Reduction by cimetropium bromide of the colonic motor response to eating in patients with the irritable bowel syndrome

Summary Cimetropium bromide is an antimuscarinic compound with antispasmodic properties. Its effect on meal-stimulated sigmoid motor activity in 30 patients with the irritable bowel syndrome, mainly with pain and constipation, has been evaluated.The mechanical activity of the sigmoid colon was recorded with a probe with three open-tipped tubes ending 45, 30, and 15 cm from the anal margin.After a recording period of 60 min, 5 mg cimetropium bromide or saline was given i.v., according to a randomized, double-blind design 5 min before a 1000 calorie meal, and motility was then recorded for 2 h.The meal caused a significant increase in motor activity for 90 min in the saline-treated group. Cimetropium bromide abolished the peak of motor activity 10–20 min after the meal and significantly inhibited postprandial colonic motility for at least 2 h (p<0.01).This effect provides a rationale for the use of cimetropium bromide in treatment of the irritable bowel syndrome.     

Effect of cholinergic agonists and antagonists on gallbladder volume in fasting man

Summary The effect of direct cholinergic stimulation and blockade on gallbladder volume, determined by real-time ultrasonography (RUS), was evaluated in twenty normal, fasting subjects. Eleven subjects received atropine sulphate or placebo and 9 subjects a series of 3 injection of prostigmine, bethanechol or placebo, randomly assigned, at intervals of 24 h.RUS was performed under basal conditions after fasting for 12 h and every 5 min after drug injection up to 45 min in the atropine study and up to 60 min after prostigmine and bethanechol.There was no significant variation from fasting gallbladder volume after placebo in either group. After atropine sulphate gallbladder volume at first decreased and then significantly increased. With bethanechol and prostigmine, the volume fell significantly to a trough after 30 to 35 min, and then it returned to the basal value within 60 min. It is suggested that cholinergic mediation is involved in maintaining fasting tone in the gallbladder and that cholinergic stimulation causes contraction of the gallbladder by a direct effect.     

橄榄油对氟比洛芬和双氯芬酸钠大鼠经皮吸收的影响

目的考察橄榄油对氟比洛芬和双氯芬酸钠透过大鼠腹部皮肤的作用。方法以离体大鼠腹部皮肤为渗透屏障,采用扩散池装置,以预处理皮肤法考察橄榄油对药物透过皮肤的影响。结果 榄油可有效促进氟比洛芬的经皮透过率,增渗倍数为2.11,但对双氯芬酸钠的经皮透过率有抑制作用。结论橄榄油能够促进氟比洛芬的经皮渗透,可能归因于其中油酸的存在,还可能含有某些成分对双氯芬酸钠的经皮渗透有抑制作用。     

Safety and tolerance of single oral doses of trandolapril (RU 44.570), a new angiotensin converting enzyme inhibitor

Summary The safety and tolerance of single oral doses of a new angiotensin converting enzyme (ACE) inhibitor, trandolapril have been examined in 90 healthy male volunteers, in a randomised, double blind, placebo-controlled study. The subjects were divided into 10 groups, each of 9 subjects and treatments (6 subjects on trandolapril and 3 on placebo per group) were allocated by unbalanced randomisation. Ten single, increasing oral doses were tested: 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 24 and 32 mg. The assessment criteria were clinical (monitoring of blood pressure, heart and respiratory rate, electrocardiogram, temperature and evaluation of behaviour and side effects) and routine laboratory tests.Blood pressure did not fall except for a slight drop in diastolic pressure during the first 4 h following the 32-mg dose. However, although an effect of the compound cannot be excluded, the reduction in blood pressure may have reflected intersubject variability. No orthostatic hypotension was observed. There was no change in the other vital signs, and in particular no increase in heart rate was observed. No serious adverse effect was encountered.The pharmacological activity of the compound was studied by assaying plasma ACE activity. Inhibition of ACE was linearly dose-dependant from 0 (placebo) to 2 mg, and above that dose, the inhibition was nearly total. ACE activity was markedly reduced within 30 min after administration of trandolapril, and maximal inhibition was observed from 2–4 h onwards, lasting for up to 24 h after dosing. For doses above 2 mg, inhibition was still 40% of the basal activity on Day 8 after dosing.     

