Association between inherited CYP2D6/2C19 phenotypes and anticholinergic measures in elderly patients using anticholinergic drugs.

BACKGROUND: To compare measures of anticholinergic activity between metabolic phenotypes of the polymorphic enzymes cytochrome P450 2D6 (CYP2D6) and CYP2C19 in the elderly patients exposed to anticholinergic agents. METHODS: Long-term nursing home patients (n = 80) with an anticholinergic drug scale (ADS) score ≥3 were recruited from 22 nursing homes in Norway. Based on pharmacogenetic analyses of mutations encoding absent CYP2D6 or CYP2C19 metabolism, patients were divided into subgroups of poor metabolizers (PMs) (n = 8) and extensive metabolizers (n = 72). Serum anticholinergic activity (SAA) was determined by a validated, 96-well format radio receptor assay and adjusted for ADS score. Unadjusted and adjusted SAAs, mouth dryness, and cognitive function (Mini-Mental State Examination and verbal recall tests from Consortium to Establish a Registry for Alzheimer Disease) were compared between the subgroups with Mann-Whitney tests. RESULTS: The study population was represented by 78% women, 68% had mild to moderate dementia, and mean age was 86 years. More than 80% used more than 1 anticholinergic agent, and their median ADS score was 4. The subpopulation of PMs had significantly higher median SAA than the extensive metabolizers (10.3 versus 4.2 pmol atropine equivalents per milliliter, P = 0.012). This difference remained significant after adjusting for ADS score (P = 0.013). No significant differences in mouth dryness and cognitive function were observed between the subgroups (P > 0.3). CONCLUSIONS: These preliminary findings suggest that elderly CYP2D6/CYP2C19 PMs with a high anticholinergic drug burden are at increased risk of elevated SAA. Whether PMs are also more prone to experience anticholinergic side effects needs to be further studied in larger patient populations.

Functionalized chitosan/NIPAM (HEMA) hybrid polymer networks as inserts for ocular drug delivery: synthesis, in vitro assessment, and in vivo evaluation.

A series of hybrid polymeric hydrogels, prepared by the reaction of acrylic acid-functionalized chitosan with either N-isopropylacrylamide or 2-hydroxyethyl methacrylate monomers, were synthesized, pressed into minitablets, and investigated for their ability to act as controlled release vehicles for ophthalmic drug delivery. For comparison, interpolymeric complex analogues synthesized using the same monomers and pure, unfunctionalized chitosan were examined by means of an identical characterization protocol. The effects of network structure and composition upon the swelling properties, adhesion behavior, and drug release characteristics were investigated. Comparative in vitro studies employing chloramphenicol, atropine, norfloxacin, or pilocarpine informed the selection of drug-specific carrier compositions for the controlled delivery of these compounds. In addition, in vivo (rabbit model) experiments involving the delivery of pilocarpine indicated that chitosan-based hybrid polymer networks containing 2-hydroxyethyl methacrylate are useful carriers for the delivery of this therapeutic agent.

Trospium chloride for the treatment of overactive bladder with urge incontinence.

BACKGROUND: Urinary incontinence is caused by an overactive bladder, leading to symptoms of urgency, frequency, and incontinence. Urge incontinence occurs predominantly in women as they age. OBJECTIVES: This article reviews the current primary literature concerning the efficacy and tolerability of the anticholinergic agent trospium chloride (TCl) in the treatment of overactive bladder with symptoms of urge incontinence, urgency, and frequency. The pharmacokinetics of TCl are also reviewed. METHODS: Pertinent articles in English were identified through a search of MEDLINE (1966-present), EMBASE Drugs & Pharmacology (1980-third quarter 2004), Current Contents/Clinical Medicine (week 42, 2003-week 41, 2004), Cochrane Database of Systematic Reviews, MICROMEDEX Healthcare Series, and International Pharmaceutical Abstracts (1970-present). The search terms were overactive bladder, urinary incontinence, trospium, randomized controlled clinical trial, oxybutynin, tolterodine, scopolamine, imipramine, desipramine, and propantheline. RESULTS: TCl, a quaternary amine, exhibits high solubility in water but low oral bioavailability (9.6%) and poor central nervous system penetration. Approximately 80% of the absorbed fraction is renally eliminated as unchanged drug via active tubular secretion, with approximately 15% hepatically metabolized into a spiroalcohol and hydrolysis/oxidation products. In 3 placebo-controlled studies, patients who received TCl had an increase in maximum bladder filling capacity and bladder compliance, with a reduction in maximum cystometric capacity (P < 0.005); however, only 1 of these studies showed an increase in bladder compliance, with reductions in maximum detrusor pressure (P < 0.001), number of voids/d (P < or = 0.001), and incontinence episodes/d (P < or = 0.001). In another placebo-controlled study, TCl reduced the number of voids/d and incontinence episodes/d (both, P < or = 0.001). In 2 double-blind studies, TCl and oxybutynin were similarly effective in significantly increasing maximum cystometric capacity and bladder compliance, and in significantly reducing maximum detrusor pressure compared with baseline (all, P < 0.001); there were no significant differences between the 2 treatments at end point. In a third double-blind study comparing TCl and tolterodine with placebo, only TCl significantly reduced the frequency of micturitions/d (P = 0.01). Commonly reported adverse effects in patients receiving TCl included dry mouth, constipation, and headache. CONCLUSIONS: In the 7 studies reviewed, TCl was effective and well tolerated in patients with urge incontinence caused by idiopathic detrusor muscle overactivity or neurogenic detrusor overactivity resulting from spinal cord injury. However, this agent was associated with anticholinergic adverse effects similar to those of other anticholinergic agents; careful monitoring of tolerability is required.

