Comparative physiology and efficacy of atropine and scopolamine in sarin nerve agent poisoning.

Anticholinergic treatment is key for effective medical treatment of nerve agent exposure. Atropine is included at a 2 mg intramuscular dose in so-called autoinjectors designed for self- and buddy-aid. As patient cohorts are not available, predicting and evaluating the efficacy of medical countermeasures relies on animal models. The use of atropine as a muscarinic antagonist is based on efficacy achieved in studies in a variety of species. The dose of atropine administered varies considerably across these studies. This is a complicating factor in the prediction of efficacy in the human situation, largely because atropine dosing also influences therapeutic efficacy of oximes and anticonvulsants generally part of the treatment administered. To improve translation of efficacy of dosing regimens, including pharmacokinetics and physiology provide a promising approach. In the current study, pharmacokinetics and physiological parameters obtained using EEG and ECG were assessed in naïve rats and in sarin-exposed rats for two anticholinergic drugs, atropine and scopolamine. The aim was to find a predictive parameter for therapeutic efficacy. Scopolamine and atropine showed a similar bioavailability, but brain levels reached were much higher for scopolamine. Scopolamine exhibited a dose-dependent loss of beta power in naïve animals, whereas atropine did not show any such central effect. This effect was correlated with an enhanced anticonvulsant effect of scopolamine compared to atropine. These findings show that an approach including pharmacokinetics and physiology could contribute to improved dose scaling across species and assessing the therapeutic potential of similar anticholinergic and anticonvulsant drugs against nerve agent poisoning.

Electrochemiluminescent sensors as a screening strategy for psychoactive substances within biological matrices.

With the rapid growth and appearance of novel psychoactive substances (NPS) onto the global drug market, the need for alternative screening methodologies for implementation within clinical environments is substantial. The immunoassay methods currently in use are inadequate for this new drug trend with the potential for misdiagnosis and subsequent administration of incorrect patient treatment increased. This contribution illustrates a strong proof-of-concept for the use of electrochemiluminescence (ECL) as a screening methodology for NPS within biological fluids, using the hallucinogen scopolamine as a model compound. A low cost, easy-to-use and portable sensor has been developed and successfully employed for the detection of scopolamine at clinically relevant concentrations within a variety of biological matrices, including human pooled serum, urine, artificial saliva and sweat, without any prior sample preparation required. Moreover, assessment of the sensor's potential as a point-of-care wearable device was performed with sample collection from the surface of skin, demonstrating its capability for the qualitative identification of scopolamine despite collection of only minimal volumes off the skins surface. The developed sensor described herein exhibits a strong proof-of-concept for the employment of such ECL sensors as point-of-care devices, where the sensors ease of use and removal of time-consuming and complex sample preparation methods will ultimately increase its usability by physicians, widening the avenues where ECL sensors could be employed.

Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects.

AIM: Subjects with increasing age are more sensitive to the effects of the anti-muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in early phase drug studies with cognition enhancing compounds. The enhanced sensitivity has always been attributed to incipient cholinergic neuronal dysfunction, as a part of the normal aging process. The aim of the study was to correlate age-dependent pharmacodynamic neuro-physiologic effects of scopolamine after correcting for differences in individual exposure. METHODS: We applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects. RESULTS: A two-compartment linear kinetics model best described the plasma concentrations of scopolamine. The estimated scopolamine population mean apparent central and peripheral volume of distribution was 2.66 ± 1.050 l and 62.10 ± 10.100 l, respectively and the clearance was 1.09 ± 0.096 l min(-1) . Age was not related to a decrease of performance in the tests following scopolamine administration in older subjects. Only the saccadic peak velocity showed a positive correlation between age and sensitivity to scopolamine. Age was, however, correlated at baseline with an estimated slower reaction time while performing the cognitive tests and to higher global δ and frontal θ frequency bands measured with the surface EEG. CONCLUSIONS: Most of the differences in response to scopolamine administration between young and older subjects could be explained by pharmacokinetic differences (lower clearance) and not to an enhanced sensitivity when corrected for exposure levels.

Simultaneous determination of atropine, scopolamine, and anisodamine from Hyoscyamus niger L. in rat plasma by high-performance liquid chromatography with tandem mass spectrometry and its application to a pharmacokinetics study.