Quantitative cancer inhibitory of hydroxytyrosol in olive oil compounds: an overview of observational and experimental studies

Hydroxytyrosol (HTyr), an important phenol present in olives, stands out as a compound of high value due to its excellent antioxidant, antimicrobial and anticarcinogenic activities. Hydroxytyrosol (HTyr, 4-(2-(hydroxyethyl)-1,2-benzendiol)) is one of the main phenolic compounds in olives, virgin oil and waste water obtained during the production of olive oil. HTyr has been confirmed as the antioxidant with the highest free radical scavenging capacity, and is more active than antioxidant vitamins (C and E) as well as the synthetic antioxidants. Studies (human, animal, in vivo and in vitro) have shown many beneficial attributes of this ortho-diphenol compound, e.g. anti-inflammatory activity and inhibition of platelet aggregation. Similar to other polyphenols, HTyr was shown to prevent atherosclerosis through the inhibition of LDL oxidation. Furthermore, polyphenols extracted from the virgin olive oil containing mainly HTyr were also shown to inhibit different kinds of cancer, e.g. proliferation of human leukemia cells and colon carcinogenesis. This work summarizes current knowledge on the bioavailability, biological activities (e.g. anticancer activity, anti-inflammatory activity) and major active components of olive oil (containing mainly HTyr).     

左归丸联合橄榄油对大鼠去势后骨组织和骨密度的影响简

目的 观察左归丸联合橄榄油对去势后大鼠骨组织和骨密度的影响,为中医药治疗绝经后骨质疏松症提供实验依据.方法 对45只5～6月龄清洁型SD雌性大鼠进行随机等分成5组：①假手术组（Sham组）、②去卵巢组（OVX组）、③去卵巢＋左归丸组（ZGW组）、④去卵巢＋橄榄油组（Olive组）、⑤去卵巢＋左归丸＋橄榄油组（复方组）.对照组（①②）用药：均以生理盐水按1 ml/100 g体重,隔天1次灌胃.治疗组（③④⑤）用药：ZGW组：以中成药左归丸水溶液（每ml含0.2 g生药）按1 ml/100 g体重,隔天1次灌胃.Olive组：以初榨橄榄油按1 ml/100 g体重,隔天1次灌胃.复方组：以左归丸水溶液和初榨橄榄油交替每日灌胃1次.12周后分别左心室取血,检测血中血清雌二醇（E2）、白细胞介素-1（IL-1）、白细胞介素-6（IL-6）水平,放血处死后取出腰椎行双能X线骨密度测定,取左侧股骨近端1/3切片观察骨组织并计算骨小梁面积.结果 OVX组中血E2值明显低于Sham组（P〈0.01）;复方组中E2、IL-1、IL-6与Sham组无差异（P〉0.05）,复方组血E2值高于OVX组、ZGW组和Olive组（均P〈0.05）,IL-1值低于OVX组、ZGW组和Olive组（均P〈0.05）,复方组中IL-6值低于Olive组,差异有统计学意义（P〈0.05）,与ZGW组相比差异无统计学意义（P〉0.05）.光镜下观察发现OVX组中骨小梁稀薄、断裂,治疗组中骨小梁变密,连续性好,骨质疏松的病理骨组织现象改善,且三组间没有明显的区别.复方组骨密度较Olive组增加（P〈0.05）,但与ZGW组无显著差异性（P〉0.05）.复方组骨小梁面积较ZGW组增加（P〈0.05）,但与Olive组无显著差异性（P〉0.05）.结论 左归丸联合橄榄油能有效地减轻大鼠卵巢切除术引起的骨质丢失,且两者联合应用疗效或可能优于单用左归丸或橄榄油.     

The effect of ageing on the response to frusemide in normal subjects

Summary The effect of IV frusemide was studied in six healthy young (mean age 26.5 years, range 21–33) and six healthy old (mean age 72.8 years, range 66–80) volunteers. A 24-h urine collection before frusemide showed no difference in volume and sodium excretion, although the old excreted less potassium. Creatinine clearance was significantly reduced in the older subjects. After frusemide, 20 mg IV, the pattern of sodium and water excretion over a 5-h period was different in the two groups. The peak effect was greater in the young and occurred within the first 30 min, but was delayed to between 30 and 60 min in the old. Thus in the young the time for 50% of the total sodium and water to be excreted was half that in the old. This delay in sodium and water excretion was related to baseline creatinine clearance. However, the total water, sodium and potassium excreted in the 5 h after frusemide did not differ in the two groups. These results suggest that the renal effects of frusemide are different in healthy elderly subjects as compared to the young. The delayed and reduced peak response is consistent with fewer nephrons in the elderly kidney.     