Tiotropium: an inhaled anticholinergic for chronic obstructive pulmonary disease.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage and administration, and formulary considerations of tiotropium are discussed. SUMMARY: Tiotropium, a long-acting inhaled anticholinergic, recently received approval from the Food and Drug Administration for the management of chronic obstructive pulmonary disease (COPD). In patients with COPD, increased parasympathetic nervous system activity leads to bronchoconstriction and mucus secretion. Tiotropium induces relaxation of the airway smooth muscle, as does ipratropium, but differs in receptor association and dissociation rates, allowing for once-daily administration. After inhalation, tiotropium reaches maximal plasma concentrations within five minutes, but clinical improvements in forced expiratory volume in one second (FEV(1)) are maintained over 24 hours. Clinical trials of tiotropium with placebo, ipratropium, and salmeterol have demonstrated the efficacy of tiotropium in improving FEV(1) and forced vital capacity values and health-related quality of life. The most commonly observed adverse effect is dry mouth. No increase in adverse effects was observed when tiotropium was administered concomitantly with other drugs for COPD, including sympathomimetic bronchodilators and oral and inhaled corticosteroids. The combination of tiotropium and other anticholinergics has not been studied and is not recommended. The recommended dosage of tiotropium is the inhalation of an 18-mug capsule with a HandiHaler breath-actuated inhalation device once daily. CONCLUSION: Tiotropium appears to be at least as effective as currently available alternatives in the treatment of patients with COPD who require daily bronchodilator treatment. Its simplified dosing and tolerable adverse-effect profile can potentially lead to enhanced patient compliance.

Tolterodine.

Tolterodine is a competitive muscarinic receptor antagonist which has recently been launched for the treatment of overactive bladder. Tolterodine shows functional selectivity for the bladder over the salivary glands in vivo, which is not attributable to muscarinic receptor subtype selectivity. It is as potent as oxybutynin in inhibiting bladder contraction, but is much less potent in inhibiting salivation, suggesting that it may have less propensity to cause dry mouth in clinical use. In patients with overactive bladder, toleterodine significantly reduces the frequency of micturition and number of incontinence episodes, while increasing the average volume voided. The onset of pharmacological action of tolterodine is < 1 hour and therapeutic efficacy is maintained during long term treatment. In comparative trials, tolterodine and oxybutynin are equivalent in terms of efficacy. However, tolterodine is significantly better tolerated than oxybutynin, particularly with respect to the incidence and severity of dry mouth. No clinically relevant ECG changes have been noted with tolterodine.

Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin.