In order to investigate the pharmacokinetics of tropane alkaloids in Hyoscyamus niger L., a sensitive and specific high-performance liquid chromatography with tandem mass spectrometry method for the simultaneous determination of atropine, scopolamine, and anisodamine in rat plasma is developed and fully validated, using homatropine as an internal standard. The separation of the four compounds was carried out on a BDS Hypersil C18 column using a mobile phase consisting of acetonitrile and water (containing 10 mmol ammonium acetate). Calibration curves were linear from 0.2 to 40 ng/mL for atropine, scopolamine, and from 0.08 to 20 ng/mL for anisodamine. The precision of three analytes was <5.89% and the accuracy was between -1.04 to 2.94%. This method is successfully applied to rat pharmacokinetics analysis of the three tropane alkaloids after oral administration of H. niger extract. The maximum concentration of these three tropane alkaloids was reached within 15 min, and the maximum concentrations were 31.36 ± 7.35 ng/mL for atropine, 49.94 ± 2.67 ng/mL for scopolamine, and 2.83 ± 1.49 ng/mL for anisodamine. The pharmacokinetic parameters revealed areas under the curve of 22.76 ± 5.80, 16.80 ± 3.08, and 4.31 ± 1.21 ng/h mL and mean residence times of 2.08 ± 0.55, 1.19 ± 0.45, and 3.28 ± 0.78 h for atropine, scopolamine, and anisodamine, respectively.

[Pharmacokinetics of scopolamine hydrobromide oral disintegrative microencapsule tablets in Beagle dogs determined with LC-MS/MS].

The study aims to elucidate the characteristics of pharmacokinetics of scopolamine hydrobromide oral disintegrative microencapsule tablets in healthy Beagle dogs. Chromatographic separation was performed on a C18 column (100 mm x 3.0 mm, 3.5 microm) with methanol - 2 mmol x L(-1) ammonium formate (25 : 75) as the mobile phase. A trip-quadrupole tandem mass spectrum with the electrospray ionization (ESI) source was applied and positive ion multiple reaction monitoring mode was operated. Six Beagle dogs were randomly devided into two groups. They received oral single dose of scopolamine hydrobromide oral disintegrative microencapsule tablets 0.6 mg (test tablet) or scopolamine hydrobromide normal tablets (reference tablet). Plasma samples were collected at designed time. Plasma concentration of scopolamine hydrobromide was determined by LC-MS/MS and pharmacokinetic parameters were calculated. The pharmacokinetic parameters of test tablet vs reference tablet were as follows: C(max): (8.16 +/- 0.67) ng x mL(-1) vs (3.54 +/- 0.64) ng x mL(-1); t1/2: (2.83 +/- 0.45) h vs (3.85 +/- 0.82) h; t(max): (1.25 +/- 0.27) h vs (0.42 +/- 0.09) h; AUC(0-12h): (25.06 +/- 3.75) h x ng x mL(-1) vs (9.59 +/- 1.02) h x ng x mL(-1); AUC(0-infinity): (26.30 +/- 3.92) h x ng x mL(-1) vs (10.80 +/- 1.45) h x ng x mL(-1); MRT(0-12h): (3.38 +/- 0.34) h vs (3.86 +/- 0.26) h; MRT(0-infinity): (3.98 +/- 0.63) h vs (5.37 +/- 1.00) h. The absorption rate and AUC of test tablet is different from that of reference tablet. The bioavailability of test tablet is better than those of reference tablet.

The efficacy of low-dose intranasal scopolamine for motion sickness.

INTRODUCTION: Scopolamine is an effective motion sickness prophylactic, but oral and transdermal formulations are slowly absorbed. To enhance absorption and potentially efficacy, an intranasal formulation of scopolamine (INSCOP) was tested. METHOD: There were 16 motion sickness susceptible subjects with an average age of 23.5 +/- 3.0 yr and an average score of 11.3 +/- 4.7 on the Modified Motion Sickness Susceptibility Questionnaire-Short Form who volunteered to participate in the study. Each subject was given 0.4 mg of INSCOP and a placebo in a randomized, double-blind crossover design and, at 40 min post-dose, experienced Coriolis cross-coupling in a staircase progression until moderate nausea. Efficacy data and cognitive, physiological, and alertness assessments were collected during baseline control and throughout experimental testing. RESULTS: Intranasal scopolamine significantly increased the mean number of head movements tolerated [INSCOP 275.9 +/- 120.5, Placebo 230.7 +/- 76.4; t (15) = 2.21]. Estimation of medication absorption via plasma concentration indicated the drug was absorbed relatively rapidly to measurable levels by 15 min post-administration. Diastolic blood pressures and heart rate were significantly lower after administration of INSCOP compared to placebo. No significant cognitive or medication side effects were reported. Subjects reported no significant decrease in alertness as indicated by the Karolinska Sleepiness Scale. CONCLUSIONS: Results of the current study strongly suggest that intranasal scopolamine is efficacious for the treatment of motion sickness in susceptible individuals with no significant cognitive or sedative effects. Intranasal delivery offers a promising alternative for use in dynamic operational environments without cognitive detriment or increased side effects.

