Adjunctive Therapy to Promote Stone Passage

MANAGEMENT UPDATE Adjunctive Therapy to Promote Stone Passage Geoffrey R. Nuss, BA, Judson D. Rackley, MD, Dean G. Assimos, MD Department of Urology, Wake Forest University School of Medicine, Winston-Salem, NC The majority of individuals with nephrolithiasis have small ureteral stones that pass spontaneously. However, patients may experience severe pain during this process, which significantly alters their quality of life and may limit their vocational responsibilities. Therefore, measures to facilitate stone passage are uniformly embraced. We discuss methods to enhance spontaneous stone passage as well as the elimination of fragments generated with extracorporeal shock-wave lithotripsy. [Rev Urol. 2005;7(2):67–74] © 2005 MedReviews, LLC Key words: Shock-wave lithotripsy • Calcium channel blockers •
-Adrenergic blockers • Progesterone • COX-2 inhibitors • Phosphodiesterase inhibitors he majority of individuals with nephrolithiasis have small ureteral stones that pass spontaneously. However, patients may experience severe pain during this process, which significantly alters their quality of life and may limit their vocational responsibilities. Therefore, measures to facilitate stone passage are uniformly embraced. Herein, we discuss methods to enhance spontaneous stone passage as well as the elimination of fragments generated with extracorporeal shock-wave lithotripsy (SWL). T VOL. 7 NO. 2 2005 REVIEWS IN UROLOGY 67 Adjunctive Therapy to Promote Stone Passage continued Physiology An understanding of the mechanics of urine transport in the collecting system and ureter provides insight into the methods used to facilitate stone passage. The ureter and collecting system are composed of syncytial-type smooth muscle—smooth muscle without neuromuscular junctions.1,2 When urine from the ducts of Bellini reaches the calyces, contraction of the calyces, renal pelvis, and ureter ensues. Contractions in the calyces are more frequent and robust than in the pelvis. Contractions in the pelvis are of higher frequency and amplitude than in the ureter.3 These relationships promote antegrade transport of urine into the bladder. These contractile events are driven by electrical activity generated by initial depolarization of these smooth muscle cells, promoting intracellular calcium influx, and resulting in contraction. This also results in release of calcium from the sarcoplasmic reticulum.4–8 The contractions are regulated by pacemaker cells located in these areas. The transmembrane resting potential of pacemaker cells is lower than that of other adjacent cells.9 The electrical activity in the pacemaker cells arises spontaneously. There are a number of second messenger intracellular molecules that play a role in the contraction as well as the relaxation of smooth muscle. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) modulate relaxation, whereas inositol 1,4,5triphosphate (IP3) and diacylglycerol (DG) are involved in contraction.10–16 Relaxation occurs after efflux of calcium from the cell and redistribution of this cation within intracellular organelles. Collecting system and ureteral activity is not dependent on the nervous system, as evidenced by renal transplant grafts.17 However, the autonomic nervous system is 68 VOL. 7 NO. 2 2005 REVIEWS IN UROLOGY involved in modulation of these events. Parasympathetic activity promotes contraction, whereas sympathetic influences are divergent:
(contraction) and ß (relaxation).18 Ureteral stones can cause obstruction of urine transport. A number of dynamic changes, thought to be modulated by several vasoactive substances, occur with ureteral obstruction. Animal experimentation indicates that renal blood flow (RBF) increases for up to approximately 90 minutes immediately following obstruction, and decreases thereafter. Collecting system pressure rises during the first 5 hours after obstruction and then it subsequently decreases.19 The initial increase in RBF is thought to be mediated, at least partially, through eicosanoids such as prostaglandin E2 and I2, and nitric oxide.20–23 The subsequent decrease in RBF has been attributed to angiotensin II and endothelin.24–26 An increase in intraluminal pressure, ureteral diameter, and length all proximal to the point of obstruction subsequently occurs.27 After a transient increase in the amplitude and frequency of smooth muscle contraction, these diminish and urinary flow is dependent on hydrostatic forces generated by the kidney.28,29 Infection may also contribute to ineffective urinary transport. Interaction between the stone surface and ureteral mucosa induces inflammation at the stone site. This may promote a decrease in ureteral compliance and luminal diameter, further inhibiting stone passage.30 Natural History