Oxybutynin is used for the treatment of urge urinary incontinence. In this randomized, open-label, two-way crossover, multiple-dose study, the pharmacokinetics of a once-daily, controlled-release formulation, OROS oxybutynin chloride, was compared with that of immediate-release (IR) oxybutynin (Ditropan). Thirteen healthy female volunteers received three 5 mg OROS oxybutynin chloride tablets once daily for 4 days or IR oxybutynin 5 mg administered every 8 hours for 4 days. On day 1, with OROS oxybutynin chloride, mean plasma concentrations rose slowly over approximately 6 hours following dosing (mean Cmax 4.2 ng/mL) and remained fairly constant over the 24-hour dosing interval, whereas with IR oxybutynin, mean plasma concentrations rose rapidly within the first hour after dosing (mean Cmax 12.0 ng/mL), then declined. The mean oxybutynin degree of fluctuation was much lower for OROS oxybutynin chloride (78%) than for IR oxybutynin (371%). For both formulations, the plasma concentration-time profiles for the metabolite N-desethyloxybutynin paralleled those of oxybutynin but at higher concentrations. Steady-state oxybutynin concentrations were achieved by day 3 for both formulations. Mean area under the concentration-time curve (AUC) values for both oxybutynin and its metabolite were similar between day 1 and day 4 for each treatment, suggesting time-invariant pharmacokinetics. With OROS oxybutynin chloride, mean relative bioavailability was higher (153%) for oxybutynin and lower (69%) for N-desethyloxybutynin compared with IR oxybutynin. This increased bioavailability may be due to reduced first-pass metabolism; within 3 to 5 hours after dosing, OROS systems are thought to reach the colon, where cytochrome P450-mediated oxidation (oxybutynin's primary metabolic pathway) may be less extensive than in the small intestine. Fewer subjects reported any adverse event with OROS oxybutynin chloride than with IR oxybutynin (including dry mouth, oxybutynin's most frequently reported anticholinergic adverse effect).

An extended-release formulation of oxybutynin chloride for the treatment of overactive urinary bladder.

Detrusor instability, or urinary incontinence, is common in elderly patients, particularly elderly women. The clinical symptoms of overactive, or unstable, urinary bladder include urge urinary incontinence, urgency, and frequency. Mixed urinary incontinence, which comprises urge urinary incontinence and stress incontinence, is manifested by increased intraabdominal pressure on coughing or sneezing. The detrusor muscle of the bladder is under the control of the parasympathetic, or muscarinic, nervous system. The drug of choice in this condition is oxybutynin chloride, which has the ability to block acetylcholine released from parasympathetic nerves in the urinary bladder, preventing contractions of the muscle and exerting a direct spasmolytic effect on the bladder. A new extended-release oral tablet formulation, OROS oxybutynin, uses osmotic pressure to deliver the drug at a controlled rate over approximately 24 hours. It resembles a conventional tablet but has a two-part core consisting of a drug layer and below it, a "push" layer containing osmotically active components, the whole surrounded by a semipermeable membrane with a laser-drilled opening in the drug side. Water in the gastrointestinal tract enters the tablet and mixes with the drug to form a suspension. The "push" layer expands and pushes the suspended drug out of the orifice and into the gastrointestinal tract for eventual absorption. Pharmacokinetic studies have indicated a slow rise in mean plasma concentration of the isomer R-oxybutynin for 4 to 6 hours after a single dose of OROS oxybutynin, followed by maintenance of steady concentrations for up to 24 hours, minimizing the fluctuations between peak and trough associated with TID dosing of 5-mg immediate-release oxybutynin tablets. Efficacy and safety studies comparing the extended-release with the immediate-release formulation of oxybutynin demonstrated equivalent efficacy in patients with overactive urinary bladder. The adverse-event profile of oxybutynin is similar to that of a typical anticholinergic agent such as atropine--dry mouth, constipation, somnolence, blurred vision, headache, and gastrointestinal pain--although in 2 clinical studies, the incidence of dry mouth was less with the extended-release formulation. Once-daily dosing with OROS oxybutynin appears to be well tolerated and effective, as well as convenient, for the treatment of overactive bladder, particularly for elderly patients using multiple medications.

Extended-release oxybutynin.

Extended-release oxybutynin (Ditropan XL) uses an osmotic system (OROS) to deliver a controlled amount of oxybutynin chloride into the gastrointestinal tract over a 24-hour period when taken once daily. Oxybutynin binds to M3 muscarinic receptors on the detrusor muscle of the bladder, preventing acetylcholinergic activation and relaxing the muscle. Mean peak plasma concentrations are lower with extended-release oxybutynin 15mg once daily than with conventional immediate-release oxybutynin 5mg taken 3 times daily. Relative bioavailabilities of parent drug and metabolite N-desethoxybutynin are 153 and 69%, respectively, for extended-release oxybutynin when compared with immediate-release oxybutynin. In short (< or =6 weeks) randomised, double-blind clinical trials of patients with detrusor instability, extended-release oxybutynin 5 to 30mg once daily significantly reduced the mean weekly number of urge incontinence episodes by 84 to 90%. Extended-release oxybutynin had similar efficacy to immediate-release oxybutynin. Adverse events reported by patients taking extended-release oxybutynin were dose-related anticholinergic effects, most frequently dry mouth, somnolence, constipation, blurred vision and dizziness. A large noncomparative study demonstrated that approximately two thirds of the patients prescribed extended-release oxybutynin for detrusor instability were still taking the medication 6 months later.