Validation of a liquid chromatographic/tandem mass spectrometric method for the determination of scopolamine butylbromide in human plasma: application of the method to a bioequivalence study.

A sensitive and specific LC/MS/MS method was developed and validated for the determination of scopolamine butylbromide in human plasma. Scopolamine butylbromide and propanolol (internal standard) were extracted from the plasma by liquid-liquid extraction with dichloromethane as the extraction solvent and separated on a C18 analytical column (50 x 4.6 mm id) maintained at 40 degrees C. The analytes were eluted at a constant flow rate of 0.45 mL/min; the mobile phase consisted of acetonitrile and a buffer of 5 mM ammonium acetate and 0.1% formic acid (60 + 40, v/v). The mass spectrometer, equipped with an electrospray source in the positive ionization mode, was set up in the multiple-reaction monitoring mode to monitor the transitions m/z 360.6 > 102.5 (scopolamine butylbromide) and m/z 259.7 > 115.6 (propanolol). The chromatographic separation was obtained within 2.0 min, and the responses were linear over the concentration range of 0.10-40.00 ng/mL. The mean extraction recoveries of scopolamine butylbromide and propanolol from plasma were 69.00 and 80.76%, respectively. Method validation parameters, such as specificity, linearity, precision, accuracy, and stability, were within the acceptable range. Moreover, when the proposed method was successfully applied to a pharmacokinetic study of healthy human volunteers, the results showed that the two scopolamine butylbromide formulations tested are not bioequivalent in rate and extent of absorption.

Evaluation of two scopolamine and physostigmine pretreatment regimens against nerve agent poisoning in the dog.

Currently, there is no viable protection against chemical warfare agents for the working dog. Physostigmine (PHY) and scopolamine (SCO) have been shown to protect dogs against nerve agents with minimal side effects. The goal of this study was to investigate whether reported protective SCO/PHY plasma concentrations of 0.2 and 0.7 ng/mL, respectively, could be reached and maintained with minimal side-effects thereby identifying possible pretreatment regimens. Two continuous regimens of SCO/PHY were administered to beagle dogs. The first regimen consisted of administering transdermal SCO and intraocular PHY, the second consisted of transdermal SCO and rectal PHY. SCO/PHY plasma concentrations for each regimen were determined, individual protective times were calculated and a computerized pharmacokinetic analysis was performed. The results showed transdermal SCO and intraocular PHY routes of delivery achieved sustained protective drug concentrations with minimal side-effects and the rectal route of delivery did not. Group median protective times for the first regimen were 54.45 h for SCO and 64.35 h for PHY, and for the second regimen 63.75 h for SCO and 0 h for PHY. The combined transdermal patch and intraocular regimen may provide a safe and effective regimen against nerve agent poisoning in dogs.

Development and validation of a sensitive LC-MS/MS method for the estimation of scopolamine in human serum.

Scopolamine is an anticholinergic alkaloid that is widely used in the form of a transdermal system to manage nausea associated with motion sickness. Currently available methods to quantify scopolamine require large sample volumes and involve cumbersome sample preparation. In this work, a simple method for the rapid separation and sensitive quantification of scopolamine in human serum was developed. Scopolamine was extracted from 0.5 mL of human serum using solid-phase extraction. The extracted samples were injected onto Zorbax XDB-C18 column (4.6 × 50 mm, 1.8 µm, and 600 bar) on an Agilent 1200 series HPLC. The chromatographic separation involved gradient elution with water and acetonitrile containing 0.1% v/v formic acid as a mobile phase. The samples were quantified in positive ion mode using a TSQ Quantum triple quadrupole mass spectrometer. The assay was validated and found to be linear over a concentration range of 5-5000 pg/mL. The total assay precision and accuracy was 6.3% and 96%, respectively. The lower limit of quantification (LLOQ) of the assay was 5 pg/mL. The assay was used in a human pharmacokinetic study to measure the concentration of scopolamine in serum after an administering scopolamine as transdermal delivery system or as an intravenous bolus dose.