The effects of citalopram in single and repeated doses and with alcohol on physiological and psychological measures in healthy subjects

Summary Citalopram, a selective 5-HT uptake inhibitor with antidepressant properties, was assessed in three studies in 12 healthy subjects using a battery of EEG, psychological, subjective and symptomatic measures.Study A involved the administration of citalopram, 20 mg and 40 mg, amitriptyline 50 mg and placebo in single dose using a balanced cross-over design. The test battery was applied before, and 1 and 3 h after each drug. Citalopram decreased slow-wave EEG activity whereas amitriptyline increased power in most EEG wavebands. Citalopram increased tapping rate and symbol copying whereas amitriptyline impaired these and other psychomotor tasks. Subjectively, amitriptyline was much more sedative than citalopram and produced more complaints of dry mouth.Study B comprised the administration of citalopram in the usual clinical dose of 40 mg, amitriptyline in the low clinical dose of 75 mg and placebo, each given for 9 nights using a balanced cross-over design. The test battery was applied on the first morning (pre-drug) and on the morning after the last nightly dose. None of the physiological tests showed any drug effects. Subjectively, citalopram was associated with feelings of shaking, nausea, loss of appetite and physical tiredness; amitriptyline produced feelings of shaking, nausea, loss of appetite, dryness of mouth, irritability, dizziness and indigestion; in general, amitriptyline effects were more marked than those of citalopram. Plasma samples were taken on the last day and plasma concentrations of both drugs and their metabolites were found to be in the expected range for the regimens used.In the third study (C), 12 healthy subjects took similar courses of citalopram, amitriptyline and placebo. On the morning of the 8th day, a test dose of ethanol was given. The battery of tests was given predrug, on Days 4/5 and on Day 8, before and 1 and 3 h after the ethanol. Amitriptyline increased the 7.5–13.5 Hz waveband. Amitriptyline impaired critical flicker fusion frequency, tapping, DSST and reaction time; citalopram affected DSST and immediate memory recall. The subjective and symptomatic effects of the drugs were similar to those in Study B. Plasma concentrations of citalopram, amitriptyline and their desmethylated metabolites were in the expected range for the regimens used.Ethanol had the expected effects, impairing performance and producing sedation. No evidence for potentiation of ethanol and drug effects were found, most interactions being additive, or even with some symptoms subtractive.It is concluded that in clinical use citalopram should have little or no effect on cognitive and psychomotor performance, produce minimal sedation but some nausea, loss of appetite and insomnia. Interactions with ethanol should be unremarkable.     

Effect of the long-term regular intake of virgin olive oil on the phenolic metabolites in human fasting plasma

The effect of repeated consumption of virgin olive oil on endogenous phenolic metabolites of fasting plasma is unknown. For this reason, we hypothesized that regular long-term virgin olive oil intake could have an indirect protection effect on the endogenous phenols. Thus, the aim of the study was to determine the phenolic profile of human plasma in a fasting state of long-term regular virgin olive oil consumers, using the fasting plasma of non-consumers as a natural control. Forty participants living in the area of Reus (Catalonia, Spain) were selected, 20 life-long regular consumers of virgin olive oil and a natural control of 20 non-consumers, the latter being Rumanians who dislike the taste of olive oil. The diet was obtained from 3-day food records. The results showed similar phenolic composition of fasting plasmas of the two volunteer groups. Of special interest is that more of the compounds quantified showed higher concentration in fasting plasma from habitual virgin olive oil consumers. The compounds were semi-quantified using caffeic acid as the calibration standard. The quantification of fasting consumer's plasma showed higher concentration of a hydroxyflavanone type compound (2.90 ± 0.04 μM vs 1.5 ± 0.04 μM) and a catecholamine derivative (0.70 ± 0.03 μM vs 0.56 ± 0.03 μM) than the plasma of non-consumers (P < 0.05). The results suggest an indirect protective mechanism of long-term regular virgin olive oil consumption related to the protection of the endogenous antioxidant system.     

