The intravesical route permits site-specific delivery of drugs with a reduced side-effect profile as compared to oral delivery systems, either by avoiding first-pass metabolism or by obtaining a local effect. We investigated mechanisms related to urothelium permeability and new physical and chemical developments in intravesical drug delivery that potentially permit successful treatment of several bladder dysfunction.
A literature review.
Pharmacologic agents increasing urothelial permeability and useful for clinical purposes have been described, such as dimethylsulfoxide, protamine sulphate, chitosan, and nystatin. Among physical approaches, electromotive drug administration appears to be more effective than intravesical passive diffusion in delivering drugs through the urothelium into deeper layers of the bladder. Experimental and clinical reports demonstrated that electric current significantly increases the transport of local anaesthetics, mytomicin C, oxybutynin, resiniferatoxin, epinephrine, and dexamethasone. Among new chemical approaches, cell-penetrating peptides posses the ability to translocate macromolecular drugs across membranes of urothelial cells. The therapeutic benefits of sustained delivery afforded by thermosensitive hydrogel, which forms a depot for hydrophilic and hydrophobic drugs, have been demonstrated by delivering anti-inflammatory drugs. Liposomes improve the aqueous solubility of several hydrophobic drugs such as taxol, amphotericin, and capsaicin.
Electromotive drug administration, new in situ delivery systems, and bioadhesive liposomes may make it possible to extend intravesical therapy and drug administration to many bladder diseases. Research to expand knowledge of the chemical and physical properties of the bladder and processes regulating drug transport across biologic membranes is needed to make this a reality.
Keywords: Electric current, Intravesical drug administration, Permeability, Sustained delivery.
The direct administration of drug solutions into the bladder overcomes systemic adverse effects of drugs used for bladder disease. Commonly used for the treatment of superficial bladder cancer, intravesical drug administration, for example, oxybutynin, has also been used to treat neurogenic detrusor overactivity
Recent observations of several receptors for different neurotransmitters (cholinergic, adrenergic, purinergic, and vanilloid receptors) at the level of the urothelial cells suggest that the target sites for pharmacologic modulation of bladder dysfunction should be readily available. In any event, the ideal chemical and physical conditions for each instilled drug solution must still be standardised. Urine is frequently hypertonic and differs markedly with respect to blood potassium and pH. Changes in intravesical ions, osmolality, and pH can alter urothelial permeability, increasing or decreasing drug penetration into the bladder wall.
Furthermore, it seems that a crucial point to obtain successful drug penetration is the vehicle of the drug solution to increase urothelial permeability. Normal saline, ethanol at different concentrations, glucidic solvents, or liposomes with hydrogel, have been used for capsaicin and resiniferatoxin (RTX) intravesical delivery, with different success rates , , , and .
As things currently stand, we do not know the best vehicle for each intravesical drug nor do we know the ideal bladder conditions to perform useful intravesical treatment. Indeed, a better knowledge of urothelial permeability and of new systems of delivery could help to optimise intravesical treatments.
This review examines the mechanisms underlying drug transport into the bladder wall and discusses exciting new frontiers for intravesical therapy.
2. Bladder urothelium: permeability and drug diffusion
The main function of the urinary bladder is to store urine while maintaining the composition of the urine similar to that produced by the kidneys. The urothelium allows the urinary bladder to minimise alterations in the composition of the urine. Urothelial cells have different properties to perform this function. First of all, the urothelium should expose a minimum surface to intravesical volume to avoid large movements of urine components across the bladder wall. The geometry of the bladder, which resembles a sphere, is ideal for obtaining a minimum epithelial surface area with respect to urine volume. Thus, the amount of movement of substances between the urine and blood is reduced. Urothelial cells should be impermeable to all substances present in the urine or blood. Movement across the urothelial cells occurs via two parallel pathways: the “transcellular pathway” (through the cells) and the “paracellular pathway” (through the tight junctions and lateral intercellular spaces)
3. Passive permeability
For prolonged periods, the mammalian bladder is able to maintain large gradients for water, small nonelectrolytes, ions, protons, and ammonium between the urine it stores and blood. It is well known that the bladder has a small but finite passive permeability to most substances (electrolytes and nonelectrolytes) found in the urine and blood
In essence, the apical membrane of the bladder urothelium contributes 80% of the resistance to water flow of the epithelium as well as >95% of the resistance to fluxes of urea, ammonia, and protons. If there is appreciable permeation of these substances through the tight junctions, then the apical membrane provides an even higher proportion of the resistance across the epithelium
4. The “blood–urine barrier”
An essential requirement for normal bladder function is that urine components should not jeopardise the barrier properties of the bladder
5. Agents that alter urothelial permeability
Several pharmacologic agents, which increase bladder urothelial permeability and can be used for clinical purposes, have been described.
