Antimuscarinic Effects Research Articles

Intravesical Atropine Compared to Oral Oxybutynin for Neurogenic Detrusor Overactivity: A Double-Blind, Randomized Crossover Trial

We tested the efficacy and side effect profiles of intravesical atropine compared to oxybutynin immediate release when used by individuals with multiple sclerosis. We performed a study to determine the most effective dose of atropine. Eight participants used increasing doses of intravesical atropine during a 12-day period. Bladder diary data showed that the instillation of 6 mg atropine 4 times daily was most effective for increasing bladder capacity (voided/catheter volumes). We then did a randomized, double-blind crossover trial. Participants received 14 days of treatment with oral oxybutynin or with intravesical atropine, followed by 14 days of alternative treatment. Participants recorded a bladder diary and rated side effects and quality of life. The primary outcome variable was bladder capacity. A total of 57 participants with multiple sclerosis completed the study. Average change in bladder capacity was higher in the atropine arm. The mean +/- SD oxybutynin change was 55.5 +/- 67.2 ml, the mean atropine change was 79.6 +/- 89.6 ml and the mean difference between arms was 24.1 ml (95% CI -0.4, 49.7; p = 0.053). Changes in incontinence events and voiding frequency were not statistically different between the arms. Changes in total side effect and dry mouth scores were significantly better in the atropine treatment arm. Intravesical atropine was as effective as oxybutynin immediate release for increasing bladder capacity and it was probably better with less antimuscarinic side effects. We recommend that intravesical atropine should be made available to patients with neurogenic detrusor overactivity and voiding problems requiring intermittent catheterization as an alternative to oral therapy, which often has troublesome side effects.

Darifenacin: a selective M3muscarinic receptor antagonist for the treatment of overactive bladder

Overactive bladder is a common and distressing disorder that imposes significant financial and quality-of-life costs. The current therapeutic paradigm aims to decrease detrusor overactivity via blockade of bladder M3 muscarinic receptors, the primary cholinergic receptors responsible for detrusor contraction. However, systemic antimuscarinic adverse effects, such as dry mouth and constipation, limit the tolerability of antimuscarinic treatment. Therefore, a uroselective M3 receptor antagonist would be considered optimal therapy for overactive bladder. Darifenacin (Enablex®) is the most recent antimuscarinic drug approved for the treatment of overactive bladder. It demonstrates M3 receptor selectivity, but is not M3 specific. Despite animal data suggesting uroselectivity, it is not sufficiently uroselective in therapeutic use. While effective in reducing symptoms related to overactive bladder, dry mouth and constipation remain common. There are no comparative trials comparing darifenacin with existing agen...

Efficacy, tolerability and safety of darifenacin, an M3 selective receptor antagonist: an investigation of warning time in patients with OAB

This double-blind, randomised placebo-controlled, multicentre study evaluated the efficacy, tolerability and safety of 12 weeks' treatment with controlled release darifenacin 15 mg once daily (qd), in 445 patients with overactive bladder (OAB). The primary endpoint was warning time (time from first sensation of urgency to voiding), and secondary endpoints included urge incontinence episodes and volume voided. Darifenacin treatment resulted in numerical increases in warning time, but these were not significant compared with placebo -- highlighting difficulties in assessing this parameter. Significant improvements were seen with darifenacin vs. placebo in urge incontinence episodes/week, volume voided and quality of life (QoL). Darifenacin was associated with increases in urgency-free time (UFT; time between any void to the next urgency event) vs. placebo. Treatment was well tolerated; the most commonly reported adverse events were the typical antimuscarinic effects of dry mouth and constipation, both infrequently leading to discontinuation. This study demonstrated the difficulty in measuring warning time, due in part to its subjective nature; the authors believe further investigation is warranted to allow urgency to be better defined. Further investigation of UFT is required to determine its role in evaluating urgency. The study confirmed that darifenacin 15 mg qd is an effective and well-tolerated treatment for OAB, which improves QoL.

Solifenacin in the management of the overactive bladder syndrome

Overactive bladder (OAB) is the term used to describe the symptom complex of urinary frequency and urgency, with or without urge incontinence. Whilst antimuscarinic drug therapy has proven to be effective in the management of patients with symptoms of the OAB syndrome, compliance with medication is often affected by the bothersome antimuscarinic adverse effects of dry mouth, constipation, somulence and blurred vision. The development of bladder selective M3 specific antagonists offers the possibility of increasing efficacy whilst minimising adverse effects. At present, there are no M3 specific antagonists currently available, although solifenacin and darifenacin are under development and are due to be registered in 2004-2005. The purpose of this article is to review the pharmacology and clinical trial data available for solifenacin in addition to examining its emerging role in the treatment of the OAB syndrome.