Influence of repeated administration of cimetidine on the pharmacokinetics and pharmacodynamics of adinazolam in healthy subjects

Summary Adinazolam is a new triazolobenzodiazepine bearing an alkyl-amino side chain. A cross-over double-blind placebo controlled study was carried out in 12 healthy volunteers, in order to check the possible interaction between cimetidine and adinazolam after repeated co-administration.Cimetidine or placebo were given during 17 days. Beginning on Day 8 of each treatment, adinazolam was given in the increasing doses following sequence of doses for 3 days: 10 mg b.i.d., 20 mg b.i.d. and 20 mg t.i.d. A pharmacokinetic and pharmacodynamic study was performed on the third day at each dose. A wash-out of three weeks was included between the two treatments.Cimetidine increased significantly the AUC values of both adinazolam and N-desmethyladinazolam, reduced the oral clearance of adinazolam, and prolonged adinazolam's half-life.The digit symbol substitution test was significantly affected at each dose level while the manual dexterity was marginally impaired by adinazolam plus cimetidine.Saftee-up interview and Clyde mood scale indicated an increased sedation under adinazolam plus cimetidine in four subjects.     

Bioequivalence, pharmacokinetic and pharmacodynamic response to combined extended release formulations of felodipine and metoprolol in healthy volunteers

Objective: The primary aim of this study was to investigate whether bioequivalence is achieved for a new fixed combination of extended-release (ER) felodipine and controlled-release (CR/ZOK) metoprolol␣compared with the free combination of felodipine ER metoprolol CR/ZOK. The second aim was to study whether there was an interaction in pharmacokinetics and pharmacodynamics between felodipine and metoprolol when administered as ER formulation. Methods: Two four-way cross-over studies were performed in 36 young subjects and 24 elderly subjects with frequent measurement of drug plasma concentrations, blood pressures and heart rate. The pharmacokinetic analysis included enantioselective analysis in six subjects. Results: Bioequivalence between the fixed combination and the free combination was observed for the two drugs (mean difference 27%) except for a minor deviation regarding C_max of metoprolol in the elderly. No significant interaction was shown except for a small increase (6%) of metoprolol AUC in the younger subjects. Mean plasma S-/R-enantiomer ratios were almost identical for the different treatments. Blood pressure and heart rate was significantly reduced for the fixed combination compared with felodipine ER in the younger and the elderly subjects. No significant difference regarding pharmacodynamics was detected between the fixed combination and the corresponding free combination. Conclusion: The fixed combination consistently provides fairly constant and effective felodipine and metoprolol concentrations after once-daily administration of one tablet. It is clinically interchangeable with the free combination of metoprolol CR/ZOK tablets and felodipine ER tablets. Finally, felodipine and metoprolol do not interact on a pharmacokinetic level when administered as the fixed combination. Received: 29 October 1996 / Accepted in revised form: 21 March 1997     

The effects of repeated doses of clomipramine and alprazolam on physiological,psychomotor and cognitive functions in normal subjects

Summary The effects of a 10 day administration of clomipramine (25–50 mg t.i.d.), alprazolam (0.25–0.75 mg t.i.d.) and placebo were assessed in normal volunteers in a double-blind cross-over study. A battery of physiological, psychomotor and cognitive tests was administered both before and 3 h after drug on days 1, 5 and 10.The effects of alprazolam on EEG and evoked potentials were characteristic of benzodiazepines; clomipramine had little effect. In contrast, reaction speed was markedly slowed by clomipramine but little affected by alprazolam.Neither drug produced any accumulation of effect on a verbal recall task but neither did tolerance develop to the acute impairments produced by active treatments. Alprazolam produced an increase in levels of forgetting, especially on day 5. Subjective ratings for mood and bodily symptoms were adversely affected by clomipramine but little altered by alprazolam.It is suggested that some of the differences between drug treatments may be due to differences in the speed of onset of tolerance.     

