Influence of garlic powder on cutaneous microcirculation. A randomized placebo-controlled double-blind cross-over study in apparently healthy subjects

In a randomized placebo-controlled double-blind cross-over study it could be shown that 5 h after the administration of garlic powder (Kwai, Sapec; total dose of 900 mg garlic powder) a significant increase in capillary skin perfusion by 55% occurs in the healthy volunteers. Placebo did not cause any changes. The difference between the two study phases is also significant. The increased erythrocyte velocity results from vasodilation of precapillary arterioles which increases diameter of erythrocyte column by an average of 8.6%. Simultaneously inflow of interstitial fluidity accompanied by a significant decrease in haematocrit and plasma viscosity occurs (rheoregulation).     

Plethysmography and impulse oscillometry assessment of tiotropium and ipratropium bromide; a randomized, double-blind, placebo-controlled, cross-over study in healthy subjects

AIMS: Spirometry, plethysmography and impulse oscillometry (IOS) measure different aspects of lung function. These methods have not been compared for their ability to assess long- and short-acting anticholinergic agents. We therefore performed a double-blind, placebo-controlled, four-way cross-over study in 30 healthy subjects. METHODS: Single doses of tiotropium bromide (Tio) 54 and 18 mcg, ipratropium bromide (IB) 40 mcg and placebo were administered. Specific conductance (sGaw), total lung capacity (TLC), inspiratory capacity (IC) and residual volume (RV) were measured using plethysmography, while IOS measured resistance (R5-25) and reactance (RF and X5). Pulmonary function was measured for 26 h post dose. RESULTS: Tio caused significant improvements in sGaw, forced expiratory voume in 1 s (FEV(1)), maximum mid-expiratory flow (MMEF) and R5-R25 at time points up to 26 h, with no clear differences between doses. IB improved the same parameters, but only up to 8 h. The weighted mean change (0-24 h) caused by Tio 54 mcg compared with placebo for FEV(1) was 240 ml (95% confidence interval 180, 300), while for sGaw the ratio of geometric means (Tio compared with placebo) was 1.35 (1.28, 1.41). Neither drug caused consistent statistically significant changes in RF, forced vital capacity, TLC or IC over 26 h. RV was significantly improved from 8 to 24 h by Tio 54 mcg only. CONCLUSIONS: In addition to spirometry, IOS resistance measurements and sGaw can distinguish between the effects of long- and shortacting anticholinergic effects in healthy subjects.     

Naltrexone augmentation in OCD: A double-blind placebo-controlled cross-over study

Current treatments for Obsessive Compulsive Disorder (OCD) rely primarily on serotonergic mechanisms. However, approximately 30% of patients do not respond to serotonin reuptake inhibitors and remain chronically ill. Given the behavioral similarities between some of the compulsive behaviors in OCD and addiction, we hypothesized that the opioid antagonist naltrexone might attenuate compulsions in OCD as well. The effect of naltrexone augmentation to SRI was compared to placebo in 10 OCD outpatients who had not responded to an adequate dose of SSRI or clomipramine for at least 2 months. Participants underwent 5 weeks of treatment with naltrexone or placebo (and 1 week of tapering) in a randomized, double-blind, cross-over design. Patients were evaluated weekly using the Y-BOCS, CGI, HAM-A, and MADRS scales. A two-way repeated measures MANOVA revealed no significant effect for Y-BOCS. However, while receiving naltrexone, patients had significantly higher scores on CGI, MADRS and HAM-A as compared to placebo. The lack of significant findings on OC symptoms could be due to either ceiling effect or alternatively, due to a non-specific exacerbation on anxiety and depression but not on OC symptoms.     

