摘要:

AbstractIn order to elucidate the possibility of the dissociation rate of drugs from plasma proteins presenting a rate limiting step in the elimination of drugs by secretion (renal or biliary) and metabolism, the kinetics of salicylazosulfa‐pyridine (SASP) binding to human serum albumin (HSA) has been investigated by stopped‐flow photometry. Equilibrium dialysis showed that HSA has three classes of binding sites for SASP with 0.93, 2.3 and 8.4 sites, respectively, and association constants of 2.1 · 106, 1.4 · 105and 3.0 · 103M‐1, respectively. The association rate constants for the first and second classes are 4.4 · 106and 1.5 · 107M‐1sec.‐1, and the dissociation rate constants are 2.1 and 109 sec.‐1. At SASP concentrations resulting from the usual therapeutic doses about 83 % will bind to the first class binding sites. The dissociation “half time” for this class being 0.34 sec., leads to the conclusion that dissociation rates of this order of magnitude are unlikely to reduce the rate of metabolism or biliary secretion whereas it may reduce renal tubular secretion. Whether this is the case depends on the intrinsic rate c

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1977.tb02151.x

出版商:Blackwell Publishing Ltd    

年代:1977

数据来源: WILEY

摘要:

AbstractA number of commonly used external agents were applied repeatedly on the skin of the mouse and rabbit. These chemicals, components of commercially available products included 4‐hydroxyanisole, benzalkonium chloride, bromodeoxyuridine, iododeoxyuridine, 5‐nitroacenaphthene, N‐N‐diethyltoluamide, hexachlorophene, para‐aminobenzoic acid, benzophenone, isopropylmyristate, pyrogallol, resorcinol and ethylhexanediol. Also tested were a commercial hairspray, a dandruff shampoo and an anti‐dandruff agent. Local and systemic changes were studied and the tumour incidence compared with that of an effective carcinogen, 9,10‐dimethylbenz(a)anthracene. The mice showed no local toxic changes or tumour formation and the systemic tumour incidence, i. e., tumours of the liver, lungs, lymphatic system and other organs, was similar to that of control animals. In rabbits, a number of proliferative, benign and malignant ear tumours were observed in the positive controls, thereby demonstrating the efficiency of this model. Local toxic changes were seen in benzalkonium‐ and hexachlorophene‐treated animals, but no skin tumours. Four animals had uterine tumours. In addition, one lung and one kidney tumour, unrelated to the method of tre

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1977.tb02152.x

出版商:Blackwell Publishing Ltd    

年代:1977

数据来源: WILEY

摘要:

AbstractWhen the number of carbon atoms on the piperidine‐nitrogen of the mepivacaine molecule was increased up to four or five carbons, the toxicity of the compounds and the duration of their local anaesthetic effects were increased. With longer N‐alkyl‐chains, the general toxicity and the local anaesthetic potency ‐ but not the tissue toxicity ‐ were reduced. In dental infiltration anaesthesia only the short‐chain compounds offered an acceptable local anaesthesia. In these tests, the medium‐chain compounds had a very unfavourable quotient between dental anaesthesia and soft tissue anaesthesia, while the long‐chain compounds could not be tested at all in man because of their tissue irrita

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1977.tb02153.x

出版商:Blackwell Publishing Ltd    

年代:1977

数据来源: WILEY

摘要:

AbstractThe effect of substance P, acetylcholine, and histamine on pulmonary resistance (RL) and on pulmonary dynamic compliance (CDYN) was studied in the anaesthetized cat and guinea‐pig. In the anaesthetized guinea‐pig, substance P (0.1‐1.0 üg/kg), acetylcholine (1.0‐10 μg/kg), and histamine (1.0‐10.0 μg/kg) produced a dose‐dependent increase in RLand decrease in CDYN. In the anaesthetized cat, the effect of substance P was weak on both RLand CDYN, whereas histamine (5‐50 μg/kg) produced a dose‐dependent increase in CDYN, but the effect on RLwas weak. The effect of acetylcholine was qualitatively the same as in the anaesthetized guina‐pig but about 10

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1977.tb02154.x

出版商:Blackwell Publishing Ltd    

年代:1977

数据来源: WILEY

摘要:

AbstractDopamine metabolismin vivowas studied after treatment with piflutixol (6‐fluoro‐9‐[3‐(4‐(2‐hydroxyethyl)piperidino)propylidene]‐2‐trifluoromethyl‐thioxanthene) a novel thioxanthene derivative with potent neuroleptic properties and sedative effects. In mice piflutixol increased both noradrenaline (NA) and dopamine (DA) turnover rate measured as increased disappearance of14C‐amines formed from14C‐L‐tyrosine. The ratio between the minimal effective doses for14C‐NA and14C‐DA disappearance was 2, which is of the same order of magnitude as obtained with cis(Z)‐chlorprothixene, pimozide and chlorpromazine. After14C‐L‐tyrosine the accumulation of14C‐dopamine was initially increased after which it decreased from day 4‐5. These changes resemble those obtained after other neuroleptics and parallel the initial receptor blockade and the subsequent receptor supersensitivity found in pharmacological experiments (MøllerNielsenet al.1977). Piflutixol induced a rapid increase in both DOPAC and HVA with a maximal effect after 2‐6 hours. After 2‐3 days the levels had returned to normal. The doses of piflutixol which at 24 hours doubled the levels of DOPAC and HVA were found to be 0.055 and 0.021 mg/kg subcutaneously, respectively. It is concluded that piflutixol is a powerful and long lasting DA receptor blocking agent, which changes the synthesis and release of