Phenolic compounds in olive oil: antioxidant, health and organoleptic activities according to their chemical structure

Hydrophilic phenols are the most abundant natural antioxidants of virgin olive oil (VOO), in which, however, tocopherols and carotenes are also present. The prevalent classes of hydrophilic phenols found in VOO are phenolic alcohols and acids, flavonoids, lignans and secoiridoids. Among these substances the last two classes include the most concentrate phenols of VOO. Secoiridoids, like aglycone derivatives of oleuropein, demethyloleuropein and ligstroside, are present in olive fruit as most abundant VOO phenolic antioxidants. Several important biological properties (antioxidant, anti-inflammatory, chemopreventive and anti-cancer) and the characteristic pungent and bitter tasty properties have been attributed to VOO phenols. Relationships between polyphenols activities and their chemical structures are discussed in this paper. Received 15 April 2008; accepted 7 November 2008     

Comparison of the effects of atropine in vivo and ex vivo (radioreceptor assay) after oral and intramuscular administration to man

The effects of an oral dose of atropine (0.03 mg/kg body weight) and an IM (0.02 mg/kg) dose on the heart rate and salivary flow in seven healthy adult volunteers were compared to see whether the oral dose was sufficient to inhibit vagal reflexes of the heart. Atropine concentrations in plasma were determined by an M₂-selective radioreceptor assay, and the in vitro occupancy of porcine cardiac M₂-cholinoceptors was measured in parallel.In ligand-binding studies, atropine has been shown to have a comparable affinity for human and porcine cardiac M₂-cholinoceptors (K_i 4.0 and 5.9, respectively). Slight changes in heart rate after oral administration were not significant. After IM administration, however, the heart rate increased significantly, by a maximum of 22 beats·min^–1 after 45 min. The slight increase in heart rate after the oral dose corresponded to a receptor occupancy in vitro near the lower limit of detection, whereas the significant increase in heart rate after the IM dose corresponded to a receptor occupancy of up to 47%. The maximum reduction in salivary flow was similar after the oral and IM doses (84.3 and 87.5%, respectively).The almost complete inhibition of salivary flow could be explained by the lower vagal tone in the salivary glands compared with to the heart. The difference in the effect on heart rate was probably due to lower absorption of the oral dose. Thus, an oral dose greater than 0.03 mg atropine/kilogram body weight is required to compensate for low gastrointestinal absorption and to overcome the high vagal tone of the heart.The results form part of the thesis of T. Waldhäuser     

Effects of single oral doses of clobazam,diazepam and lorazepam on performance tasks and memory

Summary The effects on memory and psychomotor performance and the subjective effects of three anxiolytic benzodiazepines (lorazepam 2 mg, diazepam 10 mg and clobazam 20 mg p.o.) have been evaluated in a double-blind, placebo-controlled, cross-over study in 10 healthy volunteers.At each session, measurements were made prior to and +3.5 h after drug administration, except in the case of REY's test, which was presented at H+1 h (learning) and was evaluated at H+8 h and at H+24 h (delayed recall).Single clinical doses of diazepam and lorazepam caused anterograde amnesia by disturbing acquisition, consolidation and retrieval. Clobazam did not impair memory.Lorazepam impaired performances in all the tests used to evaluate perception, immediate memory, reaction time, psychomotor skill and intellectual capacity. Diazepam caused a decrease in cortical arousal and the speed of perception of visual stimuli, whereas clobazam increased reaction time and reduced cortical arousal. Lorazepam caused a significant degradation of performance relative to the other two treatments.     

Separate and combined effects of nadolol and nifedipine on the cardiac response to exercise

Summary In a placebo controlled exercise protocol using healthy volunteers the effects of nadolol 80 mg and 160 mg orally and of nadolol 80 mg during treatment with nifedipine 20 mg 8 hourly were compared. Resting systolic and diastolic blood pressures were reduced by both nifedipine (p<0.05) and nadolol (p<0.01) acting alone. An unexpected finding was that nifedipine alone significantly inhibited exercise tachycardia (p<0.01) (8 to 12 h post dose). Predictably both doses of nadolol produced significant reduction in exercise tachycardia which was still apparent at 24 h. There was a linear relationship between log₁₀ plasma nadolol concentration and reduction in exercise heart rate. The combined inhibitory effects of nifedipine and nadolol 80 mg on exercise heart rate showed partial additivity but did not summate. There was no pharmacokinetic interaction between the 2 drugs. The inhibition of exercise tachycardia by nifedipine, not previously documented, is consistent with an effect of the drug on the sinus node, as has been reported in in-vitro studies, and may contribute to the drugs efficacy in angina.     