The effect of metoclopramide on QT dynamicity: double-blind,placebo-controlled,cross-over study in healthy male volunteers

BACKGROUND: Metoclopramide, a central and peripheral dopamine type 2 receptor antagonist, has been used as an attractive and safer alternative to cisapride. However, cardiac side-effects have also been reported with this drug. AIM: To evaluate the effects of intravenous metoclopramide administration on cardiac repolarization using QT dynamicity, a reliable indicator of arrhythmic side-effects. METHODS: The effect of metoclopramide on cardiac repolarization was evaluated in 10 healthy male volunteers in the supine position. Metoclopramide (10 mg) or placebo was administered intravenously at random in a double-blind, cross-over manner to the participants during continuous electrocardiographic recording in the supine position. The 30-min stationary segments of the recordings before and after drug administration were used to investigate QT dynamicity. RESULTS: Metoclopramide administration, but not placebo, resulted in steeper QT/RR slopes compared with the pre-drug values (metoclopramide: 0.037 +/- 0.004 vs. 0.064 +/- 0.012; P = 0.041; placebo: 0.045 +/- 0.006 vs. 0.050 +/- 0.004; P = 0.563). In a two-way analysis of variance model, metoclopramide administration also increased the QT variance independently (F = 6.225, P = 0.023). CONCLUSIONS: Metoclopramide administration increases the QT/RR slope and QT variance. These findings may partly explain the underlying mechanism of ventricular arrhythmias associated with metoclopramide.     

A double-blind,placebo-controlled study of the effects of eptastigmine on scopolamine-induced cognitive deficits in healthy male subjects

This double-blind, placebo-controlled, crossover study examined the effects of two single doses of eptastigmine, a novel cholinesterase inhibitor, on scopolamine-induced cognitive deficits in 24 healthy male volunteers. Each subject received the following treatment sequences, separated by at least 1 week, in a randomly assigned order:

Randomized placebo-controlled double-blind cross-over study on antihypoxidotic effects of piracetam using psychophysiological measures in healthy volunteers

The effects of two acute doses (1600 mg, 2400 mg) of 2-oxo-pyrrolidine-1-acetamide (piracetam, Normabra?n) on hypoxia resistance were screened vs placebo in a randomized, double-blind 3-way change-over design in 9 healthy male volunteers (mean age: 26.4 +/- 3.5 years; mean body weight: 74.9 +/- 8.4 kg). Psychophysiological measurements were done with the oculodynamic test (ODT) for oculomotor, performatory and additional cardiorespiratory parameters. Intradiurnal assessments were done under normoxia (prevalue) and hypoxic hypoxidosis (1 hypoxic prevalue, 3 postdose values: 1.0, 2.5 and 4.0 h) with a content of 10.5% O2 and 89.5% N2 in inspired air (hypoxic hypoxidosis)--as a model of brain dysfunctions, related with several types of senile dementia (Primary Degenerative Dementia = Alzheimer type; Multi Infarct Dementia). The results indicate that piracetam especially in its higher dose (2400 mg) displays antihypoxidotic effects already after a single administration in oculomotor, performatory and cardiorespiratory parameters.     

Antiparkinsonian drug-induced sleepiness: a double-blind placebo-controlled study of L-dopa, bromocriptine and pramipexole in healthy subjects

AIMS

To assess the sleepiness induced by pramipexole, a D2/D3-dopamine receptor agonist commonly used in Parkinson''s disease and restless legs syndrome, without the problem of the confounding factors related to the disease.

METHODS

Placebo, bromocriptine (2.5 mg), L-dopa (100 mg) and pramipexole (0.5 mg) were administered in a single oral dose on four separate days, with at least a 2-week wash-out period in a randomized cross-over design. Induced somnolence was assessed using Multiple Sleep Latency Test (MSLT) and subjective scaling of vigilance. Twelve male subjects (26.3 ± 5.5 years old) without anxiety, mood, sleep or sedation disorders were enrolled.

RESULTS

Pramipexole significantly reduced mean sleep latency compared with placebo 3 h 30 min [−6.1 min (−9.8, −2.4), P = 0.002] and 5 h 30 min [−5.6 min (−7.7, −3.5), P = 0.003] after administration. In addition, the total duration of sleep during the tests was higher with pramipexole than with placebo [+6.0 min (2.3, 9.7), P < 0.001]. These differences were not observed with L-dopa and bromocriptine in comparison with placebo. The induced sleepiness was not associated with an increase in subjective somnolence scaling, indicating that this adverse event may occur without prior warning.