A number of nonphysiologic factors cause alterations of the urothelial barrier function. Bacterial products, such as amphotericin B, nystatin, polymyxin B, and possibly β-hemolysin, as well as positively charged proteins released from eosinophils and found in sperm (histones and protamine), increase the ion permeability of the urothelium by interacting with the apical membrane.
Acetate, propionate, butyrate, or succinate at pH 4.4, but not at pH 5.0, also alter the transepithelial permeability of rabbit urothelium
Chitosan is a polysaccharide composed of glucosamine and N-acetylglucosamine. It is regarded as a biocompatible, biodegradable, and nontoxic polymer. Chitosan can induce desquamation of pig urothelium, which removes all diffusion barriers: glycosaminoglycans, membrane plaques, and tight junctions of umbrella cells. This ability has been proven in vitro on nasal, buccal, vaginal, and urinary bladder mucosa of different animals, thus making this polymer a promising agent in the development of controlled drug delivery systems
Nystatin and gramicidin eliminate the apical membrane as a resistive element for water diffusion. Nystatin is incorporated into the lipid bilayers of sterol-containing biologic membranes and creates aqueous pores. This effect rapidly increases with the addition of the detergent Triton X-100
5.3. Protamine sulphate
An ideal model of urothelial injury would involve selective damage to the surface of urothelial or umbrella cells. On the basis of its potential to damage the surface glycosaminoglycan layer of urothelial cells, protamine sulphate (PS) has been instilled into bladders in vivo and the effects on bladder function have been evaluated  and . It was demonstrated that exposure to PS in vivo causes a clear-cut disruption of the bladder permeability barrier, which starts within 1
5.4. Dimethyl sulfoxide
Widely used to treat interstitial cystitis, dimethyl sulfoxide (DMSO) is a solvent with anti-inflammatory and bacteriostatic activity; it produces analgesia and nerve blockade, diuresis, cholinesterase inhibition, vasodilation, and muscle relaxation. DMSO also has the unique capability to penetrate living tissues without causing significant damage. It has been used to enhance bladder absorption of chemotherapeutic agents such as cisplatin, pirarubicin, and doxorubicin  and . In addition, DMSO is approved by the US Food and Drug Administration for the treatment of interstitial cystitis and up to 50% (vol/vol) DMSO can safely be instilled in the bladder of patients.
6. Recent developments in physical approaches
Drugs absorption through the bladder wall and drug concentrations at the target site (detrusor) are important determinants of efficacy, but passive diffusion (PD) of drugs across the urothelium is complex and not easily defined.
Many factors, including pressure and concentration gradients, time of exposure, partition coefficient, molecular weight and chemical structure, pH degree of ionisation, and urinary output rate, interact to produce different transport rates.
It has been observed that recruitment of electrokinetic forces accelerates drug administration rates across biologic membranes and into underlying tissues
The idea of using electric current to allow transcutaneous drug penetration can probably be attributed to the work done by Veratti in 1747
EMDA has been recently applied in the treatment of bladder pathologies and dysfunctions. Laboratory and clinical studies have been conducted on intravesical electromotive delivery of oxybutynin  and , mitomycin C (MMC) , , and , RTX  and , verapamil and dexamethasone
Laboratory studies have been performed, first of all, to identify a sensitive method to determine tissue concentrations of different drugs after either PD or electromotive administration (
Massoud et al. found that high-performance liquid chromatography (HPLC), equipped with a diode-array spectrophotometric detector, an electrochemical detector and reversed-phase column, was a useful method to determine tissue concentrations of oxybutynin
The objectives of experimental studies were also to analyse the effects of electric current both on bladder tissues and on the chemical structure of the drug being used. Di Stasi et al. observed that EMDA did not alter the chemical structure of RTX, lidocaine and epinephrine, oxybutynin, or MMC and did not induce any damage to the exposed bladder tissues , , , , and , thus making this method a promising tool for the treatment of detrusor overactivity and superficial bladder cancer and for inducing local anaesthesia. Furthermore, through in vitro studies the authors demonstrated that EMDA significantly increased the transport rates of several drugs into the bladder wall, as compared to simple PD. Two recent laboratory studies investigated both the transport rates of RTX into pig bladder wall after either PD or EMDA and the best conditions for the stability of RTX stock solutions  and . These authors showed that the application of electric current significantly reduced the variability in transport rates of RTX as compared to PD and that glass storage in the dark and at low temperatures did not alter the stability of the drug  and . These results could allow better results with RTX intravesical treatment.
