Lower Urinary Tract Disorders as Adverse Drug Reactions-A Literature Review.

A potential complication of pharmacotherapy for a given patient is the possibility of various side effects of drugs, which are manifested in many ways and constitute iatrogenic causes of diseases. Among the systemic side effects of drugs, there are also those involving the urinary tract, although these are less reported in the literature. The use of numerous drugs-especially of anticholinergics or drugs with anticholinergic potential, opioid analgesics, non-steroidal anti-inflammatory drugs, antidepressants, first-generation antipsychotics (classic neuroleptics) and selected cardiovascular drugs (beta-blockers, thiazides potassium-sparing diuretics, statins), as well as others-may increase the risk of developing urological disorders, such as urinary retention or incontinence, urinary tract infections, urolithiasis, erectile dysfunction in men and retroperitoneal fibrosis. The purpose of this paper is to characterise the abovementioned drug-induced disorders of the lower urinary tract on the basis of a non-systematic literature review.

Depression and Its Phytopharmacotherapy-A Narrative Review.

Depression is a mental health disorder that develops as a result of complex psycho-neuro-immuno-endocrinological disturbances. This disease presents with mood disturbances, persistent sadness, loss of interest and impaired cognition, which causes distress to the patient and significantly affects the ability to function and have a satisfying family, social and professional life. Depression requires comprehensive management, including pharmacological treatment. Because pharmacotherapy of depression is a long-term process associated with the risk of numerous adverse drug effects, much attention is paid to alternative therapy methods, including phytopharmacotherapy, especially in treating mild or moderate depression. Preclinical studies and previous clinical studies confirm the antidepressant activity of active compounds in plants, such as St. John's wort, saffron crocus, lemon balm and lavender, or less known in European ethnopharmacology, roseroot, ginkgo, Korean ginseng, borage, brahmi, mimosa tree and magnolia bark. The active compounds in these plants exert antidepressive effects in similar mechanisms to those found in synthetic antidepressants. The description of phytopharmacodynamics includes inhibiting monoamine reuptake and monoamine oxidase activity and complex, agonistic or antagonistic effects on multiple central nervous system (CNS) receptors. Moreover, it is noteworthy that the anti-inflammatory effect is also important to the antidepressant activity of the plants mentioned above in light of the hypothesis that immunological disorders of the CNS are a significant pathogenetic factor of depression. This narrative review results from a traditional, non-systematic literature review. It briefly discusses the pathophysiology, symptomatology and treatment of depression, with a particular focus on the role of phytopharmacology in its treatment. It provides the mechanisms of action revealed in experimental studies of active ingredients isolated from herbal antidepressants and presents the results of selected clinical studies confirming their antidepressant effectiveness.

A Synopsis of Current Theories on Drug-Induced Nephrotoxicity.

The overriding goal of the treatment of patients is its effectiveness and safety. However, all medications currently being used also exert some adverse pharmaceutical reactions, which may be regarded as an unintended but inevitable cost of pharmacotherapy. The kidney, as the main organ that eliminates xenobiotics, is an organ especially predisposed and vulnerable to the toxic effects of drugs and their metabolites during their excretion from the body. Moreover, some drugs (e.g., aminoglycosides, cyclosporin A, cisplatin, amphotericin B, and others) have a "preferential" nephrotoxicity potential, and their use is associated with an increased risk of kidney damage. Drug nephrotoxicity is, therefore, both a significant problem and a complication of pharmacotherapy. It should be noted that, currently, there is no generally recognized definition of drug-induced nephrotoxicity and no clear criteria for its diagnosis. This review briefly describes the epidemiology and diagnosis of drug-induced nephrotoxicity and characterizes its pathomechanisms, including immunological and inflammatory disturbances, altered kidney blood flow, tubulointerstitial injury, increased lithogenesis-crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy. The study also lists the basic drugs with nephrotoxicity potential and provides a short overview of the preventive methods for reducing the risk of drug-related kidney damage developing.

POTENTIAL THERAPEUTIC OPTIONS TARGETING THE GUT DYSBIOSIS IN CHRONIC KIDNEY DISEASE.