Analysis of rapid heart rate variability in the assessment of anticholinergic drug effects in humans

Anticholinergic agents have widespread therapeutic indications in clinical medicine. In addition, certain other drug groups-such as neuroleptics, antidepressants and antihistamines-possess distinct anticholinergic properties that reduce tolerance and compliance. Especially in patients with heart disease, attention should be paid to cardiac anticholinergic drug effects. The analysis of short-term heart rate variability (HRV) provides a noninvasive tool to estimate vagal cholinergic outflow. In this review article, we present the basic principles of the most relevant techniques to study rapid HRV: the time domain analysis methods RMSSD and pNN50, and the high-frequency (HF) spectral component of HRV. We provide examples of previously reported effects of anticholinergic agents on these measures and also describe how adrenergic drugs may influence them. We have the following recommendations for a clinical pharmacologist investigating anticholinergic agents. (1) If the breathing rate of the study subject can be controlled during the assessment and the electrocardiogram recordings contain good-quality, stationary segments that are at least a few minutes long, then the HF power of HRV should be the method of choice. (2) During uncontrolled conditions, RMSSD should be included in the analyses, because it is less affected by changes in the respiratory pattern and it can be measured from shorter segments of electrocardiogram data. (3) Reduced short-term HRV suggests an anticholinergic, but not necessarily an antimuscarinic drug effect, since the inhibition of cholinergic vagal efferent activity may also originate from central or peripheral adrenergic influences.

Darifenacin in the treatment of overactive bladder

Antimuscarinic drug therapy has been shown to be effective in the management of patients with symptoms of the overactive bladder syndrome (OAB), but the bothersome antimuscarinic adverse effects of dry mouth, constipation, somnolence and blurred vision often affect compliance with medication. The development of bladder selective M3 specific antagonists offers the possibility of increasing efficacy whilst minimising adverse effects. The M3 specific antagonist solifenacin has recently been marketed, and darifenacin will soon be available. The purpose of this article is to review the pharmacology and clinical trial data available for darifenacin, in addition to examining its role in the treatment of the OBS.

Pilocarpine Treatment of Xerostomia Induced by Psychoactive Medications

Back to table of contents Previous article Next article Letter to the EditorFull AccessPilocarpine Treatment of Xerostomia Induced by Psychoactive MedicationsKIM J. MASTERS, M.D., KIM J. MASTERSSearch for more papers by this author, M.D., St. Simons Island, Ga.Published Online:1 May 2005https://doi.org/10.1176/appi.ajp.162.5.1023AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Dry mouth (xerostomia) is a frequent complication of psychoactive medications with antimuscarinic and anticholinergic side effects. The lack of saliva is annoying to patients, impairs their ability to masticate and digest food, and is a potential source of dental morbidity, including increased risk for caries and oral infection. Pilocarpine is a cholinergic muscarinic agonist. It has been used to treat xerostomia induced in cancer patients by head and neck radiotherapy (1). It has recently been found to be effective in doses of 20 mg/day in a randomized, placebo-controlled dose-adjustment study in the treatment of dry mouth and dry eyes in patients with Sjogren’s syndrome (2). It has been used to treat dry mouth as a complication of opioid treatment (3). Toxicity has been infrequently reported (4). However, it is contraindicated in patients with angle-closure glaucoma.We have empirically used pilocarpine in doses of 10–30 mg/day, divided into dosing of two or three times a day. We have used it with our acute psychiatric inpatients, ages 20–69, who complained of dry mouth after they had been started on psychoactive medication. These included atypical antipsychotic agents, particularly clozapine and olanzapine; anticholinergic agents, primarily benztropine; and antidepressants, particularly tricyclic antidepressants and mirtazapine. Substantial relief of dry mouth was achieved in most patients. Side effects were mainly sweating and increased urination. We did not observe any adverse impact on psychiatric symptoms. The patients were generally pleased that their dry mouth symptoms responded rapidly, usually within 1 day, to pilocarpine treatment. Further investigation into the use of pilocarpine for the treatment of xerostomia induced by psychoactive medication seems warranted.