The majority of ureteral stones spontaneously pass. Stone size and position influence stone passage. Ueno and associates reported that 286 of 520 (53%) subjects harboring ureteral stones passed their stones spontaneously. Size significantly influenced passage rates and time to pass. The mean dimensions of passed stones was a length (L) of 6.3 mm and a width (W) of 4.0 mm; stones requiring removal had mean dimensions of 11.7 mm (L) and 7.1 mm (W). Ueno and colleagues reported that spontaneous stone passage was unlikely if stone width was > 8 mm.31 Morse and Resnick reported on a cohort with ureteral calculi and stratified passage by stone width and position. The spontaneous passage rates were as follows: 1 mm width, middle ureter (M) 85% and distal ureter (D) 100%; 2 mm width, proximal ureter (P) 100%, M 83%, D 93%; 3 mm width, P 42%, M 55%, D 69 %; 4 mm width, P 20%, M 62%, D 55%; 5 mm width, P 6%, M 57%, D 45%; and 6 mm width, D 25%. These results indicate that smaller stones located in the middle or distal ureter, at presentation, are more apt to pass spontaneously than larger calculi, especially when in the proximal ureter.32 Miller and Kane reported a similar relationship in a prospective study. They also stratified results by time to spontaneous passage. It took 31 days for stones < 2 mm wide, 40 days for those 2–4 mm wide, and 39 days for those 4–6 mm wide.33 The Miller and Kane series used measurements obtained from plain film radiography. However, similar results have been cited for noncontrast helical computed tomography (CT), the current imaging modality of choice for the initial evaluation of patients suspected of having a ureteral stone.34 Pharmacologic Therapy Calcium Channel Blockers Ureteral smooth muscle contraction is dependent on transcellular and intracellular calcium fluxes. Calculi may induce ureteral spasm that inhibits stone passage. An effective pharmacologic agent would inhibit spasm without significantly impacting ureteral peristalsis because the latter Adjunctive Therapy to Promote Stone Passage is thought to promote stone passage. Calcium channel blockers, which inhibit the influx of extracellular calcium, have been prescribed to facilitate stone passage. Nifedipine, verapamil, and diltiazem have been shown to inhibit ureteral contraction in guinea pigs and humans.35–38 Furthermore, Hertle and Nawrath demonstrated that verapamil and nifedipine suppressed fast phasic contraction without effecting slow tonic contraction, suggesting that spasm may be inhibited without affecting peristaltic contraction.37,38 Studies suggest that a combination of nifedipine and corticosteroid therapy is effective in facilitating stone passage. Borghi and associates, in a randomized double-blind controlled trial of 86 patients with ureteral stones less than 15 mm in width, demonstrated a statistically significant increased stone expulsion rate for patients given 40 mg nifedipine and 16 mg methylprednisolone daily for a maximum of 45 days than for patients receiving placebo and 16 mg methylprednisolone daily (86% vs 65%). Furthermore, mean time to passage was also statistically significantly less with this regimen than with placebo (11.2 days vs 16.5 days). Reported drug-related side effects were moderate, resulting in 9 subjects discontinuing the study. The actual benefit of steroid therapy was not defined in this study as there were no true controls or a group receiving nifedipine alone.39 Similarly, Cooper and associates reported increased passage rates for patients with ureteral calculi 2–6 mm in size in a randomized controlled trial. The control group received 10 mg ketorolac 4 times daily for 5 days, then oxycodone/acetaminophen and prochlorperazine suppository as needed, while the treatment arm received control medications plus 30 mg nifedipine XL daily for 7 days, 10 mg prednisone twice daily for 5 days, and trimethoprim/sulfamethoxazole (double strength) daily for 7 days. The passage rates were statistically significantly lower for the control than the treatment group, 54% versus 86%. Mean work days lost for the treatment group was also statistically significantly decreased (means of 1.76 days and 4.96 days). Drug-related side effects were reported to be similar for both cohorts and did not result in study withdrawal.40 Most recently, Porpiglia and colleagues, in a randomized prospective trial, demonstrated the efficacy of therefore decrease contractile activity associated with ureteral spasm induced by calculi, thus facilitating passage. Peters and Eckstein demonstrated that in obstructed and partially obstructed canine ureters, phentolamine (a nonselective