The gut microbiota plays an important physiological role in controlling not only the function of the gastrointestinal tract, but also in maintaining systemic homeostasis. Quantitative and /or qualitative disturbances of the gut microbiota (dysbiosis) are an important element in the complex pathogenesis of many diseases, including chronic kidney disease (CKD). In the disease, the mutual interactions between disturbed gut microbiota and the progression of CKD (pathophysiological "kidney-gut axis") have been demonstrated. The kidney failure causes water and nitrogen waste retention which leads to disturbances of motility, secretion and absorption in the gastrointestinal tract. These abnormalities contribute to the development of gut dysbiosis, accompanied by overproduction of toxic bacterial metabolites, with their translocation to the peripheral blood and development of endotoxemia. As a consequence, chronic kidney "low-grade" inflammation and oxidative stress develop, with further deterioration of kidney function in the mechanism of the "vicious cycle" of the kidney-gut axis. Considering the key role of gut dysbiosis and the kidney-gut axis, the attempts to restore the gut eubiosis seem to have an important role in the treatment of CKD and may be even regarded as a form of causal therapeutic intervention. The paper briefly discusses the basics of the pathophysiological kidney-gut axis in CKD and potential methods of modulating the abnormal gut microbiota in this disease, including the use of probiotic or prebiotic preparations, agents that absorb bacterial-derived toxins in the intestinal lumen, fecal microbiota transplantation and drugs used so far for other indications (acarbose, meclofenamate, lubiprostone).

Antibiotics and the Nervous System-Which Face of Antibiotic Therapy Is Real, Dr. Jekyll (Neurotoxicity) or Mr. Hyde (Neuroprotection)?

Antibiotics as antibacterial drugs have saved many lives, but have also become a victim of their own success. Their widespread abuse reduces their anti-infective effectiveness and causes the development of bacterial resistance. Moreover, irrational antibiotic therapy contributes to gastrointestinal dysbiosis, that increases the risk of the development of many diseases, including neurological and psychiatric. One of the potential options for restoring homeostasis is the use of oral antibiotics that are poorly absorbed from the gastrointestinal tract (e.g., rifaximin alfa). Thus, antibiotic therapy may exert neurological or psychiatric adverse drug reactions which are often considered to be overlooked and undervalued issues. Drug-induced neurotoxicity is mostly observed after beta-lactams and quinolones. Penicillin may produce a wide range of neurological dysfunctions, including encephalopathy, behavioral changes, myoclonus or seizures. Their pathomechanism results from the disturbances of gamma-aminobutyric acid-GABA transmission (due to the molecular similarities between the structure of the ß-lactam ring and GABA molecule) and impairment of the functioning of benzodiazepine receptors (BZD). However, on the other hand, antibiotics have also been studied for their neuroprotective properties in the treatment of neurodegenerative and neuroinflammatory processes (e.g., Alzheimer's or Parkinson's diseases). Antibiotics may, therefore, become promising elements of multi-targeted therapy for these entities.

Chronopharmacology in Therapeutic Drug Monitoring-Dependencies between the Rhythmics of Pharmacokinetic Processes and Drug Concentration in Blood.

The objective of the optimization of pharmacotherapy compliant with the basic rules of clinical pharmacology is its maximum individualization, ensuring paramount effectiveness and security of the patient's therapy. Thus, multiple factors that are decisive in terms of uniqueness of treatment of the given patient must be taken into consideration, including, but not limited to, the patient's age, sex, concomitant diseases, special physiological conditions (e.g., pregnancy, lactation, extreme age groups), polypharmacotherapy and polypragmasia (particularly related to increased risk of drug interactions), and patient's phenotypic response to the administered drug with possible genotyping. Conducting therapy while monitoring the concentration of certain drugs in blood (Therapeutic Drug Monitoring; TDM procedure) is also one of the factors enabling treatment individualization. Furthermore, another material, and yet still a marginalized pharmacotherapeutic factor, is chronopharmacology, which indirectly determines the values of drug concentrations evaluated in the TDM procedure. This paper is a brief overview of chronopharmacology, especially chronopharmacokinetics, and its connection with the clinical interpretation of the meaning of the drug concentrations determined in the TDM procedure.