Bioavailability of intranasal scopolamine in normal subjects.

The bioavailability of scopolamine in three dosage forms was compared in 12 healthy nonsmoking male volunteers. Subjects received 0.4-mg doses of scopolamine bromide in intravenous (i.v.), intranasal (i.n.), or oral (p.o.) dosage forms on three occasions, with at least 2 weeks separating the doses. Scopolamine concentrations in plasma were determined with a combined reverse-phase liquid chromatographic-radioreceptor binding assay. Saliva volume and flow rate and percent suppression of control flow rate were determined from each sample. Absorption after i.n. and po scopolamine administration was rapid; plasma concentrations [1680 (i.n.) and 164 pg/mL (p.o.)] peaked within 1 h of dosing [0.37 (i.n.) and 0.78 h (p.o.)], respectively. i.n. and i.v. scopolamine suppressed salivary flow rate to similar extents (95% and 99.7%), respectively. Times to reach maximum effect were 1.05 and 0.27 h after i.n. and i.v. dosage, respectively. Absolute intranasal bioavailability, calculated from the area under the drug concentration vs time curve, was found to be significantly greater than that of p.o. scopolamine (83% vs 3.7%, p < 0.05). The i.n. route may provide a noninvasive, reliable, fast, and effective route for administering scopolamine.

Paying attention to pharmacokinetic and pharmacodynamic mechanisms to progress in the area of anticholinergic use in geriatric patients.

Many naturalistic studies agree that adverse drug reactions (ADRs), particularly cognitive deficits, frequently occur when medications with anticholinergic activity are used in geriatric patients. However, the studies disagree on which anticholinergic drugs may have clinical relevance. The three most important methods to establish clinically relevant anticholinergic activity are: 1) the drug's affinity for muscarinic receptors, demonstrated by in vitro studies and a profile compatible with antagonist properties; 2) serum anticholinergic activity measured by radioreceptor assay; and 3) the presence of typical antimuscarinic ADRs, such as dry mouth and constipation, in patient studies or clinical trials. More recently, brain imaging of muscarinic receptors and scales for quantifying antimuscarinic activity were developed. A comprehensive approach can be crafted only by paying attention to the pharmacodynamic and pharmacokinetic mechanisms of these drugs. ADR studies on drugs with anticholinergic activity should not only consider central muscarinic receptor blockade, but also peripheral receptor blockade. The ability to cross the blood-brain barrier is important in the drug's ADR profile. Patient personal characteristics, drug-drug interactions (DDIs) and probably genetic variations may contribute to increased ADR risk through pharmacokinetic and/or pharmacodynamic mechanisms. Sophisticated clinical designs and the evidence-based medicine approach cannot succeed unless the list of drugs of anticholinergic activity is agreed upon, and the studies include a sophisticated pharmacological approach guided by our current understanding of their pharmacodynamic and pharmacokinetic mechanisms. If one agrees that antimuscarinic ADRs are probably dose-related, future studies must consider all drugs, administration routes, doses, muscarinic receptor affinity, DDIs, and brain access.

Safety and tolerability profiles of anticholinergic agents used for the treatment of overactive bladder.