antagonist) decreased frequency of contraction, leading to a statistically significant increase in urinary flow in the partially obstructed ureter. However, phentolamine was not noted to have a significant impact on the amplitude of contraction.42 Lindsey and colleagues found that implantation of stones in canine ureters induced peristaltic waves An effective pharmacologic agent would inhibit spasm without significantly impacting ureteral peristalsis because the latter is thought to promote stone passage. nifedipine and deflazacort (an oral steroid) in treating distal ureteral stones ≤ 10 mm in length. The spontaneous passage rate for the control arm (75 mg diclofenac as needed) was statistically significantly lower, 35%, as compared to 79% for the treatment group (30 mg deflazacort daily for up to 10 days, 30 mg nifedipine daily for up to 4 weeks, 75 mg diclofenac as needed). Mean time to expulsion was also statistically significantly decreased with the treatment arm (7 days vs 20 days) as was average amount of diclofenac used (15 mg vs 105 mg). Serious side effects were minimal, but included transient hypotension and palpitations.41
-Adrenergic Blockers Although ureteral smooth muscle lacks direct innervation, its contractile activity is modulated by the autonomic nervous system. Stimulation of
-1 adrenergic receptors enhances contractile frequency and amplitude. A pharmacologic agent that antagonizes the
-1 receptor activity should of higher pressure than controls. This hyperperistalsis was decreased by administering the nonselective
antagonist phenoxybenzamine.43 There have been reports indicating that the administration of selective
-1 blocking agents facilitates passage of ureteral calculi. Cervenakov and associates, in a nonrandomized study, administered 0.4 mg of tamsulosin, a selective
-1 antagonist, per day to 51 patients with ureteral calculi (mean W 4.0 mm and mean L 7.6 mm) and compared them to a similar number of patients with ureteral stones of similar size (mean W 3.8 mm and mean L 7.5 mm) receiving standard supportive care. Forty-one of the 51 (80.4%) receiving tamsulosin passed their stones spontaneously as compared to 32 (62.8%) in the other cohort. Time to passage was also more expeditious in the tamsulosin group.44 A recent randomized controlled trial by Dellabella and associates demonstrated that tamsulosin may be effective in facilitating the passage of distal ureteral calculi. The VOL. 7 NO. 2 2005 REVIEWS IN UROLOGY 69 Adjunctive Therapy to Promote Stone Passage continued patients in this study had calculi ranging from 3.8 mm to 13 mm in width. Patients in the treatment group were given oral floroglucinetrimetossibenzene 3 times daily for up to 4 weeks, 30 mg deflazacort daily for 10 days, co-trimoxazole twice daily for 8 days, and 75 mg diclofenac intramuscularly as needed, while the treatment group received 0.4 mg tamsulosin daily for up to 4 weeks with the same dosages of deflazacort, co-trimoxazole, and diclofenac. Passage rates were 70% for the placebo group and 100% for the treatment group. Furthermore, mean hours to expulsion (111.1 vs 65.7), mean number of analgesic injections (2.83 vs 0.13), number of hospitalizations (10 vs 0), and number of stones requiring ureteroscopic intervention (9 vs 0) were all statistically significantly decreased in the treatment group. No drug-related side effects were noted in any of the 60 patients included in the trial.45 More recently, Dellabella and associates showed, in another randomized controlled trial, that treatment of patients with distal ureteral calculi with tamsulosin was superior to both placebo and nifedipine. All enrolled subjects received 30 mg deflazacort daily for 10 days, co-trimoxazole twice daily for 8 days, and 75 mg diclofenac intramuscularly as needed. The control group received floroglucinetrimetossibenzene tablets 3 times daily, and the treatment groups received either tamsulosin 0.4 mg daily or 30 mg slow-release nifedipine daily. The group treated with tamsulosin experienced a more statistically significant increase in passage rates than both the control and nifedipine groups (97.1% vs 65.7% and 75.6%, respectively). Furthermore, a statistically significant decrease in time to passage, lower analgesic requirement, decrease in work days lost, and decrease in hospitalization and need 70 VOL. 7 NO. 2 2005 REVIEWS IN UROLOGY for endoscopic stone removal were also demonstrated for the group treated with tamsulosin. Drug-related side effects were not mentioned, although all 210 patients enrolled completed the study.46 Terazosin, another selective