DRUG-RELATED URINARY TRACT INFECTIONS.

OBJECTIVE: Bacterial urinary tract infection (UTI) is the most common infection, both in outpatient treatment and in hospital settings. Clinically, UTIs are classified into lower or upper urinary tract infections and can be either episodic or recurrent, and either uncomplicated or complicated. A severe UTI can lead to urosepsis and septic shock, while recurrent episodes of uncomplicated UTIs are considered to be an important etiological factor for the development of chronic kidney disease. The aim of this paper was to briefly discuss the classification, symptomatology and pathophysiology of a UTI and describe the rationale for the development of some drug-related urinary tract infections. The pathophysiology of a UTI is associated with multiple, anatomical and physiological dysfunctions that predispose infection, but there are also some iatrogenic factors, including the use of certain medications, that contribute to UTI development. Among drugs associated with an increased risk of UTI development one should mention immunosuppressants, agents affecting normal voiding processes and increasing the intravesical volume of residual urine, drugs promoting lithogenesis in the urinary tract with the subsequent favouring of urinary stone formation or drugs that reduce glucose reabsorption in the kidneys, causing glycosuria ("gliflozins"). CONCLUSION: Conclusions: Therefore, a UTI may also be a specific manifestation of adverse drug reactions and it should be taken into account in the monitoring and diagnosing of druginduced disorders.

An Outline of Renal Artery Stenosis Pathophysiology-A Narrative Review.

Renal artery stenosis (RAS) is conditioned mainly by two disturbances: fibromuscular dysplasia or atherosclerosis of the renal artery. RAS is an example of renovascular disease, with complex pathophysiology and consequences. There are multiple pathophysiological mechanisms triggered in response to significant renal artery stenosis, including disturbances within endothelin, kinin-kallikrein and sympathetic nervous systems, with angiotensin II and the renin-angiotensin-aldosterone system (RAAS) playing a central and key role in the pathogenesis of RAS. The increased oxidative stress and the release of pro-inflammatory mediators contributing to pathological tissue remodelling and renal fibrosis are also important pathogenetic elements of RAS. This review briefly summarises these pathophysiological issues, focusing on renovascular hypertension and ischemic nephropathy as major clinical manifestations of RAS. The activation of RAAS and its haemodynamic consequences is the primary and key element in the pathophysiological cascade triggered in response to renal artery stenosis. However, the pathomechanism of RAS is more complex and also includes other disturbances that ultimately contribute to the development of the diseases mentioned above. To sum up, RAS is characterised by different clinical pictures, including asymptomatic disorders diagnosed in kidney imaging, renovascular hypertension, usually characterised by severe course, and chronic ischemic nephropathy, described by pathological remodelling of kidney tissue, ultimately leading to kidney injury and chronic kidney disease.

KIDNEY STONE DISEASE WITH SPECIAL REGARD TO DRUG-INDUCED KIDNEY STONES - A CONTEMPORARY SYNOPSIS.

OBJECTIVE: Kidney stone disease (nephrolithiasis; urolithiasis) is a clinical entity with long-term course and recurrence, primarily affecting mature and ageing men, involving the formation and presence of urinary stones in the kidneys and urinary tract. The pathogenesis of this disorder is complex and still not fully understood. A rare, potentially modifiable, form of kidney stone disease takes the form of drug-induced urinary stones. The aim of the review was a brief description of the classification and pathophysiology of kidney stone disease, along with the short characteristics of drug-induced urinary stones. This type of stones is formed as a result of crystallisation in the kidneys and urinary tract of sparingly soluble drugs and their metabolites, or as a result of metabolic changes caused by drugs, predestinating the development of stones containing endogenous compounds. CONCLUSION: Conclusion: Therefore, during treatment with the use of drugs with high lithogenic potential, the safety of pharmacotherapy should be monitored in the context of its increased risk of developing urinary stones.

The Effect of Acetylcysteine on Renal Function in Experimental Models of Cyclophosphamide-and Ifosfamide-Induced Cystitis.