CONCLUSIONS

These results show that a single oral dose of pramipexole induces sleepiness as assessed by MSLT in healthy young subjects, independent of disease-related sleep dysfunction.     

Endoscopic study of gastric tolerance of paracetamol and acetylsalicylic acid. A placebo-controlled double-blind study on healthy subjects

Endoscopic Studies on the Gastric Tolerance of Paracetamol and Acetylsalicylic Acid/A placebo-controlled double-blind study in healthy volunteers. In placebo-controlled randomized double-blind cross-over fashion the gastric and duodenal tolerance of 1000 mg acetylsalicylic acid (ASA; as a commercially available preparation and 1000 mg paracetamol (Tylenol) were directly compared in 12 healthy volunteers. An endoscopic evaluation of the gastric and duodenal mucosa was performed. 1000 mg ASA evoked a lesion score of 2.5 whereas 1000 mg paracetamol and placebo displayed a score of 1.0 and 0.92, respectively. This difference between paracetamol and ASA reached a statistical significance. Based on the comparable analgetic potency of both compounds and the apparently better gastro-duodenal tolerability paracetamol is the drug of choice when a non-inflammatory problem requires an analgesic.     

Nutcracker oesophagus: a double-blind, placebo-controlled, cross-over study of the effects of lansoprazole

BACKGROUND: Nutcracker oesophagus is characterized by high-amplitude oesophageal contractions. Recent data have shown a high prevalence of gastro-oesophageal acid reflux in patients with nutcracker oesophagus and, in open-label trials, patients seemed to benefit from acid suppression. Therefore, it has been suggested that non-cardiac chest pain in patients with nutcracker oesophagus may be related to reflux rather than to the motor abnormality itself. AIMS: To investigate the effect of intensive acid-suppressive treatment on chest pain in patients with nutcracker oesophagus. METHODS: Nineteen patients with nutcracker oesophagus received lansoprazole or placebo in a double-blind, randomized, cross-over study. RESULTS: Significant reductions in pain intensity (P < 0.006) and pain duration (P < 0.05) were registered during the study. The magnitude of symptom relief achieved with lansoprazole did not differ significantly from that achieved with placebo. The motility pattern did not change during the study. CONCLUSIONS: This study does not prove that acid-suppressive therapy is effective for pain relief in nutcracker oesophagus. As the amelioration of pain was not accompanied by any change in the nutcracker oesophagus pattern, it is unlikely that the high-amplitude oesophageal contractions are the cause of pain. Thus, the possible role of acid in the pathophysiology of pain in nutcracker oesophagus needs further study.     

Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects

Growing interest has been seen in using lysergic acid diethylamide (LSD) in psychiatric research and therapy. However, no modern studies have evaluated subjective and autonomic effects of different and pharmaceutically well-defined doses of LSD. We used a double-blind, randomized, placebo-controlled, crossover design in 16 healthy subjects (eight women, eight men) who underwent six 25 h sessions and received placebo, LSD (25, 50, 100, and 200 µg), and 200 µg LSD 1 h after administration of the serotonin 5-hydroxytryptamine-2A (5-HT_2A) receptor antagonist ketanserin (40 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 24 h. The pharmacokinetic-subjective response relationship was evaluated. LSD showed dose-proportional pharmacokinetics and first-order elimination and dose-dependently induced subjective responses starting at the 25 µg dose. A ceiling effect was observed for good drug effects at 100 µg. The 200 µg dose of LSD induced greater ego dissolution than the 100 µg dose and induced significant anxiety. The average duration of subjective effects increased from 6.7 to 11 h with increasing doses of 25–200 µg. LSD moderately increased blood pressure and heart rate. Ketanserin effectively prevented the response to 200 µg LSD. The LSD dose–response curve showed a ceiling effect for subjective good effects, and ego dissolution and anxiety increased further at a dose above 100 µg. These results may assist with dose finding for future LSD research. The full psychedelic effects of LSD are primarily mediated by serotonin 5-HT_2A receptor activation.Subject terms: Drug development, Pharmacology, Human behaviour     

Differential effects of escitalopram on attention: a placebo-controlled, double-blind cross-over study

Rationale

The role of serotonin (5-HT) in attention is not fully understood yet.