-1 adrenergic antagonist, has also recently been shown to facilitate stone passage. Tekin and colleagues, in a prospective randomized trial of 75 patients with distal ureteral calculi ≤ 15 mm in width, found that patients treated with 5 mg terazosin daily for 4 weeks had a more statistically significant increase in stone passage rate than those patients receiving no treatment (77% vs 46%). Treatment with terazosin was particularly effective for stones < 8 mm, as a statistically significant increase in passage rate was noticed for this subgroup (95% vs 56%). Drug-related side effects were minimal and no patient dropped out of the study.47 Nonsteroidal Anti-Inflammatory Drugs In vitro studies of the human ureter have demonstrated that prostaglandins increase ureteral smooth muscle contractility.48,49 Nonsteroidal anti-inflammatory drug (NSAID) agents that inhibit cyclooxygenase (COX), an enzyme involved in prostaglandin synthesis from fatty acids, have been used extensively in the management of patients with renal colic. Their benefits are based on various mechanisms including a reduction in RBF that decreases pressure in the collecting system, ureteral smooth muscle relaxation, and a decrease in stoneinduced ureteral edema. The latter 2 effects of NSAIDs have been hypothesized to facilitate stone passage as well. Two randomized controlled trials have assessed the ability of NSAIDs to facilitate stone passage. Kapoor and colleagues demonstrated that patients receiving indomethacin suppositories (a nonselective COX inhibitor) did not experience increased stone passage rates or decreased time to passage when compared to patients receiving placebo. However, the patients receiving indomethacin did require a statistically significantly decreased amount of narcotic analgesics.50 Laerum and associates showed that oral diclofenac, a nonselective COX inhibitor, did not increase stone expulsion rate compared to placebo. However, diclofenac significantly decreased pain and hospital admissions.51 Progesterone The increased prevalence of hydroureteronephrosis beginning during the second trimester of gestation and ending within 1 month postpartum suggests that progesterone and/or estrogen may affect ureteral function. It has been proposed that progesterone promotes ureteral dilatation during pregnancy and delays the rate of its disappearance postpartum. Mikkelsen and colleages treated 24 patients of both genders with a 250 mg intramuscular dose of hydroxyprogesterone to see if this would facilitate stone passage. Fourteen patients (59%) passed calculi while all other patients required surgical removal.52 However, the efficacy of this approach cannot be determined as there was no control group. Future Direction of Pharmacotherapy COX-2 Inhibitors The aforementioned studies suggest that nonselective COX inhibitors are not effective in facilitating stone passage. However, COX-2 inhibitors have not been assessed in this setting. These may prove to be effective agents to facilitate stone passage. Nakada and associates have found that the COX-2 protein and its mRNA are expressed to a greater degree in obstructed human ureter as Adjunctive Therapy to Promote Stone Passage compared to normal human ureter.53 Furthermore, this group demonstrated that a selective COX-2 inhibitor reduced the contractility of both human and swine ureter.53,54 Phosphodiesterase Inhibitors The second messengers, cAMP and cGMP, are mediators of smooth muscle relaxation. cAMP and cGMP breakdown occurs via the activity of a family of isoenzymes known as the phosphodiesterases. Phosphodiesterase blinded controlled trial, showed that drotaverine, a selective PDE IV inhibitor, significantly reduced acute renal colic when compared to placebo.59 Although no studies have evaluated PDE inhibitors as agents to facilitate stone passage, the aforementioned properties suggest that this should be investigated. Shock-Wave Lithotripsy and Adjunctive Therapy Shock-wave lithotripsy (SWL) may While nonselective PDE inhibitors, such as papaverine, have been shown to attenuate renal colic, animal studies have shown that systemic side effects may render them unsuitable clinical agents. (PDE) inhibitors are a class of drugs that inhibit the breakdown of cAMP and cGMP, enhancing smooth muscle relaxation. Therefore, PDE inhibitors may be able to decrease ureteral spasm and facilitate stone passage. While nonselective PDE inhibitors, such as papaverine, have been shown to attenuate renal colic, animal studies have shown that systemic side effects may render them unsuitable clinical agents.55,56 Taher and colleagues identified the isoenzyme PDE IV as being dominant over other PDEs in regulation of ureteral smooth muscle.57 Rolipram, a selective PDE IV inhibitor, has been shown to facilitate ureteral relaxation. Kühn and associates assessed the ability of sodium nitroprusside and various PDE inhibitors to promote relaxation of explanted human ureter. They found that sodium nitroprusside and rolipram were the most effective in promoting ureteral relaxation of the agents tested.58 Becker and associates showed that in rabbits rolipram promoted ureteral relaxation without