156: Dpi-221 Increases Micturition Interval after Repeat Administration: A Delta Agonist with Striking Differences to Mu Opioid and Anti-Muscarinic Effects in Normal Rats

156: Dpi-221 Increases Micturition Interval after Repeat Administration: A Delta Agonist with Striking Differences to Mu Opioid and Anti-Muscarinic Effects in Normal Rats

Influence of estradiol pretreatment on antimuscarinic action of oxybutynin in rat detrusor muscle

Objectives To investigate the antimuscarinic effect of oxybutynin in the rat detrusor muscle after estrogen pretreatment because, to our knowledge, no study has been done on the interaction of estrogen with antimuscarinic drugs. Estrogen has been shown to affect muscarinic receptors in the detrusor muscle of animals. In addition, oxybutynin has been shown to block muscarinic receptors in the bladder. Methods Estradiol benzoate (150 μg/kg) or saline was given subcutaneously to virgin female Wistar albino rats (n = 6, each group) for 10 consecutive days. On the 11th day, isolated detrusor muscle strips were taken, and acetylcholine (ACh)-induced contractions were evaluated in the absence or presence of oxybutynin (10 and 100 nM). Results ACh induced concentration-dependent contractions in the detrusor muscle. In the estradiol-pretreated group, the maximum of the ACh-induced contractions was diminished compared with that in the control group ( P < 0.05). Oxybutynin (10 and 100 nM) inhibited ACh-induced contractions competitively (pK B 8.85). In the estradiol-pretreated group, the concentration-response curve to ACh was shifted further to the right in the presence of oxybutynin (100 nM). Conclusions We have demonstrated for the first time that oxybutynin further inhibits ACh-induced and muscarinic receptor-mediated contractions in rat detrusor muscle after pretreatment with estrogen.

Effects of first and second generation antihistamines on muscarinic induced mucus gland cell ion transport

BackgroundThe first generation antihistamines, such as diphenhydramine, are fairly potent muscarinic antagonists in addition to being H1 selective antihistamines. The antimuscarinic action is often not desirable since it is in part responsible for the drying of secretions in the airways and the sedative effect. We therefore examined a number of antihistamines for antimuscarinic effects on ion transport by mucus gland cells isolated from the airways of swine. Enzymatically isolated airway mucus gland cells were purified utilizing density gradients and grown in culture on porous inserts (Millicell HA™) at an air interface. Cells grown in this manner maintain phenotype and polarity. Transport of ions, as short-circuit current measured under voltage-clamp, was measured in response to acetylcholine (ACh) or histamine applied to the serosal side of the gland cell layers. Concentration-response relationships for ACh or histamine were generated in the presence and absence of various drugs. The potencies against muscarinic receptor activation were estimated using the dose-ratio method of Schild.ResultsThree known muscarinic antagonists were used to validate the system. Atropine had a pA2 of 9.4 ± 0.1 (n = 9). 4-DAMP and methoctramine had pA2 values of 8.6 ± 0.1 and 5.6 ± 0.1, respectively (n = 12, 11) all consistent with inhibition of an M3 subtype muscarinic receptor. The rank order of potency of the antihistamines against the inhibition of M3 receptors was desloratadine = diphenhydramine > hydroxyzine (pA2; 6.4, 6.2, 4.8, respectively). pA2 values for fexofenadine, loratadine and cetirizine were not determined since they had no effect on the cholinergic response at the highest drug concentrations tested (10, 10 and 100 μM, respectively). The pA2 values for the antihistamines against the histamine response could not be calculated, but the estimates of the rank order of potency were estimated to be desloratadine> cetirizine ≈ hydroxyzine > fexofenadine > loratadine > diphenhydramine.ConclusionThe rank order of selectivity for histamine receptors over muscarinic receptors was estimated to be cetirizine ≈ fexofenadine > loratadine > desloratadine ≥ hydroxyzine ≥ diphenhydramine.