Objective

We aimed to investigate whether attention is modulated after treatment with escitalopram, a selective serotonin reuptake inhibitor (SSRI).

Methods

We administered 10 mg of escitalopram to 20 healthy subjects in a placebo-controlled, double-blind cross-over design for 1 day or to another 20 participants for a period of 7 days. Attention was assessed at time of plasma peak escitalopram concentration using the computerised Attention Network Test (ANT), which is a combined flanker and cued reaction time task.

Results

The results showed differential effects of serotonergic manipulation on attention depending on sequence of intake. For the acute treatment, we found significant differences between escitalopram and placebo for all warning conditions dependent of sequence of intake: participants receiving escitalopram as first treatment showed significant slower reaction times in all warning conditions as compared with placebo while participants receiving escitalopram as second treatment showed significant faster reaction times as compared with placebo. For the sub-chronic treatment, we found significant differences between escitalopram and placebo depending on sequence of intake, but only for the flanker condition: participants receiving escitalopram first had significant slower reaction times in incongruent trials with escitalopram as compared with placebo while participants starting with placebo had significant shorter reaction times in incongruent trials with escitalopram.

Conclusions

Thus, the results showed a differential effect of escitalopram in cognition, especially in attention, and are discussed with regard to an interaction between serotonin and familiarity with the attention test.     

A double-blind, placebo-controlled study on the effects of Gotu Kola (Centella asiatica) on acoustic startle response in healthy subjects

Investigations of the pharmacologic profile of medicinal plants have revealed that a number of plants with purported anxiolytic activity bind to cholecystokinin (CCK) receptors. This finding is intriguing in view of the proposed involvement of CCK in the pathophysiology of fear and anxiety. This double-blind, placebo-controlled study was undertaken to evaluate the anxiolytic activity of Gotu Kola (Centella asiatica) in healthy subjects. Gotu Kola has been used for centuries in Ayurvedic and traditional Chinese medicine to alleviate symptoms of depression and anxiety. Recent studies in the rat have shown that long-term pretreatment with Gotu Kola decreases locomotor activity, enhances elevated-plus maze performance, and attenuates the acoustic startle response (ASR). In this study, the authors evaluated the effects of Gotu Kola on the ASR in humans. Subjects were randomly assigned to receive either a single 12-g orally administered dose of Gotu Kola (N = 20) or placebo (N = 20). The results revealed that compared with placebo, Gotu Kola significantly attenuated the peak ASR amplitude 30 and 60 minutes after treatment. Gotu Kola had no significant effect on self-rated mood, heart rate, or blood pressure. These preliminary findings suggest that Gotu Kola has anxiolytic activity in humans as revealed by the ASR. It remains to be seen whether this herb has therapeutic efficacy in the treatment of anxiety syndromes.     

Amisulpride treatment of clozapine-induced hypersalivation in schizophrenia patients: a randomized, double-blind, placebo-controlled cross-over study

The beneficial effect of sulpiride augmentation of clozapine therapy for treatment-resistant schizophrenia patients is enhanced by its antisalivatory effect on clozapine-induced hypersalivation (CIH). Amisulpride, similar to sulpiride, is a substitute benzamide derivative with higher selective binding to the D2/D3 dopamine receptor. We hypothesized that add-on amisulpride would also be beneficial in controlling CIH. In a randomized, double-blind, placebo-controlled cross-over study, 20 clozapine-treated schizophrenia (DSM-IV criteria) inpatients with CIH were randomly initially assigned to add-on amisulpride (nine patients; 400 mg/day up-titrated from 100 mg/day over 1 week) or placebo (11 patients). Primary outcome was change in the five-point Nocturnal Hypersalivation Rating Scale (NHRS). Other measures included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression scale (CGI) and Simpson-Angus Scale (SAS). Mean NHRS indices were considerably lower with amisulpride (1.79 +/- 1.25) than with placebo (2.63 +/- 1.33) [F(1,38) = 5.36, P < 0.05]. With amisulpride treatment, there was a significant improvement on the negative symptoms subscale of the PANSS [F(3,57) = 3.76, P < 0.05], but not on the SAS, CGI or other subscales of the PANSS (all F < 1). Short-term amisulpride augmentation has a strong ameliorating effect on CIH. A long-term, large-scale study with a broader dose range is warranted to evaluate the stability of this effect across time.     