significant effects on systemic blood pressure.55 Most recently, Romics and colleagues, in a randomized double- be an effective treatment for patients with upper urinary tract stones. However, a significant disadvantage of SWL is that it requires patients to pass stone fragments. Stones remaining in the kidney after SWL may act as foci for stone growth. Patients with ureteral stones that do not pass will usually require more invasive treatments, such as ureteroscopy, to render them stone free. Therefore, methods to facilitate complete stone evacuation after SWL are of merit. Various means of enhancing these stone fragments have been proposed. Medical Therapy Medical therapy has been utilized to slow-release nifedipine and 30 mg deflazacort daily for 10 days had a statistically significant increase in complete stone passage as compared to 40 patients given placebo (75% vs 50%). Furthermore, patients in the treatment group required a statistically lower total amount of diclofenac for analgesia (37.5 mg vs 86.25 mg). No significant drug-related side effects were reported in both cohorts.60 Although these are encouraging results, more clinical trials are warranted for confirmation. Inversion Therapy and Physiotherapy Stone fragments generated by SWL have been shown to accumulate in the lower calyces.61,62 Gravity, as well as the geometric configuration of the renal collecting system, may play a role in this process.62 It has been postulated that inversion therapy, mechanical percussion, and administration of diuretics, or a combination thereof may enhance the passage of lower pole calculi.63 Brownlee and colleagues assessed the safety of inversion with forced hydration, percussion, and diuresis, and tested the benefits of single and multiple sessions.64 Nine healthy volunteers were initially tested. They received 2 liters of intravenous hydration over 1 hour, 20 mg furosemide administered intravenously, and were inverted for 2.5 hours without complication. Patients with lower pole stone fragments after Patients with ureteral stones that do not pass after shock-wave lithotripsy will usually require more invasive treatments, such as ureteroscopy, to render them stone free. promote stone passage in patients undergoing SWL of ureteral stones. Porpiglia and associates, in a prospective randomized trial, demonstrated that 40 patients undergoing SWL for ureteral stones who received 30 mg SWL were then evaluated. Sixteen patients were subjected to the same protocol; 12 patients passed fragments, and 2 became stone free after 1 session of therapy. Another 8 patients with lower pole fragments VOL. 7 NO. 2 2005 REVIEWS IN UROLOGY 71 Adjunctive Therapy to Promote Stone Passage continued underwent multiple sessions of inversion therapy in conjunction with percussion therapy administered by a family member at home. Treatment started within 7 days after SWL, and patients were instructed to use these maneuvers 3 to 4 times a day for 2 weeks. They hydrated themselves by drinking 1 quart of water before these sessions. Seven of 8 (86%) patients who began this process within 1 week after SWL became stone free. This pilot study demonstrated the potential efficacy of inversion and percussion therapy, especially when repeated regularly over a several week period. D’a Honey and associates assessed 12 patients with lower pole residual stone fragments at least 2 weeks after SWL who were treated with mechanical percussion, inversion, and diuresis induced with 20 mg intravenous furosemide immediately before initiation of therapy.65 Patients were given only 1 session of treatment. In 8 patients, the lower pole was entirely clear of stone debris after treatment as assessed by plain radiography. Four patients passed stone fragments in their first void posttreatment, and 10 patients passed stone debris within the 2 week follow-up period. Although this study suggested a potential benefit of this regimen, it was again limited by the lack of a control group. However, this same group performed a study in which a regimen of mechanical percussion, inversion, and furosemide-induced diuresis was compared with observation alone in patients who had lower caliceal stone fragments no greater than 4 mm in diameter 3 months after SWL.66 Sixty-nine patients were included in the study. Thirty-five patients were randomized to receive a treatment regimen of inversion to at least 60°, 20 mg intravenous furosemide, and the application of a chest percussion device to the flank for 10 minutes once weekly for 3 weeks or until the patient became stone free. The treatment group had a statistically significantly higher stone-free rate than the observation group (40% vs 3%), and the remainder of treated patients had a statistically significant decrease in their stone burden. In addition, there