Oxybutynin for treatment of urge urinary incontinence and overactive bladder: an updated review

Urge urinary incontinence (UUI) and overactive bladder are common conditions often associated with profound impairment of the health and quality of life of the patient. Antimuscarinic medications have been the mainstay of treatment for these disorders. Oxybutynin hydrochloride, one of the most widely used antimuscarinic agents, has attracted considerable interest from both clinicians and pharmacologists over the last three decades. Although efficacy of this drug has been proven to be high, its use is limited by antimuscarinic adverse effects, possibly related to its active metabolite N-desethyloxybutynin (N-DEO). The extended-release form of oxybutynin uses a push-pull osmotic release system which has significantly improved its tolerability and safety profile. A transdermal transport system has also been developed, bypassing the first-pass metabolism in the liver and gut. This system is associated with significant reduction in the production of the primary metabolite and additional improvement in the tolerability profile of the drug. Intravesical instillation of oxybutynin has been reported although the efficacy and safety of this delivery system has yet to be determined. This article comprehensively reviews the contemporary literature on the pharmacology, clinical efficacy and adverse reactions of oxybutynin in its various delivery forms, and compares them to other frequently used medications for UUI and overactive bladder.

Safety and Efficacy of 2% Pirenzepine Ophthalmic Gel in Children WithMyopia

To evaluate the safety and efficacy of the relatively selective M(1) antagonist pirenzepine hydrochloride in slowing the progression of myopia in school-aged children. This was a parallel-group, placebo-controlled, double-masked study in healthy children, aged 8 to 12 years, with a spherical equivalent of -0.75 to -4.00 diopters (D) and astigmatism of 1.00 D or less. Patients underwent a baseline complete eye examination and regular examinations during a 1-year period. The setting was 13 US academic clinics and private practices. Patients were randomized in a 2:1 ratio to receive 2% pirenzepine ophthalmic gel or a placebo control twice daily for 1 year. At study entry, the spherical equivalent was mean +/- SD -2.098 +/- 0.903 D for the pirenzepine group (n = 117) and -1.933 +/- 0.825 D for the placebo group (n = 57, P = .22). At 1 year, there was a mean increase in myopia of 0.26 D in the pirenzepine group vs 0.53 D in the placebo group (P < .001). No patients in the placebo group and 13 (11%) of 117 patients in the pirenzepine group discontinued participation in the study because of adverse effects (5 [4%] of 117 due to excessive antimuscarinic effects). Pirenzepine is effective and relatively safe in slowing the progression of myopia during a 1-year treatment period.

The emerging role of solifenacin in the treatment of overactive bladder

Although antimuscarinic drug therapy has been proven to be effective in the management of patients with symptoms of the overactive bladder syndrome, compliance with medication is often affected by the antimuscarinic adverse effects of dry mouth, constipation, somnolence and blurred vision. The development of bladder-selective M3-specific antagonists offers the possibility of increasing efficacy whilst minimising adverse effects. At present there are no M3-specific antagonists currently available although solifenacin and darifenacin are both under development and are due to be launched in 2004. The purpose of this article is to review the pharmacology and clinical trial data available for solifenacin, in addition to examining its role in the treatment of the overactive bladder syndrome.

419 Systematic evaluation of antimuscarinic drug effects in human, porcine and mouse detrusor smooth muscle

419 Systematic evaluation of antimuscarinic drug effects in human, porcine and mouse detrusor smooth muscle

Prevalence of autonomic signs and symptoms in antimuscarinic drug poisonings

Classically described antimuscarinic poisoning signs and symptoms include mydriasis, decreased secretions, ileus, urinary retention, hyperthermia, tachycardia, and altered mental status. These features may be used clinically to assist in the diagnosis of patients with unknown poisonings. We sought to analyze the prevalence of antimuscarinic physical examination findings in evaluating patients presenting with acute poisoning from antimuscarinic agents. We conducted a retrospective, medical record review at two urban tertiary care teaching hospitals. The study population consisted of patients presenting to the Emergency Department with a diagnosis of acute poisoning secondary to medications with known antimuscarinic side effects during a 78-month period between January 1994 and July 2001. Cases were excluded for incomplete medical records or unreliable histories of ingestion, and when concomitant ethanol intoxication was present on laboratory analysis. Clinical information obtained from each patient included vital signs, pupillary size, electrocardiogram abnormalities, the presence of mucous membrane and axillary secretions, initial urine output after bladder catheterization, quality of bowel sounds, mental status changes, the occurrence of seizures and coma, need for orotracheal intubation, and time required for clinical resolution. Diagnostic and therapeutic information including laboratory tests, administration of sodium bicarbonate, and usage of physostigmine was also collected. We identified a total of 345 cases, 213 of which met inclusion criteria. Of these cases, the most common documented findings included decreased secretions in 75.1%, tachycardia in 68.1%, confusion in 49.3%, drowsiness in 48.2%, and hypoactive or absent bowel sounds in 44.6%. Combining signs and symptoms to predict this toxic syndrome was not very reliable. Tachycardia, decreased oral or axillary secretions, and mydriasis proved to be the most predictive trio of clinical signs, but were found in only 28.2% of cases. At least one of these three signs was documented in 94% of our patients. The combination of tachycardia and decreased secretions was the most common pair of findings, recorded in 55.4% of cases. We conclude that the clinical presentation of antimuscarinic syndrome is variable.