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1977.tb02155.x

出版商:Blackwell Publishing Ltd    

年代:1977

数据来源: WILEY

摘要:

AbstractA rapid procedure for the measurement of serum diazepam (D), N‐desmethyldiazepam (ND), and N‐desalkylflurazepam (NF), levels in clinical samples is described. The single step extraction procedure yields quantitative extraction for the drugs mentioned above. No solvent evaporation step is needed. No interference of endogenous substances or generally used psychotropic drugs containing halogen atoms has been observed. The conditions provide excellent precision, due to a clear separation of the internal standard, medazepam, from the solvent front. The frequency response electron capture detector provides a linear response to the drugs over a 5 × 102concentration range making serial dilution of the samples unnecessary. The automatic data reduction system indicates the serum levels directly in ng/ml without manual calculat

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1977.tb02156.x

出版商:Blackwell Publishing Ltd    

年代:1977

数据来源: WILEY

摘要:

AbstractThe excretion of carbamazepine in the saliva of six normal adults after receiving a single oral dose of 400 mg carbamazepine is described. There was a good correlation between carbamazepine concentrations in the plasma and saliva (r = 0.94, P<0.001). This indicates that the concentrations of carbamazepine in the saliva can be used to monitor carbamazepine therapy. The half‐life of carbamazepine in the plasma was not significantly different from the half‐life in the saliva. Thus areas under concentration‐time curves, apparent volumes of distribution (Vd) and the total body clearances were significantly dependent (P<0.001) upon the distribution of carbamazepine between plasma and saliva. Calculated from saliva concentrations, 75 % of the total carbamazepine plasma concentration is bound to protein while 25 % is unbound in diffusional equilibrium with saliva. These figures are consistent with data in the liter

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1977.tb02157.x

出版商:Blackwell Publishing Ltd    

年代:1977

数据来源: WILEY

摘要:

AbstractCorrelations of serum nortriptyline (NT) and amitriptyline (AT) levels with psychomotor performance choice reaction performance, eye‐hand coordination, and divided attention was studied in two experiments each with 20 healthy subjects. In the first experiment serum NT level was measured with an isotope derivative method after treatment for 14 days with NT. In the second trial plasma AT and NT concentrations were measured with gas‐chromatography after treatment for 14 days with AT. No linear correlations between the levels of the antidepressants and performance variables were found. Low levels of NT (<50 ng/ml) tended to shorten reaction time, and intermediate levels (50‐80 ng/ml) to prolong it, when compared with the reaction times during placebo. The correlation between serum NT levels and the increase of the tyramine dose in the tyramine pressor test was not significant. A new assay method for AT and NT is pres

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1977.tb02158.x

出版商:Blackwell Publishing Ltd    

年代:1977

数据来源: WILEY

摘要:

AbstractRats treated chronically with digoxin were treated with two different dose levels of phenytoin, either as a single dose or chronically. Digoxin concentrations were measured by radioimmunoassay in the serum, urine, heart, muscle, liver, and the kidney. Chronic treatment with the high dose of phenytoin significantly increased the digoxin levels in the serum and tissues and decreased the renal clearance of digoxin. The low dose of phenytoin significantly reduced the serum and tissue levels of digoxin and increased the renal clearance. Single doses of phenytoin had a tendency to cause similar changes. Levels of digoxin were altered during the phenytoin treatment. In contrast to man. digoxin is extensively metabolized in the rat. Enzyme induction in connection with low phenytoin dosage and inhibition by high dosage is the suggested mechanism. It can be speculated that the tissue distribution and excretion of digoxin are altered.

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1977.tb02159.x

出版商:Blackwell Publishing Ltd    

年代:1977

数据来源: WILEY

摘要:

AbstractThe effects of two beta‐adrenergic receptor blocking drugs, the non‐selective propranolol and the beta1selective metoprolol, were studied on hemodynamics and plasma renin activity (PRA) of healthy volunteers in an ergometric exercise test. Oral doses of 160 mg of propranolol and 200 mg of metoprolol were tested against placebo. The drug plasma concentrations were determined. Heart rate and systolic blood pressure were equal and significantly lower during treatment with both active drugs when compared to placebo. The effect of drugs on exercise heart rate was correlated with the logarithm of drug plasma concentration with both propranolol and metoprolol. Propranolol, but not metoprolol, decreased the basal level of PRA. The ergometric exercise induced a significant rise in PRA after placebo but this increase was partially inhibited by the both active drugs. On the basis of these findings it is suggested that in man the basal level of PRA could be decreased mainly by blocking the beta2‐adrenoceptors. Instead the exercise induced increase of PRA could be inhibited by blocking the beta1‐adrenergic re

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1977.tb02160.x

出版商:Blackwell Publishing Ltd    

年代:1977

数据来源: WILEY