Liquid chromatography-electrospray ionization ion trap mass spectrometry for analysis of in vivo and in vitro metabolites of scopolamine in rats.

In vivo and in vitro metabolism of scopolamine is investigated using a highly specific and sensitive liquid chromatography-mass spectrometry (LC-MSn) method. Feces, urine, and plasma samples are collected individually after ingestion of 55 mg/kg scopolamine by healthy rats. Rat feces and urine samples are cleaned up by a liquid-liquid extraction and a solid-phase extraction procedure (C18 cartridges), respectively. Methanol is added to rat plasma samples to precipitate plasma proteins. Scopolamine is incubated with homogenized liver and intestinal flora of rats in vitro, respectively. The metabolites in the incubating solution are extracted with ethyl acetate. Then these pretreated samples are injected into a reversed-phase C18 column with mobile phase of methanol-ammonium acetate (2 mM, adjusted to pH 3.5 with formic acid) (70:30, v/v) and detected by an on-line MSn system. Identification and structural elucidation of the metabolites are performed by comparing their changes in molecular masses (DeltaM), retention-times and full scan MSn spectra with those of the parent drug. The results reveal that at least 8 metabolites (norscopine, scopine, tropic acid, aponorscopolamine, aposcopolamine, norscopolamine, hydroxyscopolamine, and hydroxyscopolamine N-oxide) and the parent drug exist in feces after administering 55 mg/kg scopolamine to healthy rats. Three new metabolites (tetrahydroxyscopolamine, trihydroxy-methoxyscopolamine, and dihydroxy-dimethoxyscopolamine) are identified in rat urine. Seven metabolites (norscopine, scopine, tropic acid, aponorscopolamine, aposcopolamine, norscopolamine, and hydroxyscopolamine) and the parent drug are detected in rat plasma. Only 1 hydrolyzed metabolite (scopine) is found in the rat intestinal flora incubation mixture, and 2 metabolites (aposcopolamine and norscopolamine) are identified in the homogenized liver incubation mixture.

[Acute Datura stramonium poisoning in an emergency department]. / Intoxications aiguës à Datura stramonium aux urgences.

BACKGROUND: The toxic effects of Datura stramonium most often include visual and auditory hallucinations, confusion and agitation. Severe and even fatal complications (coma, respiratory distress or death in more than 5% of cases) are not rare since the lethal concentration of the drug's toxic substances (i.e., atropine and scopolamine) is close to the level at which delirium occurs. CASES: A 17-year-old man was admitted to our emergency department with agitation, delirium with persecutory ideation and frightening hallucinations of being assaulted by animals. Blood samples taken 12 hours after Datura stramonium ingestion and analyzed with liquid chromatography and mass spectrometry (LC-MS/MS) found 1.7 ng/mL of atropine, close to the lethal level. After restraint and treatment with the antipsychotic drug cyamemazine, the young man returned to normal 36 hours after drug ingestion. A 17-year-old woman was admitted to our emergency department after losing consciousness on a public thoroughfare. At the emergency department, 2 hours after she had ingested Datura stramonium, she was agitated, with delirium, anxiety, and frightening visual and tactile hallucination of green turtles walking on her as well as auditory hallucinations. Blood samples at D0, D1 and D2 after Datura stramonium ingestion, analyzed with LC-MS/MS, found: 1.4, 1.0, and 0.2 ng/mL of scopolamine, respectively. Atropine was massively eliminated in urine on D1 (114 ng/mL). After restraint and cyamemazine treatment, the young woman returned to normal 40 hours after she had first ingested this hallucinogen. DISCUSSION: These cases of intoxication with Datura stramonium are, to our knowledge, the first clinical reports correlated with toxicologic analysis by the reference method (LC-MS/MS) in an emergency setting. Since neither the drug-users nor those accompanying them usually volunteer information about drug use, it is important to consider this specific risk in cases of agitation and confusion in adolescents or young adults.

[Toxicological analysis of a case of Datura stramonium poisoning].