Benefit-risk assessment of tolterodine in the treatment of overactive bladder in adults.

Overactive bladder is associated with symptoms of urgency, with or without urge incontinence, usually with daytime frequency and nocturia in the absence of local pathological factors. Muscarinic receptor antagonists (antimuscarinics) are the first-line pharmacotherapy. Tolterodine, a competitive, nonselective antimuscarinic specifically developed for the treatment of overactive bladder, demonstrated tissue selectivity for the bladder over the parotid gland in an animal model. As of March 5, 2003, the immediate-release (IR) formulation had been approved in 72 countries and the extended-release (ER) formulation had been approved in 28 countries, and tolterodine had been administered to 5 million patients. This review evaluates the benefit-risk profile of tolterodine in the treatment of adults with overactive bladder, summarising clinical trial and postmarketing surveillance data. Tolterodine has been found to significantly reduce micturition frequency, urgency perception and the number of episodes of urge incontinence and increase the volume voided per micturition. Dry mouth, an antimuscarinic class effect, is the most commonly reported adverse effect but is mostly mild to moderate in severity. Serious adverse effects are reported infrequently. Based on summary and review of postmarketing surveillance and clinical trial safety data received by the market authorization holder and contained in the Periodic Safety Update Reports for tolterodine, several monitored serious events of the gastrointestinal tract (e.g. ileus or haemorrhage), nervous system (e.g. syncope, convulsions and memory disorders) and cardiovascular system (e.g. ventricular arrhythmia, atrial fibrillation, palpitations, bradycardia, transient ischaemic attacks and hypertension) were not considered related to tolterodine. QT or corrected QT (QTc) prolongation was not observed in any of the five cases of verified ventricular arrhythmia in patients administered tolterodine; there is insufficient evidence to indicate that tolterodine causes ventricular arrhythmia or extrasystoles or any specific type of cardiac rhythm abnormality. The safety profile of tolterodine is similar in patients aged > or =65 years and in younger adults. Clinically relevant drug interactions are limited to cytochrome P450 3A4 inhibitors, such as ketoconazole, and co-administration with such agents warrants a tolterodine dosage decrease. In addition, tolterodine IR 2mg twice daily is similar in efficacy to oxybutynin IR 5mg three times daily, and tolterodine ER 4 mg once daily is similar in efficacy to oxybutynin ER 10mg once daily. Dry mouth occurred less frequently with tolterodine than oxybutynin, and moderate to severe dry mouth occurred more than three times less frequently. Based on the low frequency of adverse events, the absence of unexpected adverse events and the very low frequency of serious adverse events, we conclude that tolterodine is a well tolerated treatment for overactive bladder in adults, in whom it should be considered as first-line therapy.

Muscarinic mechanisms of antipsychotic atypicality

The interactions of the atypical antipsychotic drugs (APD) clozapine, olanzapine, risperidone, quetiapine and ziprasidone with muscarinic receptors were reviewed. Only clozapine and olanzapine have marked affinity for muscarinic receptors in radioligand binding studies; however, the affinity of these compounds is considerably lower than classical muscarinic antagonists. Although functional assays in cell lines transfected with muscarinic receptors suggest that olanzapine and clozapine have weak partial agonist activity at muscarinic receptors, particularly M 4 receptors, studies in vitro and in vivo indicate that the compounds function as antagonists. In animal studies and in humans, clozapine has pronounced antimuscarinic effects whereas olanzapine has weak antimuscarinic effects. However, olanzapine significantly occupies central muscarinic receptors in humans. Overall, the role of muscarinic receptors in the antipsychotic effects of clozapine and olanzapine is controversial and complex.

Mechanisms of relaxant action of S-petasin and S-isopetasin, sesquiterpenes of Petasites formosanus, in isolated guinea pig trachea.