Anticholinergics are the mainstay of pharmacotherapy for overactive bladder (OAB). The anticholinergics used to treat OAB differ in their pharmacological profiles, which may affect their propensity for causing commonly observed adverse effects. The purpose of this is review is to use published clinical data to evaluate the safety and tolerability of commonly prescribed anticholinergics for OAB, provide a context for safety and tolerability in terms of drug pharmacology, summarize the impact of adverse effects on adherence, and discuss the influence of study design on safety and tolerability outcomes. A MEDLINE search was conducted for the period 1990-2010 to identify studies evaluating mechanisms of action, pharmacological profiles, safety issues and adverse events pertaining to anticholinergics used in the treatment of OAB. Compared with immediate-release preparations, the extended-release, once daily and transdermal formulations are associated with lower rates of anticholinergic adverse effects, due to improved consistency in serum levels. The most significant adverse effects in terms of affecting the use of anticholinergics agents are CNS and cardiac disturbances. CNS issues are associated with pharmacological properties such as serum concentration, blood-brain barrier permeability and active transport, and receptor binding affinity. Cardiac safety (corrected QT interval) is more dependent on specific molecular attributes. However, more common but less bothersome adverse effects associated with systemic blockade of the muscarinic receptors include dry mouth, constipation, headache and blurred vision. A high potential for interaction between anticholinergics and drugs that compete with the same pathways for hepatic metabolism via cytochrome P450 and renal excretion increases the risk of adverse effects for both antimuscarinic and associated medications, especially in the elderly, who are more likely to be taking multiple drugs. This literature review demonstrates that all OAB anticholinergics are effective in reducing symptoms of OAB; however, important pharmacodynamic/pharmacokinetic differences between these agents may influence their efficacy and incidence of associated adverse effects. Because OAB is a chronic disease requiring long-term therapy, careful assessment of the pharmacological differences is needed in order to tailor therapy to the individual patient's clinical needs, and thereby maximize the chance of treatment success and long-term adherence to therapy. Since anticholinergic adverse effects are known to affect treatment adherence and persistence, the potential for adverse effects should be considered when selecting treatment for an individual patient.

Effect of OROS controlled-release delivery on the pharmacokinetics and pharmacodynamics of oxybutynin chloride.

UNLABELLED: Aims : Dry mouth is a common side-effect seen with immediate-release oxybutynin (IR-Oxy). Ditropan XL [(Oxy-XL), a controlled-release formulation of oxybutynin chloride, is a once-daily oral dosage form that incorporates the OROS technology. Dry mouth as the pharmacodynamic measure was compared between Oxy-XL and IR-Oxy administration. The steady state stereospecific pharmacokinetics were also established for the two formulations and the kinetic-dynamic relationship of oxybutynin was examined. METHODS: This was a randomized, repeated-dose, double-blind, two-treatment, two-period, crossover study. After a baseline assessment day, volunteers were randomly assigned to one of two treatment sequences and received 4 days of each treatment with a washout period of 7 days between treatments. The treatments were: 1) Oxy-XL 10 mg in the morning and placebo 8 h later, and 2) IR-Oxy 5 mg in the morning and again 8 h later. Volunteers assessed dry mouth severity subjectively using a 100 mm visual analogue scale, VAS (Baseline, treatment days 1 and 4) and objectively by collecting saliva (Baseline and treatment day 4) before dosing and every hour after the morning dose for approximately 16 h. Several blood samples were collected during each treatment, with frequent sampling on day 4 to analyse for plasma R- and S-oxybutynin and R- and S-desethyloxybutynin concentrations. RESULTS: Relatively constant plasma concentrations of oxybutynin and its metabolite were seen over 24 h following Oxy-XL administration with the degree of fluctuation being much lower (P = 0.001; 66% to 81% reduction for the various analytes) than IR-Oxy. Compared with IR-Oxy, Oxy-XL yielded higher (131% and 158% for the R- and S-isomer, respectively) oxybutynin and lower (62% and 78% for the R- and S-isomer, respectively) desethyloxybutynin bioavailability, suggesting reduced first-pass metabolism. Saliva output (area under the effect curve) was significantly higher [P = 0.001; 37% (95% confidence interval: 24, 51%)] with Oxy-XL than with IR-Oxy and, accordingly, dry mouth severity (VAS) integrated over the day was significantly lower with Oxy-XL. The decrease in saliva output and the consequent increase in dry mouth severity correlated with the metabolite R-desethyloxybutynin concentration, and no apparent relationship was observed with the R-oxybutynin concentration. This suggests that the metabolite may contribute to the dry mouth. Therefore, the reduction in metabolite exposure with Oxy-XL may be a possible explanation for the observed decrease in dry mouth severity with OXY-XL compared with IR-Oxy. CONCLUSIONS: Oxy-XL maintains relatively constant plasma drug and metabolite concentrations and minimizes first-pass metabolism of oxybutynin. The metabolite appears to contribute to dry mouth associated with oxybutynin, and following Oxy-XL metabolite exposure is reduced compared with IR-Oxy. Consequently less dry mouth was observed with Oxy-XL as compared with IR-Oxy.

Pharmacokinetic and pharmacodynamic characterization of OROS and immediate-release amitriptyline.

