirenzepine (PZ) vs 3H-N-methylscopolamine as radioligand revealed a characteristic distribution of muscarinic receptor subtypes in different regions of rat brain. Based on non linear least squares analysis, the binding data were compatible with the presence of three different subtypes: the M1 receptor (high affinity for PZ), the cardiac M2 receptor (high affinity for AF-DX 116) and the glandular M2 receptor (low affinity for PZ and AF-DX 116). The highest proportion of M1 receptors was found in the hippocampus, whilst the cerebellum and the hypothalamus were the regions with the largest fraction of the cardiac M2 and glandular M2 receptors, respectively. In certain brain areas, depending on the relative proportions of the subtypes, flat binding curves were seen for AF-DX 116 and PZ. Based on these data, an approximate distribution pattern of the subtypes in the various brain regions is presented.
Animals↗
Tiapamil and hydrochlorothiazide: a double-blind comparison of two antihypertensive agents.
Tiapamil is an investigational calcium-channel antagonist that is chemically related to verapamil. The antihypertensive efficacies of tiapamil and hydrochlorothiazide (HCTZ) were compared in a randomized double-blind trial. Thirty patients, age 44 to 80 years, with mild to moderate hypertension (World Health Organization stage I-II) entered and completed the study. Previous therapy, if any, was stopped for at least one week prior to study initiation, and patients received placebo tablets for two weeks. The participants were then given active medication, which was titrated for the next three weeks; HCTZ 25 to 50 mg bid or tiapamil 300 to 600 mg bid was given until supine diastolic blood pressure (BP) was no higher than 90 mm Hg or the ceiling dose was reached. Both drugs caused a significant reduction in systolic as well as in diastolic blood pressure (P less than .01). The reduction was seen in both the supine and erect position. The median decrease in supine systolic blood pressure from baseline to the end of treatment was 20 mm Hg in the tiapamil group and 27 mm Hg in the hydrochlorothiazide group, whereas the median decrease in supine diastolic blood pressure was 14 mm Hg and 18 mm Hg, respectively. The median difference in supine diastolic BP reduction after HCTZ and tiapamil administration was 3.8 mm Hg (not significant). There were no significant changes in heart rate. Dizziness occurred in one patient taking tiapamil and in three receiving HCTZ. One patient receiving HCTZ developed acute arthritis urica.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