From a clinical standpoint (
Fatal side-effects have never been reported during or after treatment with EMDA. Hinkel and Pannek reported systemic neurologic alterations after EMDA in two older patients treated for chronic noninfectious cystitis, probably related to epinephrine systemic absorption
It has been reported that, compared to spinal or general anaesthesia, the local anaesthesia induced by lidocaine with EMDA saves around 15% of the costs
7. Recent developments in chemical approaches
A number of substances have been developed to increase drug transport across the bladder wall. Sasaki reported that intravesical instillation of saponin before administering anticancer drugs (4′-O-tetrahydropyranyldoxorubicin [THP]) can cause vacuolisation and swelling of superficial cells, and the concentration of THP in bladder tissues was significantly higher than that of untreated animals. In any case, no difference was found in plasma  and .
Certain peptides called cell-penetrating peptides or protein transduction domains have been shown to posses the ability to translocate macromolecular drugs across the blood–brain barrier and membranes of other cells
One of the authors of the present study (M.B.C.) examined the effect of short-length transactivators of transcription peptides, deriving from immunodeficiency virus, for the intravesical administration of macromolecular drugs such as peptide nucleic acids (PNAs). PNAs have been used for their “antisense” effect in various studies; in other words, they bind to RNA and completely block transcription
7.1. Sustained drug delivery
Sustained intravesical delivery of drugs can ensure the continuous presence of the drug in the bladder without needing intermittent catheterisation, and drug concentration in the bladder would be constant without any peaks and valleys. It is also plausible to expect increased efficacy with increased duration of direct contact between the drug and the abnormal urothelium
A simple and sensible approach for sustained intravesical drug delivery is prolonged infusion into the bladder. This technique has often been applied to achieve slow and sustained release of drugs inside the bladder. Prolonged instillation of RTX was recently demonstrated as a feasible procedure for treating interstitial cystitis
Forming a drug depot inside the bladder appears to be an attractive option over prolonged infusion. Aqueous solutions of poly(ethylene glycol-b-[DL-lactic acid-co-glycolic acid]-b-ethylene glycol) (PEG-PLGA-PEG) triblock copolymers form a free-flowing solution at room temperature and become a viscous gel at body temperature of 37
Liposomes were first studied in England in 1961 by Bangham
Liposomes are versatile drug delivery vehicles due to the flexibility of their compositions. Liposomes were used for intracellular delivery of anticancer drugs and biologics into the bladder cancer cell line. Use of multilamellar liposomes proved favourable in cell culture studies and the antiproliferative capacity of interferon α (IFN-α) in resistant bladder cancer cell lines was improved by using liposomes as a delivery vehicle. Instillation of liposomes encapsulated radiolabelled IFN-α or radiolabelled liposomes into mouse bladder was able to achieve localised therapy with negligible penetration to other organs.
Earlier it was reported that liposomes can form a film on the cell surface and have been tested as possible therapeutic agents to promote wound healing. Such reports prompted evaluation of empty liposomes devoid of any drug in a rat model of bladder hyperactivity. Liposomes alone were able to partially reverse the high urinary frequency induced by PS/KCl. These observations suggested that liposomes might enhance the barrier properties of a dysfunctional uroepithelium and increase resistance to irritant penetration.
The lower urinary tract is ideally suited for minimally invasive intravesical therapy that would limit the risk of systemic side-effects. Although treatment with intravesical passive delivery of drugs is commonly used today in patients on intermittent catheterisation, new physical approaches such as EMDA or in situ delivery systems and bioadhesive liposomes may expand intravesical therapy and drug administration to many bladder diseases. New agents modulating bladder neurotransmitters and neuroreceptors are being discovered, and they may be appropriate for advanced intravesical therapy. Research to expand the knowledge of chemical and physical properties of the bladder and processes regulating drug transport across biologic membranes is needed to make this a reality.
This comprehensive article on intravesical therapies reviews the less accessible, nonmedical literature for the urologist and links the information to clinical practice and empirical therapies for which I offer my congratulations. The physical and chemical properties of the urothelium are worth further study in the future and empirically found applications need confirmation in randomised trials so that a larger introduction into clinical practice is possible. Improving anaesthesia of the bladder is useful for general urologic practice. In functional urology, interstitial cystitis and the overactive bladder are demanding indications for any improvement in the intravesical route (botulinum toxin, resiniferatoxin, dimethyl sulfoxide, oxybutynin, etc). Electromotive drug administration (EMDA) is not routinely used in clinical practice and intraluminal drug delivery devices need confirmation in the literature along with pertinent indications. New chemical approaches are discussed but are still considered experimental. This review is hopefully the impetus for a large series of studies, publications, and new developments.
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a Department of Urology, University of Perugia, Perugia, Italy
b Department of Urology, “Tor Vergata” University of Rome, Rome, Italy
c McGowan Institute of Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
© 2006 European Association of Urology, Published by Elsevier B.V.