We encountered a patient in a restless excitable state after eating boiled jimson weed grown in the patient's garden. The patient mistook the weed for Angelica keiskei. Pupillary dilation (7/7mm), weak light reflex, body temperature of 37 degrees C, respiratory frequency of 19/min, blood pressure of 138/88 mmHg, pulse rate of 108/min, and hot feeling were observed. No abnormalities nor special findings were detected by general examination of the peripheral blood, biochemical examination of the blood, general examination of the urine, or electrocardiography. Atropine and scopolamine, which are tropane alkaloids, were detected by the GC/MS. The retention time of atropine-TMS was 17.0 min, and the mass spectra were m/z 124, 82, and 140. The retention time of scopolamine-TMS was 17.7 min, and the mass spectra were m/z 138, 108, 154 and 375. At the time of consultation, the serum concentrations of atropine and scopolamine were 31.3 ng/ml, and 30.6 ng/ml, respectively, and decreased to 6.7 ng/ml and 8.5 ng/ml, respectively, after 2 hours. The patient underwent injection of activated carbon after gastrolavage with 2,000 ml warm water, and neostigmine was administered. The patient awoke the following morning, and was discharged with mild pupillary dilation 2 days after poisoning.

Pharmacokinetics and pharmacodynamics of a novel Acetylcholinesterase Inhibitor, DMNG-3.

DMNG-3(3ß-Methyl-[2-(4-nitrophenoxy)ethyl]-amino]con-5-enine), is a new and the potentially most potent acetylcholinesterase inhibitor recently obtained from conessine by N-demethylation and nucleophilic substitution reaction. In the present study, a step-down passive avoidance test was used to investigate whether DMNG-3 could modulate impairment of learning and memory induced by scopolamine, and a high performance liquid chromatography(HPLC) method for the determination of DMNG-3 in biological samples was applied to study its pharmacokinetics and tissues distribution. Separation was achieved on C18 column using a mobile phase consisting methanol-water (70:30, v/v) at a flow rate of 1.0ml/min. The intra- and inter-day precisions were good and the RSD was all lower than 1.30%. The mean absolute recovery of DMNG-3 in plasma ranged from 88.55 to 96.45 %. Our results showed oral administration of DMNG-3(10,25,50 mg/kg/day) can significantly improve the latency and number of errors and had a positive effect of improvement of learning and memory in mice in passive avoidance tests. The elimination half-life (T1/2) was 14.07±1.29, 15.87±1.03h, and the total clearance (CL) values were 0.70±0.11, 0.78±0.13 L/h/kg, respectively. The pharmacokinetic studies showed that DMNG-3 has a slowly clearance and large distribution volume in experimental animals, and its disposition is linear over the range of doses tested. The liver, small intestine, stomach, and large intestine were the major distribution tissues of DMNG-3 in mice. It was found that DMNG-3 could be detected in brain, suggesting that DMNG-3 can cross the blood-brain barrier. The present study shows that DMNG-3 can be possible developed as a new drug for the treatment of Alzheimer's disease in the future.

Pharmacokinetics of scopolamine in serum and subcutaneous adipose tissue in healthy volunteers.

OBJECTIVE: The objective was to develop a microdialysis set-up to measure the concentration-time course of scopolamine in the interstitium of subcutaneous adipose tissue. MATERIALS AND METHODS: Six healthy male volunteers were eligible for data analysis. Subjects received 0.5 mg scopolamine as a 15-minute intravenous infusion. Microdialysis samples from interstitial space fluid of subcutaneous adipose tissue and blood samples were taken at predefined intervals over a period of 360 minutes. Scopolamine concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS). RESULTS: High inter-individual variability was observed in all pharmacokinetic parameters. The mean peak serum concentration (C(max)) of 6.5 +/- 3.9 ng/ml (data in mean +/- SD) was attained after 15 +/- 3 minutes (t(max)), whereas in dialysate, a mean peak concentration of 2.7 +/- 1.7 ng/ml was measured after 27 +/- 8 minutes. The ratio of the area under the concentration versus time curve from 0-360 min for interstitium (AUC(interstitium 0-360 min0) to the AUC for serum (AUC(serum 0-360 min)) was 0.96 +/- 0.7. The elimination half-life of scopolamine was 121 +/- 85 minutes in serum and 166 +/- 117 minutes in dialysate. Values for total clearance and volume of distribution in serum were 99.1 +/- 35.0 1/h and 188 +/- 76 1, respectively. CONCLUSIONS: In the present study, we were able to define a microdialysis set-up, which allows for the measurement of scopolamine concentrations in target tissues. In addition, we demonstrated that the concentrations of scopolamine in subcutaneous adipose tissue resemble closely the concentration-time course in serum of healthy volunteers.