INTRODUCTION: Urotoxicity is a characteristic attribute of cy-clophosphamide and ifosfamide. Acetylcysteine is perceived as a uroprotective and possible nephroprotective compound. The purpose of the study was to assess the effect of acetylcysteine treatment on the morphology of the kidneys and the urinary bladder, and renal function in rats with cystitis induced by cyclophosphamide or ifosfamide. METHODS: Cystitis was induced in rats belonging to groups 2 and 3, as well as 4 and 5, by five administrations of cyclophosphamide (75 mg/kg) or ifosfamide (80 mg/kg) respectively. Additionally, groups 3 and 5 received acetylcysteine (200 mg/kg). Group 1 was "sham treated" as a control. Upon conclusion of the experiment, the animals were euthanized and their kidneys and urinary bladders were collected for histopathological analysis. The assessment of renal function was based on classic nitrogen blood parameters (urea, creatinine, and uric acid), as well as proteinuria and cystatin C (CysC) and kidney injury molecule-1 (KIM-1) urinary concentrations, and their 24-hour elimination with urine. RESULTS: Reduction of blood urea nitrogen and uric acid, and urinary pH with a significant increase of CysC and KIM-1 urinary concentrations, and their 24-hour elimination with urine were observed in groups 2 and 4. The acetylcysteine treatment did not cause a significant change of blood parameters, but significantly decreased 24-hour elimination of CysC and KIM-1 with urine, and accounted for alleviation of the histopathological abnormalities of urinary bladders, with no significant effects on the structure of the kidneys. CONCLUSIONS: Acetylcysteine used in the experimental model of cyclophosphamide- and ifosfamide-induced cystitis had a uroprotective effect and also reduced renal dysfunction, which suggests its potential use as a nephroprotective compound in cyclophosphamide/ifosfamide therapy.

Urinary incontinence in women: biofeedback as an innovative treatment method.

Urinary incontinence is an involuntary urination (leakage of urine). About 200 million people suffer from this condition, and 60% of cases are concealed and untreated because of shame. It is estimated that an increasing number of young women and women of menopausal age will suffer from urinary incontinence. This disease occurs during the perinatal, perimenopausal period, as a result of brain damage or an unhealthy lifestyle. There are four main types of urinary incontinence: stress, urge, overflow and mixed form. Treatment is adapted to the severity of disease, its type and includes physiotherapeutic treatment (kinesiotherapy, physiotherapy, massage), pharmacological, psychological and surgical treatment. In recent years, growing interest has been observed in the noninvasive biofeedback method. The patient learns to contract the weakened pelvic floor muscles, constantly monitoring progress in treatment. She is also motivated by visual and auditory stimuli. Growing evidence confirms the effectiveness of this method, which to a large extent eliminates urinary incontinence. Nevertheless, attention should also be paid to prevention, which reduces the risk of involuntary leakage of urine.

Effect of α-1-adrenolytic agent and 5-α-reductase inhibitor on renal function in an experimental model of hyperprolactinemia-induced benign prostatic hyperplasia.

The standard pharmacotherapy of benign prostatic hyperplasia (BPH) may also alleviate potential kidney dysfunction resulting from the development of obstructive uropathy in the course of BPH. AIM: The aim of study was to evaluate the effect of treatment with α-1- adrenolytic agent (tamsulosin) and 5-α-reductase inhibitor (finasteride) on renal function in rats. MATERIALS AND METHODS: Four groups of rats were studied: 1 - controls, 2 - rats with metoclopramide-induced hyperprolactinemia BPH model, 3 - rats with BPH treated with tamsulosin, 4 - rats with BPH treated with finasteride. BPH presence was verified by histopathological examination. The renal function was assessed by histopathological examination, and the laboratory assessment of the classic nitrogen parameters and new kidney function markers (cystatin C; CysC, kidney injury molecule-1; KIM-1). RESULTS: In group 2, BPH development was confirmed by histopathological examination, without simultaneous significant kidney disturbances. Compared to the controls, BPH animals exhibited significant proteinuria, and increased concentration and daily urinary excretion of CysC and KIM- 1. Treatment with tamsulosin significantly improved the histopathological image of the prostate without affecting renal structure and led to reduced blood urea and proteinuria. Treatment with finasteride also significantly reduced the histopathological signs of BPH without changing the image of the kidneys, and reduced CysC concentration and daily CysC excretion with urine compared to group 2 individuals. CONCLUSIONS: In the course of experimental hyperprolactinemiainduced BPH, kidney tubulopathy developed, which was indicated by KIM-1 and CysC disturbances in urine. The administration of finasteride reduced renal dysfunction to a higher degree, bringing the concentration and daily excretion of CysC back to normal.