was a treatment crossover for those who had stones remaining after observation and a similar degree of success was obtained with this regimen. There has been one study that did not demonstrate any benefits of such an approach. Netto and colleagues failed to demonstrate an improvement in the passage of small stone debris in patients who underwent multiple sessions of controlled inversion therapy, diuresis, and percussion after SWL.67 The patients included in the study had stone fragments that were no more than 3 mm in diameter, and inversion/percussion therapy was begun 3 to 5 days after SWL, 3 to 4 times daily for 4 weeks. No diuretic or intravenous hydration was given; however, patients were asked to drink 1 liter of water 15 minutes prior to treatment. The control group had a higher stone-free rate at 3 months post-SWL (84%) than the group that received adjunctive therapy (64.7%). Although the benefits of such a regimen are not definitively established, it is reasonable to consider it for patients with lower pole fragments as it is generally well tolerated. Studies are warranted to help confirm that it works and to determine the best frequency and duration of therapy. Conclusions This review highlights an exciting area in urology that has ample room for Main Points • Interaction between the stone surface and ureteral mucosa induces inflammation at the stone site. This may promote a decrease in ureteral compliance and luminal diameter, further inhibiting stone passage. • The majority of ureteral stones spontaneously pass. • Calcium channel blockers, which inhibit the influx of extracellular calcium, have been prescribed to facilitate stone passage; verapamil and nifedipine suppress fast phasic contraction without effecting slow tonic contraction, suggesting that ureteral spasm may be inhibited without affecting peristaltic contraction. • Stimulation of
-1 adrenergic receptors enhances contractile frequency and amplitude. A pharmacologic agent that antagonizes the
-1 receptor activity should decrease contractile activity associated with ureteral spasm induced by calculi, facilitating passage. • In vitro studies of the human ureter have demonstrated that prostaglandins increase ureteral smooth muscle contractility. • Shock-wave lithotripsy may be an effective treatment for patients with upper urinary tract stones. Medical therapy has been utilized to promote stone passage in patients undergoing shock-wave lithotripsy of ureteral stones. • It has been postulated that inversion therapy, mechanical percussion, and administration of diuretics, or a combination thereof, may enhance the passage of lower pole calculi. 72 VOL. 7 NO. 2 2005 REVIEWS IN UROLOGY Adjunctive Therapy to Promote Stone Passage innovation and growth. Certain steps will facilitate this process. Better designed clinical trials are needed to assess the efficacy and safety of such approaches. More insight into collecting system and ureteral physiology and the development of better animal models to assess stone passage are also necessary. The ability to better predict who will pass stones spontaneously and benefit from pharmacotherapy is an important goal. This may be achieved with refinements in computed tomographic imaging and development of noninvasive methods to assess collecting system dynamics. 13. 14. 15. 16. 17. 18. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Engelmann TW. Zur Physiologie des Ureters. Pflugers Arch. 1869;2:243. Engelmann TW. Uber die electrische Erregung des Ureter, mit Bemerkungen uber die electrische Erregung im Allgemeinen. Pflugers Arch. 1870;2:247. Morita T, Ishizuka G, Tsuchida S. Initiation and propagation of stimulus from the renal pelvic pacemaker in pig kidney. Invest Urol. 1981;19:157-160. Brading AF, Burdyga THV, Scripnyuk ZD. The effects of papaverine on the electrical and mechanical activity of the guinea pig ureter. J Physiol (Lond). 1983;334:79-89. Hertle L, Nawrath H. Stimulation of voltagedependent contractions by calcium channel activator Bay K 8644 in the human urinary tract in vitro. J Urol. 1989;141:1014-1018. Yoshida M, Latifpour J, Weiss RM. Age-related changes in calcium antagonist receptors in rabbit ureter. Dev Pharmacol Ther. 1992;18:100107. Maggi CA, Giuliani S, Santicioli P. Effect of Bay K8644 and ryanodine on the refractory period, action potential and mechanical response of the guinea-pig ureter to electrical stimulation. Naunyn Schmiedebergs Arch Pharmacol. 1994; 349:510-522. Maggi CA, Giuliani S. A pharmacological analysis of calcium channels involved in phasic and tonic responses of the guinea-pig ureter to high potassium. J Auton Pharmacol. 