Nicotine and behavioral markers of risk for schizophrenia: a double-blind, placebo-controlled, cross-over study.

We investigated the effect of nicotine on three behavioral markers of risk for schizophrenia: sustained attention (using the Continuous Performance Task (CPT)), antisaccade performance, and smooth pursuit. Smooth pursuit was investigated in two conditions, one in which attention was enhanced (monitoring target changes) and one in which attention was not enhanced (no monitoring). Patients with schizophrenia (n = 15) and controls (n = 14) were given a 14-mg nicotine patch in a double-blind, placebo-controlled, crossover design and plasma nicotine concentrations were monitored. Nicotine concentrations were similar in both groups. A Group x Drug interaction (p <.02) on CPT hits indicated that nicotine improved sustained attention in patients but not in controls. Nicotine significantly decreased antisaccade errors (p <.01) in both groups. A Drug x Monitoring condition interaction (p <.01) on pursuit gain indicated that nicotine significantly increased pursuit gain in the no-monitoring condition in patients and controls equally, but did not improve pursuit in the monitoring condition. Thus, improvement in pursuit may have been mediated via an effect on attention rather than by an effect on oculomotor function per se. In patients, the magnitude of improvement in attention on nicotine was correlated with the improvement on eye movement tasks. Thus, nicotine improves performance on both attention and oculomotor markers of risk for schizophrenia, possibly via common mechanisms.     

Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects

Growing interest has been seen in using lysergic acid diethylamide (LSD) and psilocybin in psychiatric research and therapy. However, no modern studies have evaluated differences in subjective and autonomic effects of LSD and psilocybin or their similarities and dose equivalence. We used a double-blind, randomized, placebo-controlled, crossover design in 28 healthy subjects (14 women, 14 men) who underwent five 25 h sessions and received placebo, LSD (100 and 200 µg), and psilocybin (15 and 30 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics. The doses of 100 and 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. The 15 mg psilocybin dose produced clearly weaker subjective effects compared with both doses of LSD and 30 mg psilocybin. The 200 µg dose of LSD induced higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 µg dose. The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin. LSD at both doses had clearly longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. However, both LSD and psilocybin showed comparable cardiostimulant properties, assessed by the rate-pressure product. Both LSD and psilocybin had dose-proportional pharmacokinetics and first-order elimination. Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. Any differences between LSD and psilocybin are dose-dependent rather than substance-dependent. However, LSD and psilocybin differentially increased heart rate and blood pressure. These results may assist with dose finding for future psychedelic research.Trial registration: ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT03604744","term_id":"NCT03604744"}}NCT03604744Subject terms: Drug development, Human behaviour     

A phase I multiple-dose escalation study characterizing pharmacokinetics and safety of ABT-578 in healthy subjects

ABT-578, a sirolimus analog, is being developed for administration from drug-eluting stents to prevent postimplantation neointimal hyperplasia. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of multiple doses of ABT-578. Healthy subjects randomly received placebo or ABT-578 (200, 400, or 800 microg) as daily intravenous infusions for 14 days. ABT-578 blood pharmacokinetics and urine excretion on days 1 and 14 were determined. The effect of ABT-578 on mitogen-stimulated lymphocyte proliferation was assessed. ABT-578 pharmacokinetics was described by a 3-compartment open model. The mean CL, V(ss), and t(1/2) ranges were 4.0 to 4.6 L/h, 92.5 to 118.0 L, and 24.7 to 31.0 hours, respectively. ABT-578 pharmacokinetics was dose and time invariant. Approximately 0.1% of ABT-578 was excreted in the urine. ABT-578 was well tolerated, and no systemic changes were observed in the mitogen-stimulated lymphocyte proliferation. ABT-578 was shown to be safe over a wide range of systemic exposures.     