Osteopontin and Fatty Acid Binding Protein in Ifosfamide-treated Rats.

INTRODUCTION: Ifosfamide (IF) is a cytostatic that exhibits adverse nephrotoxic properties. Clinically, IF-induced nephrotoxicity takes various forms, depending on applied dose and length of treatment. OBJECTIVES: The aim of the study was to evaluate the two proteins: osteopontin (OP) and fatty acid binding protein (FABP), as markers of kidney function in rats treated with ifosfamide. MATERIAL AND METHODS: Rats receiving a single IF dose (250 mg/kg b.w.; group 1) or treated with five consecutive IF doses administrated on following days (50mg/kg b.w.; group 3), compared with control groups 2 and 4, respectively, were studied. Kidney function was assessed using classical (urea, creatinine) and novel (FABP, OP) laboratory parameters and by histopathology. RESULTS: Single IF dose administration resulted in significant total proteinuria with urinary concentrations and 24-hour excretions of both FABP and OP comparable to the appropriate control. In rats treated with five consecutive IF doses, the urinary concentrations and 24-hour excretion of both FABP and OP were significantly higher compared to the appropriate control. The development of cystitis was revealed in groups 1 and 3, which was not accompanied by significant histopathological kidney damage. CONCLUSIONS: Both OP and FABP may be useful laboratory markers of tubulopathy in the early stage of chronic nephrotoxicity of ifosfamide.

Analysis of proteinuria in experimental model of ascending acute kidney injury.

Proteinuria accompanies kidney diseases of various etiology and correlates with the degree of organ damage. Analysis of proteinuria allows the location of pathophysiological process in the kidney, and assessment of the severity of the kidney disease in chronic and acute kidney injury (AKI). Ascending bacterial acute kidney injury develops as a consequence of pyelonephritis. It is a rare complication in patients with anatomical or functional dysfunctions of the urinary tract. AIM: The aim of the study was to perform the laboratory analysis of proteinuria in bacterial ascending AKI in an experimental model. MATERIALS AND METHODS: Female Wistar rats (n = 24) were intravesically administrated bacterial suspension of Escherichia coli (E. coli) to induce: pyelonephritis (group 1, 105 CFU/ml); AKI (group 2, 107 CFU/ml); AKI and urosepsis (group 3, 109 CFU/ml) respectively. Bacterial strain - E.coli, was isolated from a patient with acute pyelonephritis. The daily diuresis and urine protein excretion was measured the following days: 0, 7, 14 and 21. Moreover, electrophoretic separation of urine protein, densitometric analysis of albumin fraction and uromodulin concentration in urine were performed. Moreover, the key parameters for the diagnosis of AKI were assayed. RESULTS: Increased urinary protein excretion was observed in each of the study groups. Moreover, the study groups showed significant changes in protein selectivity in the urine. CONCLUSIONS: Moderately severe proteinuria was revealed while its selectivity suggested significant damage of glomeruli and renal tubules in groups with complications caused by AKI induced by ascending pyelonephritis.

The outline of stress pathophysiology and pharmacodynamic action of plant-based eustressors - adaptogens.