Dose escalation pharmacokinetics of intranasal scopolamine gel formulation.

Astronauts experience Space Motion Sickness requiring treatment with an anti-motion sickness medication, scopolamine during space missions. Bioavailability after oral administration of scopolamine is low and variable, and absorption form transdermal patch is slow and prolonged. Intranasal administration achieves faster absorption and higher bioavailability of drugs that are subject to extrahepatic, first pass metabolism after oral dosing. We examined pharmacokinetics of 0.1, 0.2, and 0.4 mg doses of the Investigational New Drug formulation of intranasal scopolamine gel (INSCOP) in 12 healthy subjects using a randomized, double-blind cross-over study design. Subjects received one squirt of 0.1 g of gel containing either 0.1 mg or 0.2 mg/0.1 mL scopolamine or placebo in each nostril. Serial blood samples and total urine voids were collected after dosing and drug concentrations were determined using a modified LC-MS-MS method. Results indicate dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range tested. Plasma drug concentrations were significantly lower in females than in males after administration of 0.4 dose. All three doses were well tolerated with no unexpected or serious adverse side effects reported. These results suggest that intranasal scopolamine gel formulation (INSCOP) offers a fast, reliable, and safe alternative for the treatment of motion sickness.

Association of low serum anticholinergic levels and cognitive impairment in elderly presurgical patients.

Low-dose scopolamine, given as presurgery medication, resulted in low levels of serum anticholinergic activity and caused measurable cognitive impairment in 18 psychiatrically healthy elderly patients. The degree of impairment was directly related to serum anticholinergic activity levels and, in the small subgroup of patients scheduled for spinal anesthesia, to CSF anticholinergic activity. Two of the mental status tests used, the Rey Auditory-Verbal Learning Test and the Saskatoon Delirium Checklist, were sensitive enough to detect these mild drug-induced changes, while two other tests, the Mini-Mental State and the Symbol Digit Modalities Test, were not.

Low-dose transdermal scopolamine decreases blood pressure in mild essential hypertension.

BACKGROUND: Increasing cardiovascular parasympathetic nervous activity could have antihypertensive effects. Low-dose transdermal scopolamine increases vagal-cardiac modulation of sinus node and baroreflex sensitivity in healthy subjects and in cardiac patients. OBJECTIVE: To study the short-term effects of transdermal scopolamine on blood pressure and cardiovascular autonomic control in patients with mild essential hypertension. DESIGN: A randomized, double-blind, placebo-controlled crossover trial with 12 untreated middle-aged [aged 39+/-5 years (mean+/-SD)] patients with mild essential hypertension. METHODS: We recorded the electrocardiogram, auscultatory sphygmomanometric and continuous photoplethysmographic finger arterial pressure, and spirometry signals with patients supine and 70 degrees tilted during controlled (0.25 Hz) breathing. Cardiovascular autonomic regulation was analyzed with power spectrum analysis of R-R interval and arterial pressure variability and a spontaneous sequence method for baroreflex sensitivity. In addition, a deep-breathing test was performed to assess maximal breathing-related sinus arrhythmia. RESULTS: Transdermal scopolamine treatment significantly decreased blood pressure both when patients lay supine and when they were in the 70 degrees tilted position. Scopolamine also slowed heart rate and increased baroreflex sensitivity and R-R interval high-frequency variability for both body positionings. In addition, scopolamine accentuated respiratory sinus arrhythmia during deep breathing and blunted the tilt-induced increase in heart rate. Scopolamine did not affect blood pressure variability. CONCLUSIONS: Transdermal scopolamine decreases arterial pressure, increases baroreflex sensitivity and accentuates vagal-cardiac modulation of sinus node in patients with mild hypertension. Our study supports the hypothesis that increasing cardiovascular parasympathetic activity could have antihypertensive effects in essential hypertension.

Caffeine attenuates scopolamine-induced memory impairment in humans.