Adoption of polymeric micelles to enhance the oral bioavailability of dexibuprofen: formulation,in-vitro evaluation and in-vivo pharmacokinetic study in healthy human volunteers

Abstract

This work aimed to incorporate Dexibuprofen (DXI), the pharmacologically active and more potent form of ibuprofen, into polymeric micelles based tablets with enhanced oral bioavailability. Thin film hydration technique was employed to prepare DXI polymeric micelles using Pluronic® F127 and/or P123 solutions in different ratios (ranging from 1:1 up to 1:10). Prepared micelles were characterized regarding particle size, drug loading and entrapment efficiency. Selected formulae were lyophilized in presence of cryoprotectants and subjected to solid-state characterization as well as scanning and transmission electron microscopy. Subsequently, tablets were prepared and evaluated in-vitro regarding physical properties and drug release. An in-vivo pharmacokinetic study was performed in six healthy human volunteers in comparison to the commercially available tablet of DXI. Solid-state characterization proved that DXI was homogenously dispersed in Pluronic micelles’ matrices. Formula TF5 tablets comprising lyophilized micelles (F5; DXI: Pluronic F127 in 1:1 ratio and 0.25% mannitol) showed higher C_max and earlier t_max values than those of the commercial formula, where the relative bioavailability was calculated to be 160.15%. The experimental evidence in this research leads to the conclusion that polymeric micelles present enabling properties for oral delivery of drugs with low solubility.     

Effects of combined exposure to pyridostigmine bromide and shaker stress on acoustic startle response, pre-pulse inhibition and open field behavior in mice

The present study investigated the effect of combined exposure of pyridostigmine bromide (PB) and chronic shaker stress on acoustic startle responses (ASR), pre-pulse inhibition (PPI) and open field behavior of adult C57BL/6J mice. PB (10 mg kg(-1) day(-1) for 7 days) or saline was administered subcutaneously using osmotic Alzet minipumps implanted under the skin on the back of the mice. At the same time, the mice were exposed to 7 days of intermittent shaker stress. They were tested for ASR (100 dB and 120 dB stimuli) and PPI (70 dB + 100 dB and 70 dB + 120 dB) in the acoustic startle monitor system. The mice were assessed during the shaker stress on days 2 and 7 and 7, 14, 21 and 28 days after discontinuation of treatment. Separate groups of mice were tested in the open field in 15 min sessions on days 1, 3 and 6 during shaker stress and PB treatment. Exposure of mice to PB resulted in an exaggerated ASR, reduced PPI and non-significant decrease in locomotor activity. These behavioral changes were apparent only during exposure to PB. Repeated shaker stress did not have any effect on sensorimotor functions or open field behavior of mice. There was no prolonged or delayed effect of PB and/or stress on individual behavioral variables. The study found C57BL/6J mice to be behaviorally sensitive to PB treatment.     

Effect of urinary pH on the plasma and urinary kinetics of remoxipride in man

Summary The influence of urinary pH on the plasma and urinary kinetics of remoxipride in man has been studied in an open crossover trial in ten healthy male volunteers. Ammonium chloride (urinary pH 5.2) and sodium hydrogen carbonate (urinary pH 7.8) were used as pretreatments on two occasions in randomized order. On each occasion remoxipride 50 mg solution was administered orally and plasma and urinary concentrations of the drug were determined by HPLC and plasma prolactin concentrations by RIA.Remoxipride was rapidly distributed in the body according to a one-compartment model. The mean plasma elimination half-life (t_1/2) was 3.6 h in the ammonium chloride experiment and 6.2 h in the sodium hydrogen carbonate experiment. The mean plasma clearance of remoxipride was 141 and 89.9 ml·min^–1 in the acidic and alkaline conditions, respectively, and the corresponding mean renal clearances were 58.5 ml·min^–1 and 11.7 ml·min^–1. The urinary excretion of remoxipride up to 72 h after drug administration was 43.1% and 12.3% following acidification and alkalinization, respectively. Remoxipride induced a similar rapid, transient elevation of plasma prolactin under both conditions.Thus, the urinary pH has a marked effect on the elimination kinetics of remoxipride. After an overdose, treatment with ammonium chloride might be valuable in hastening elimination of remoxipride from the body.