In modern pharmaceutical market, there is an increasing number of preparations declaring some stress-protective and stress-relieving effects and delaying aging processes. It is an answer to the fast lifestyle, high social and professional requirements contributing to the increased burden and stress. Chronic stress leads to numerous disorders. For that reason, methods for relieving adverse stress symptoms and allowing an easier adaptation to stress are still being investigated. One of the phytopharmacological methods of stress reduction is the use of "adaptogens" - plants containing active constituents that regulate mechanisms enabling a better adaptation to stress ("eustressors"). In general, the use of adaptogen-based preparations increases the non-specific phase of stress resistance, facilitating the achievement and prolonged maintenance of the, socalled, allostasis. Conducted studies revealed some detailed effects of adaptogens on a molecular level, that allow broadening their pharmacodynamic description. In this short review, the phenomenon of stress with its neuroendocrine background, examples of plants with adaptogenic activity, dietary supplements containing these kinds of plants, and some aspects of adaptogen's pharmacodynamic action have been briefly discussed.

The influence of oxazaphosphorine agents on kidney function in rats.

BACKGROUND AND OBJECTIVE: The application of cytostatic oxazaphosphorines such as cyclophosphamide (CP) and ifosfamide (IF) is associated with the risk of kidney damage that, depending on the type of drug, dose and route of administration, adopts a different clinical entity and severity. The aim of our study was to assess the influence of CP and IF on the kidney histology and function in rats intraperitoneally treated with four doses of either CP or IF. MATERIALS AND METHODS: A total of 30 rats were divided into three groups (10 in each group): group 1 (control), sham treated with saline solution, group 2 (treated with 75mg/kg b.w. of CP), and group 3 (treated with 60mg/kg b.w. of IF). After the treatment rats were sacrificed, blood was collected and nephrectomy and cystectomy were performed. Qualitative and quantitative parameters (including neutrophil gelatinase-associated lipocalin-1, NGAL-1) of kidney function were assayed in urine and plasma. RESULTS: CP-treated rats were characterized by a significant polyuria, decreased urine pH and by decreased daily urinary excretion of sodium, potassium, urea and uric acid accompanied by increased NGAL-1 excretion. A significant decrease of the plasma uric acid concentration was also observed. IF-treated animals were also characterized by decreased urine pH but with normal daily urinary excretion of assessed substances (except for reduced uric acid excretion). Both CP and IF treated rats did not show any histopathological abnormalities in their kidneys. CONCLUSIONS: CP caused more advanced kidney dysfunction and some indices suggested the development of prerenal acute kidney injury. In the CP-treated group some particularly marked urinary and plasma uric acid disturbances suggested compensation of increased oxidative stress as uric acid is considered to exert also antioxidant properties.

Altered sympathovagal balance and pain hypersensitivity in TNBS-induced colitis.

INTRODUCTION: Pain hypersensitivity, abnormal motility and autonomic dysfunction contribute to functional symptoms of inflammatory bowel disease (IBD). MATERIAL AND METHODS: The aim of this study was to assess: nociceptive thresholds for mechanical allodynia (MA) and thermal hyperalgesia (TH), intestinal motility (distal colonic transit and emptying), and cardiac autonomic neuropathy (indices of heart rate variability - HRV) in male Wistar rats with experimental trinitrobenzene sulfonic acid (TNBS) induced colitis. To identify a potential vagal contribution the bilateral subdiaphragmatic vagotomy (SDV) was performed. RESULTS: Experimental colitis resulted in a significant decrease in pain threshold (MA 23.60 ±2.12, p < 0.001, TH 8.51 ±1.49, p < 0.001), reduced expulsion time (6.2 ±3.5, p < 0,01) and increase in the sympathetic autonomic activity (LFnu 32.54 ±21.16, p < 0.03). The animals with diminished vagal integrity presented with reduced gastrointestinal motility (39.8 ±25.1, p < 0.01) and a decrease in the parasympathetic high-frequency domain of HRV (HFnu 55.37 ±22.80, p < 0.002). The vagotomized rats with colitis showed the strongest nociceptive response (MA 22.46 ±3.02, p < 0.004; TH 7.99 ±1.12, p < 0.003) as well as significant changes in sympatho-vagal balance on HRV testing (LFnu 28.25 ±14.66, p < 0.04; HFnu 71.34 ±14.55, p < 0.04). CONCLUSIONS: The relationship between the cardiovascular and gastrointestinal system is modulated by neural, hormonal and inflammatory factors. This leads to dysregulation of the brain-gut interactions in the course of IBD. Sensitization and visceral-somatic convergence trigger pain hypersensitivity and autonomic sympathovagal imbalance. While integral vagal innervation impacts analgesic mechanisms via modulation of the immune response, SDV raises sympathetic activity and induces excessive hyperalgesia.