Caffeine consumption can be beneficial for cognitive functioning. Although caffeine is widely recognized as a mild CNS stimulant drug, the most important consequence of its adenosine antagonism is cholinergic stimulation, which might lead to improvement of higher cognitive functions, particularly memory. In this study, the scopolamine model of amnesia was used to test the cholinergic effects of caffeine, administered as three cups of coffee. Subjects were 16 healthy volunteers who received 250 mg caffeine and 2 mg nicotine separately, in a placebo-controlled double-blind cross-over design. Compared to placebo, nicotine attenuated the scopolamine-induced impairment of storage in short-term memory and attenuated the scopolamine-induced slowing of speed of short-term memory scanning. Nicotine also attenuated the scopolamine-induced slowing of reaction time in a response competition task. Caffeine attenuated the scopolamine-induced impairment of free recall from short- and long-term memory, quality and speed of retrieval from long-term memory in a word learning task, and other cognitive and non-cognitive measures, such as perceptual sensitivity in visual search, reading speed, and rate of finger-tapping. On the basis of these results it was concluded that caffeine possesses cholinergic cognition enhancing properties. Caffeine could be used as a control drug in studies using the scopolamine paradigm and possibly also in other experimental studies of cognitive enhancers, as the effects of a newly developed cognition enhancing drug should at least be superior to the effects of three cups of coffee.

Pharmacokinetic consequences of spaceflight.

Spaceflight induces a wide range of physiological and biochemical changes, including disruption of gastrointestinal (GI) function, fluid and electrolyte balance, circulatory dynamics, and organ blood flow, as well as hormonal and metabolic perturbations. Any of these changes can influence the pharmacokinetics and pharmacodynamics of in-flight medication. That spaceflight may alter bioavailability was proposed when drugs prescribed to alleviate space motion sickness (SMS) had little therapeutic effect. Characterization of the pharmacokinetic and/or pharmacodynamic behavior of operationally critical medications is crucial for their effective use in flight; as a first step, we sought to determine whether drugs administered in space actually reach the site of action at concentrations sufficient to elicit the therapeutic response.

Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effects of scopolamine in healthy volunteers.

Scopolamine is a muscarinic receptor antagonist commonly used as a pharmacological model substance based on the "cholinergic hypothesis" of memory loss in senile dementia of the Alzheimer type. The objective of the study was to relate pharmacodynamic electroencephalogram (EEG) changes and scopolamine serum concentration using pharmacokinetic-pharmacodynamic (PK-PD) modeling techniques. This was a randomized, three-way crossover, open-label study involving 10 healthy nonsmoking young male volunteers who received either scopolamine 0.5 mg as an intravenous (i.v.) infusion over 15 minutes or an intramuscular (i.m.) injection or a placebo. The pharmacodynamic EEG measure consists of the total power in delta, theta, alpha, and beta bands over frontal, central, and occipital brain areas. The values of the pharmacokinetic parameters of scopolamine after i.v. infusion were clearance (CL) 205 +/- 36.6 L/h, volume of distribution (Vd) 363 +/- 66.7 L, distribution half-life (t1/2 alpha) 2.9 +/- 0.67 min, and terminal half-life (t1/2 beta) 105.4 +/- 9.94 min (mean +/- SEM). Mean peak serum concentrations (Cmax) were 4.66 and 0.96 ng/ml after i.v. and i.m. administration, respectively (p < 0.05). The area under the serum concentration versus time curve (AUC) after i.m. administration (81.27 +/- 11.21 ng/ml/min) was significantly lower compared to the value after i.v. infusion (157.28 +/- 30.86 ng/ml/min) (mean +/- SEM, p < 0.05). Absolute bioavailability of scopolamine after i.m. injection was 57% +/- 0.08% (mean +/- SEM). After both i.v. and i.m. administration, scopolamine induced a decrease in EEG alpha power (7.50-11.25 Hz) over frontal, central, and occipital brain areas compared to placebo (p < 0.05). The individual concentration-EEG effect relationships determined after i.v. infusion of scopolamine were successfully characterized by a sigmoidal Emax model. The averaged values of the pharmacodynamic parameters were E0 = 0.58 microV2, Emax = 0.29 microV2, EC50 = 0.60 ng/ml, and gamma = 1.17. No time delay between serum concentrations and changes in alpha power was observed, indicating a rapid equilibration between serum and effect site. The results provide the first demonstration of a direct correlation between serum concentrations of scopolamine and changes in total power in alpha frequency band in healthy volunteers using PK-PD modeling techniques. As regards the effect on the EEG, 0.5 mg of scopolamine administered i.v. appears to be a suitable dose.