AIMS: To characterize the pharmacokinetics of amitriptyline and its metabolite nortriptyline following OROS and IR treatments, and to correlate them with anticholinergic side-effects. METHODS: The pharmacokinetics and safety of amitriptyline following administration of an osmotic controlled release tablet (OROS and an immediate release (IR) tablet were evaluated in 14 healthy subjects. In this randomized, open label, three-way crossover feasibility study, the subjects received a single 75 mg OROS tablet, three 25 mg IR tablets administered every 8 h, or 3x25 mg IR tablets administered at nighttime. In each treatment arm serial blood samples were collected for a period of 84 h after dosing. The plasma samples were analysed by gas chromatography for amitriptyline and its metabolite nortriptyline. Anticholinergic effects such as saliva output, visual acuity, and subject-rated drowsiness and dry mouth were measured on a continuous scale during each treatment period. RESULTS: Following dosing with OROS (amitriptyline hydrochloride), the mean maximal plasma amitriptyline concentration Cmax (15.3 ng ml-1 ) was lower and the mean tmax (25.7 h) was longer than that associated with the equivalent IR dose administered at nighttime (26.8 ng ml-1 and 6.3 h, respectively). The bioavailability of amitriptyline following OROS dosing was 95% relative to IR every 8 h dosing, and 89% relative to IR nighttime dosing. The metabolite-to-drug ratios after the three treatment periods were similar, suggesting no change in metabolism between treatments. The relationships between plasma amitriptyline concentration and anticholinergic effects (e.g. reduced saliva weight, dry mouth, and drowsiness) were similar with all three treatments. Of the anticholinergic effects, only decreased saliva weight and dry mouth correlated well with plasma amitriptyline concentrations; drowsiness did not. There was no apparent correlation between anticholinergic effects and the plasma nortriptyline concentration. CONCLUSIONS: The bioavailability of OROS (amitriptyline hydrochloride) was similar to that of the IR treatments and the pharmacokinetics of amitriptyline after OROS dosing may decrease the incidence of anticholinergic effects compared with that seen with nighttime dosing of the IR formulation. Therefore, this controlled-release formulation of amitriptyline may be appropriate for single daily administration.

Effect of time interval between food and drug ingestion on the absorption of oxybutynin from a controlled-release tablet.

The effect of time interval between food and drug ingestion on the bioavailability of oxybutynin was investigated in a randomized, three-phase cross-over study in 31 healthy volunteers. The serum concentrations of oxybutynin and the metabolite, N-desethyloxybutynin were measured up to 48 hr after ingestion of a controlled-release 10 mg oxybutynin tablet either in fasting state, 2 hr after breakfast or 1 hr before. The Cmax of both oxybutynin (P < 0.0001) and N-desethyloxybutynin (P < 0.0001) and the AUC0-1 of N-desethyloxybutynin (P < 0.05) were significantly larger when oxybutynin was ingested 2 hr after breakfast, than during the fasting, but the AUC0-1 of oxybutynin remained unchanged. Breakfast ingested 1 hr after oxybutynin did not affect the pharmacokinetic parameters of oxybutynin or N-desethyloxybutynin. The saliva secretion rate decreased slightly more (P < 0.05), when oxybutynin was administered 2 hr after breakfast than during fasting. The effect of food ingestion on the serum concentrations of oxybutynin and N-desethyloxybutynin is expected to have minor clinical significance only. However, ingestion of the controlled-release tablet 1 hr before meal increases the likelihood of obtaining constant drug levels with lower peak concentrations during the dosage interval, and thus ingestion of the controlled-release tablet 0.5-1 hr before food may well improve tolerability and compliance in patients who suffer from adverse reactions.

New perspectives on the overactive bladder: pharmacokinetics and bioavailability.

In the United States alone, approximately 17 million men and women have symptoms of overactive bladder (OAB). For many years, oxybutynin was the drug of choice for treating OAB. Although it provided effective treatment, multiple daily doses were required, and adverse events, such as dry mouth and constipation, were decided drawbacks. Controlled drug delivery systems seen in commercially available OAB formulations alter the pharmacokinetics of antimuscarinic medications in ways that maintain efficacy and allow once-daily dosing and reduction of adverse events. In the future, OAB medications will not only incorporate new chemical entities, such as the S-enantiomer of oxybutynin, but will also use novel drug delivery technologies, including transdermal patches and bladder implants.