We investigated the mechanisms of action of S-petasin and S-isopetasin, from Petasites formosanus Kitamura which is used as a folk medicine for treating hypertension, tumors, and asthma in Taiwan. The tension changes of tracheal segments were isometrically recorded on a polygraph. S-Petasin and S-isopetasin non-competitively inhibited cumulative histamine-, and carbachol-induced contractions with an exception that S-isopetasin produced a parallel, rightward shift of the concentration-response curve of carbachol in a competitive manner. S-Petasin also non-competitively inhibited cumulative Ca(2+)-induced contractions in depolarized (K+, 60 mM; histamine, 100 microM; or carbachol, 10 microM) guinea-pig tracheas. S-Isopetasin did in depolarized (K+, 60 mM) trachea too. The nifedipine (10 microM)-remaining tension of carbachol (0.2 microM)-induced precontraction was further relaxed by S-petasin or S-isopetasin, suggesting that no matter whether either blocked VDCCs or not, S-petasin or S-isopetasin may have other mechanisms of relaxant action. The relaxant effect of S-petasin or S-isopetasin was unaffected by the presence of propranolol (1 microM), 2',5'-dideoxyadenosine (10 microM), methylene blue (25 microM), glibenclamide (10 microM), N omega-nitro-L-arginine (20 microM), or alpha-chymotrypsin (1 U/ml). However, S-petasin (100-300 microM), but not S-isopetasin, significantly inhibited cAMP-, but not cGMP-dependent PDE activity of the trachealis. The above results reveal that the mechanisms of relaxant action of S-petasin and S-isopetasin may be primarily due to its non-specific antispasmodic and antimuscarinic effects, respectively.

Effects of two atypical neuroleptics, olanzapine and risperidone, on the function of the urinary bladder and the external urethral sphincter in anesthetized rats

BackgroundA previous report showed that the atypical neuroleptic clozapine resulted in marked changes in urodynamic parameters and greatly inhibited the activity of the external urethral sphincter in anesthetized rats. Such findings may help explain the high incidence of urinary disturbances reported during clozapine therapy. In an effort to extend our observations to other atypical neuroleptic agents, the present study investigated the effects of two newer atypical antipsychotics, olanzapine and risperidone, on the bladder and external urethral sphincter during cystometry in anesthetized rats.ResultsAt a dose of 0.1 mg/kg (i.v.), olanzapine decreased the micturition volume and increased the residual volume. In addition, olanzapine decreased the expulsion time and the amplitude of the high frequency oscillations observed during the expulsion phase. Larger doses (1 mg/kg) had a greater effect. Olanzapine also reduced the activity recorded from the external urethral sphincter, and the bursting observed during the expulsion phase was abolished by 1.0 mg/kg. Risperidone had similar effects although the maximal effects were smaller than those observed with olanzapine. The amplitude of bladder contractions elicited by electrical stimulation of the pelvic nerve was reduced by olanzapine but not risperidone suggesting a possible anti-muscarinic peripheral effect of olanzapine.ConclusionsOlanzapine and risperidone significantly altered several voiding parameters and decreased the activity of the external urethral sphincter in the anesthetized rat. We propose that these effects are due to the central action of these drugs and not to peripheral effects. These findings may explain some of the clinical reports of urinary incontinence with risperidone and may predict similar occurrences with olanzapine therapy.

Neuroprotective effects of currently used antidotes in soman-poisoned rats

The neuroprotective effects of antidotes (atropine, obidoxime, obidoxime/atropine mixture) on rats poisoned with soman at a sublethal dose (54 μg/kg, im, 80% of LD 50 value) were studied. The soman-induced neurotoxicity was monitored using a functional observational battery (FOB) and an automatic measurement of motor activity. The neurotoxicity of soman was monitored at 24 h and 7 days following soman challenge. The results indicate that obidoxime alone is not able to protect the rats from the lethal effects of soman. Three soman-poisoned rats treated with obidoxime alone died within 24 h. On the other hand, atropine alone or combined with obidoxime allows all soman-poisoned rats to survive within 7 days following soman challenge. Atropine alone and combined with obidoxime seems to be relatively effective antidotal treatment for the elimination of soman-induced neurotoxicity in the case of sublethal poisonings, although the antidotal mixture is significantly less effective than atropine alone because obidoxime can counteract the beneficial effects of atropine. Obidoxime appears to be practically ineffective to diminish soman-induced neurotoxicity. The neuroprotective effects of antidotal mixture consisting of atropine and obidoxime depend on the antimuscarinic effects of atropine only. Thus, the replacement of obidoxime by more effective acetylcholinesterase (AChE) reactivators is necessary to increase the neuroprotective efficacy of antidotal treatment in the case of soman poisonings.