1995; 15:55-64. Lang RJ, Zhang Y. The effects of K+ channel blockers on the spontaneous electrical and contractile activity in the proximal renal pelvis of the guinea pig. J Urol. 1996;155:332-336. Andersson R, Nilsson K. Cyclic AMP and calcium in relaxation in intestinal smooth muscle. Nat New Biol. 1972;238;119-120. Weiss RM, Vulliemoz Y, Verosky M, et al. Adenylate cyclase and phosphodiesterase activity in rabbit ureter. Invest Urol. 1977;15:15-18. Weiss RM, Hardman JG, Wells JN. Resistance of a separated form of canine ureteral phosphodiesterase activity to inhibition by xanthines and papaverine. Biochem Pharmacol. 1981; 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 30:2371-2374. Stief CG, Taher A, Truss M, et al. Phosphodiesterase isoenzymes in human ureteral smooth muscle: identification, characterization, and functional effects of various phosphodiesterase inhibitors in vitro. Urol Int. 1995;55:183-189. Berridge MJ. Inositol triphosphate and diacylglycerol as second messengers. Biochem J. 1984;220;345-360. Park S, Rasmussen H. Activation of tracheal smooth muscle contraction: synergism between Ca2+ and activators of protein kinase C. Proc Natl Acad Sci U S A. 1985;82:8835-8839. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumor production. Nature 1984;308:693-698. O’Conor VJ Jr, Dawson-Edwards P. Role of the ureter in renal transplantation. I: Studies of denervated ureter with particular reference to ureteroureteral anastomosis. J Urol. 1959; 82:566-572. Morita T, Wada I, Saeki H, et al. Ureteral urine transport: changes in bolus volume, peristaltic frequency, intraluminal pressure and volume of flow resulting from autonomic drugs. J Urol. 1987;137:132-135. Moody TE, Vaughn ED Jr, Gillenwater JY. Relationship between renal blood flow and ureteral pressure during 18 hours of total unilateral urethral occlusion. Implications for changing sites of increased renal resistance. Invest Urol. 1975;13:246–251. Allen JT, Vaughan ED Jr, Gillenwater JY. The effect of indomethacin on renal blood flow and ureteral pressure in unilateral ureteral obstruction in awake dogs. Invest Urol. 1978;15:324–327. Currie MG, Needleman P. Renal arachadonic acid metabolism. Ann Rev Physiol. 1984;46:327–341. Morrison AR, Nishikawa K, Needleman P. Unmasking of thromboxane A2 synthesis by ureteral obstruction in the rabbit kidney. Nature. 1977;267:259–260. Chevalier RL, Thornhill BA, Gomez RA. EDRF modulates renal hemodynamics during unilateral ureteral obstruction in the rat. Kidney Int. 1992;42:400–406. Franke J, Mc Dougal W. The mechanism of the preservation of renal function during obstruction by enalapril. J Urol. 1991;145:466a. Pimentel JL Jr, Martinez-Maldonado M, Wilcox JN, et al. Regulation of renin-angiotensin system in unilateral ureteral obstruction. Kidney Int. 1993;44:390–400. Syed N, Gulmi F, Chou S, et al. Renal actions of endothelin-1 under endothelin receptor blockade by BE-18257B. J Urol. 1998;159:563–566. Biancani P, Zabinski MP, Weiss RM. Bidimensional deformation of acutely obstructed in vitro rabbit ureter. Am J Physiol. 1973;225:671-674. Rose JG, Gillenwater JY. Pathophysiology of ureteral obstruction. Am J Physiol. 1973;225:830837. Rose JG, Gillenwater JY. Effects of obstruction on ureteral function. Urology. 1978;12:139-145. Holmlund D, Hassler O. A method of studying the ureteral reaction to artificial concrements. Acta Chir Scand. 1965;130:335-343. Ueno A, Kawamura T, Ogawa A, Takayasu H. Relation of spontaneous passage of ureteral calculi to size. Urology. 1977;10:544–546. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. Morse RM, Resnick MI. Ureteral calculi: natural history and treatment in an era of advanced technology. J Urol. 1991;145:263–265. Miller OF, Kane CJ. Time to stone passage for observed ureteral calculi: a guide for patient education. J Urol. 1999;162:688–691. Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to stone size and location as revealed by unenhanced helical CT. AJR Am J Roentgenol. 2002;178:101–103. Golenhofen K, Lammel E. Selective suppression of some components of spontaneous activity in various types of smooth muscle by iproveratril (Verapamil). Pfleugers Arch. 1972;331:233–243. Forman A, Andersson KE, Henriksson I, et al. Effects of nifedipine on the smooth muscle of the human urinary tract in vitro and in vivo. Acta Pharmacol Toxicol (Copenh) 1978; 43:111–118. Hertle L, Nawrath H. Calcium channel blockade in smooth muscle of the human upper urinary tract. I. Effects on depolarization-induced activation. J Urol. 1984;132:1265–1269. Hertle L, Nawrath H. Calcium channel blockade in smooth muscle of the human upper urinary tract. II. Effects on norepinephrine-induced activation. J Urol. 1984;132:1270–1274. Borghi L, Meschi T, Amato F, et al. Nifedipine and methylprednisolone in facilitating ureteral stone passage: a randomized, double-blind, placebocontrolled study. J Urol. 1994;152:1095–1098. Cooper JT, Stack GM, Cooper TP. Intensive medical management of ureteral calculi. Urology. 