Ritanserin versus lorazepam: a double-blind, cross-over study of reaction times in healthy volunteers

Ritanserin, a benzydrilen-piperidine derivative, with a potent, selective and long-lasting antagonist activity on serotonin type 2 receptors, has shown anxyolitic properties and a lesser sedative profile than benzodiazepines. Ritanserin and lorazepam at therapeutical doses, were compared in eight healthy volunteers in a double-blind, cross-over study in order to detect possible different impairments of performances. Before and during the treatment, all subjects were daily submitted to a test of rapidity and regularity of response to acoustic and visual stimuli by means of an electronic device. A visual analogue scale for the self-assessment of the drowsiness degree was also administered. Ritanserin did not modify reaction times, while lorazepam significantly prolonged them. The analysis of data within treatments significantly favoured ritanserin, while between treatments there was only a trend in favour of ritanserin. The analogical scale for concentration showed a significant reduction with lorazepam, whereas for drowsiness no alteration occurred with either drug.     

Delay of ovulation by meloxicam in healthy cycling volunteers: A placebo-controlled, double-blind, crossover study

This study aimed to assess the effect of meloxicam on female ovulation. Twenty consented fertile females were monitored for 4 menstrual cycles: a baseline cycle, 2 treatment cycles, and a washout cycle between treatment cycles. In the first cycle visit, transvaginal ultrasound was performed, a blood sample for progesterone and meloxicam analysis was withdrawn, and volunteers were given a luteinizing hormone (LH) urine test kit and meloxicam or placebo. Volunteers started the treatment on the following day and asked to return the day the LH kit was positive to detect the dominant follicle. At subsequent visits, transvaginal ultrasound and progesterone and meloxicam levels were investigated. Compared to placebo, a 5-day delay in follicle rupture, a 55.7% increase in the mean maximum follicle diameter, and 33.5% decrease of plasma progesterone level were observed in the meloxicam-treated group. Such demonstrated meloxicam effects were reversed in participants who were randomized to meloxicam first and then placebo. Only minor side effects were reported by volunteers during the course of treatment. It is concluded that meloxicam resulted in a reversible delay of ovulation, an increase in follicular diameter, and a decrease in plasma progesterone level.     

Therapeutic effect of pirenzepine for clozapine-induced hypersalivation: a randomized, double-blind, placebo-controlled, cross-over study.

The objective of this study was to investigate the efficacy of pirenzepine in the treatment of clozapine-induced hypersalivation. Pirenzepine is reported to counteract hypersalivation by its selective antagonistic activity on the M4-muscarinic receptor, which is stimulated by clozapine. Twenty patients with clozapine-induced hypersalivation underwent a random-order, double-blind, placebo-controlled, cross-over trial which lasted 8 weeks each for the pirenzepine and placebo investigations, with a 4-week washout period in between. The severity of hypersalivation was assessed using an objective measure: saliva production monitored through the diameter of wetted surface on tissue paper placed over the patient's pillow. Our study showed that pirenzepine had no significant therapeutic effect on hypersalivation compared with placebo, suggesting that hypersalivation induced by clozapine might have a neurobiological basis other than the M4-muscarinic receptor.     

Single- and multiple-dose pharmacokinetics of nufenoxole in healthy human subjects

1. In 12 healthy subjects, after single doses of 20, 40 and 80 mg of nufenoxole, mean peak plasma drug concentrations of 400, 815 and 1463 ng/ml were reached at 2.2, 2.5 and 2.5 h respectively. 2. Nufenoxole was absorbed with an apparent half-life of less than one hour at all three doses. Nufenoxole concentrations declined biphasically after the peak, with an initial and terminal half-life of four to five hours and about 27 h respectively. These half-lives were independent of the administered dose. 3. AUC and Cmax increased with increasing dose, but AUC did not increase proportionately to dose, due to a lower value for 80 mg than expected, possibly reflecting reduced absorption. 4. Observed nufenoxole concentrations, in another 12 healthy subjects receiving single, daily 80 mg oral doses of nufenoxole for eight days, were in excellent agreement with those predicted from single-dose pharmacokinetics.