2000;56:575–578. Porpiglia F, Destefanis P, Fiori C, Fontana D. Effectiveness of nifedipine and deflazacort in the management of distal ureter stones. Urology. 2000;56:579–582. Peters HJ, Eckstein W. Possible pharmacological means of treating renal colic. Urol Res. 1975;4:55–59. Lindsey D, Parker DA, Arganese T, et al. Modification by dipyrone (noramidopyrine methanesulphonate) of stone-induced ureteric hyperperistalsis in the dog. Urol Res. 1979;7:13–17. Cervenakov I, Fillo J, Mardiak J, et al. Speedy elimination of ureterolithiasis in lower part of ureters with the alpha 1-blocker—tamsulosin. Int Urol Nephrol. 2002;34:25–29. Dellabella M, Milanese G, Muzzonigro G. Efficacy of tamsulosin in the medical management of juxtavesical ureteral stones. J Urol. 2003;170:2202–2205. Dellabella M, Milanese G, Muzzonigro G. The medical-expulsive therapy for distal ureteral stones: which is the optimal choice [abstract]? J Urol. 2004;171(Suppl):Abstract 1151. Tekin A, Alkan E, Beysel M, et al. Alpha-1 receptor blocking therapy for lower ureteral stones: a randomized prospective trial [abstract]. J Urol. 2004;171(Suppl);Abstract 1152. Cole RS, Fry CH, Shuttleworth KED. The action of the prostaglandins on isolated human ureteric smooth muscle. Br J Urol. 1988;61:19-26. Zwergel U, Zwergel T, Ziegler M. Effects of prostaglandins and prostaglandin synthetase inhibitors on acutely obstructed kidneys in the dog. Urol Int. 1991;47:64–69. Kapoor DA, Weitzel S, Mowad JJ, et al. Use of VOL. 7 NO. 2 2005 REVIEWS IN UROLOGY 73 Adjunctive Therapy to Promote Stone Passage continued 51. 52. 53. 54. 55. 56. 74 indomethacin suppositories in the prophylaxis of recurrent ureteral colic. J Urol. 1989; 142:1428–1430. Laerum E, Ommundsen OE, Gronseth JE, et al. Oral diclofenac in the prophylactic treatment of recurrent renal colic. Eur Urol. 1995;28:108–111. Mikkelsen AL, Meyhoff HH, Lindahl F, Christensen J. The effect of hydroxyprogesterone on ureteral stones. Int Urol Nephrol. 1988;20:257–260. Nakada SY, Jerde TJ, Jacobson LM, et al. Cyclooxygenase-2 expression is up-regulated in obstructed human ureter. J Urol. 2002; 168:1226–1229. Nakada SY, Jerde TJ, Bjorling DE, Saban R. Selective cyclooxygenase-2 inhibitors reduce ureteral contraction in vitro: a better alternative for renal colic? J Urol. 2000;163:607–612. Becker AJ, Stief CG, Meyer M, et al. The effect of the specific phosphodiesterase-IV-inhibitor rolipram on the ureteral peristalsis of the rabbit in vitro and in vivo. J Urol. 1998;160:920–925. Gruber, CM. The effect of morphine and papaverine upon the peristaltic and antiperistaltic contractions of the ureter. J Pharmacol VOL. 7 NO. 2 2005 REVIEWS IN UROLOGY 57. 58. 59. 60. 61. 62. Exp Ther. 1928;33:191. Taher A, Schulz-Knappe P, Meyer M, et al. Characterization of cyclic nucleotide phosphodiesterase isoenzymes in the human ureter and their functional role in vitro. World J Urol. 1994;12:286–291. Kühn R, Ückert S, Stief, CG, et al. Relaxation of human ureteral smooth muscle in vitro by modulation of cyclic nucleotide-dependent pathways. Urol Res. 2000;28:110–115. Romics I, Molnár DL, Timberg G, et al. The effect of drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU Int. 2003;92:92–96. Porpiglia F, Destefanis P, Fiori C, et al. Role of adjunctive medical therapy with nifedipine and deflazacort after extracorporeal shock wave lithotripsy of ureteral stones. Urology. 2002; 59:835–838. Elbahnasy AM, Clayman RV, Shalhav AL, et al. Lower-pole caliceal stone clearance after shockwave lithotripsy, percutaneous nephrolithotomy, and flexible ureteroscopy: impact of radiographic spatial anatomy. J Endourol. 1998;12:113-119. Sampaio FJ, Aragao AH. Limitations of extra- 63. 64. 65. 66. 67. corporeal shockwave lithotripsy for lower caliceal stones: anatomic insight. J Endourol. 1994;8:241-247. McCullough, DL. Extracorporeal shock wave lithotripsy and residual stone fragments in lower calices. J Urol. 1989;141:140. Brownlee N, Foster M, Griffith DP, Carlton CE Jr. Controlled inversion therapy: an adjunct to the elimination of gravity-dependent fragments following extracorporeal shock wave lithotripsy. J Urol. 1990;143:1096–1098. D’a Honey RJ, Luymes J, Weir MJ, et al. Mechanical percussion inversion can result in relocation of lower pole stone fragments after shock wave lithotripsy. Urology. 2000;55:204–206. Pace KT, Tariq N, Dyer SJ, et al. Mechanical percussion, inversion and diuresis for residual lower pole fragments after shock wave lithotripsy: a prospective, single blind, randomized controlled trial. J Urol. 2001; 166:2065–2071. Netto NR Jr, Claro JFA, Cortado PL, Lemos GC. Adjunct controlled inversion therapy following extracorporeal shock wave lithotripsy for lower pole caliceal stones. J Urol. 1991;146:953–954.