THE INFLUENCE OF MONTELUKAST ON THE ACTIVITY OF THE AUTONOMIC NERVOUS SYSTEM ESTIMATED BY HEART RATE VARIABILITY IN EXPERIMENTAL PARTIAL BLADDER OUTLET OBSTRUCTION IN RATS.

Due to their paracrine action, leukotrienes released from the urothelium are involved in control of the bladder function. Anti-leukotriene agents appear to exert an ameliorating effect in bladder overactivity. It is unknown, whether their possible, modulatory impact on the autonomic nervous system (ANS) activity may also contribute to the potentially beneficial effect of those compounds. Therefore, our aim was to indirectly estimate the ANS function using the heart rate variability (HRV) study in rats with experimental partial bladder outlet obstruction (PBOO), reflecting human benign prostatic hyperplasia (BPH), treated with leukotriene receptor antagonist - montelukast (MLKT). Twenty rats with surgically induced PBOO lasting for 14 days, divided into two groups: group 1 (10 control subjects) and group 2 (10 MLKT-treated rats; 2 mg/rat/day) were subjected to HRV recordings, preceded by daily urine collection and a subsequent cystectomy with histopathological evaluation of collected bladders. Standard HRV time and spectral parameters were calculated. MLKT-treated animals demonstrated an increase in power of non-normalized LF (low frequency) and HF (high frequency) components with no change of the total HRV power. Moreover, an increase and decrease in normalized nLF and nHF, respectively, were assessed in those animals compared to the control. Additionally, a decrease in daily diuresis measurement was demonstrated in MLKT-treated animals. Montelukast treatment resulted in the functional ANS status re-arrangement, with sympathetic overdrive and parasympathetic withdrawal. Those changes may contribute to alleviation of bladder overactivity symptoms, independently on leukotriene receptors blockade.

Urinary kidney injury molecule-1 (KIM-1) excretion in rats with experimental cystitis induced by oxazaphosphorines.

Introduction: Oxazaphosphorine agents (cyclophosphamide - CP, ifosfamide - IF) are causative factors of cystitis and also exert a characteristic nephrotoxic effect, clinically manifested by a broad spectrum of disturbances. The aim of the study was to estimate the toxic effect of the abovementioned oxazaphosphorines on the renal tubules by assessment of diuresis and urinary concentration and daily urinary excretion of the kidney injury molecule-1 (KIM-1) in rats with induced and histologically confirmed cystitis. Material and Methods: The study involved 60 rats (equal amounts of ♀ and ♂), including animals treated with CP, administrated four times at the dose 75 mg/kg (group 1; n=10) and treated with IF, administrated four times at the dose 50 mg/kg IF (group 2; n=10) with the suitable control group A (group 3; n = 10), as well as animals receiving either a single dose 150 mg/kg of CP (group 4) or IF (group 5), with an appropriate control group B (group 6). Results: In both groups 1 and 4, a significant increase in the daily diuresis and decrease of the urinary pH were revealed, compared to the appropriate control group A (group 3) and B (group 6), while IF-treated animals, regardless of the applied doses (groups 2 and 5), were characterized by a urinary pH decrease. KIM-1 urinary concentration in rats from group 1 and 4 was almost three times higher compared to the appropriate control groups A or B, respectively, and the difference was statistically significant. In animals with chronic (group 2) and acute (group 5) ifosfamide- induced cystitis, no statistically significant difference concerning KIM- 1 urinary concentration compared to a control A and B groups was revealed, although a clear tendency of increase of the parameter was observed in the IF-treaded animals. Analysis of daily KIM-1 urinary excretion showed a statistically significant, almost six-fold increase in group 1 and almost two-fold increase in group 2. In the groups with acute model of cystitis, the highest, nearly eight-fold, daily KIM-1 urinary excretion, was revealed in animals treated with single CP dose, compared to the respective control B group, while rats treated with a single IF dose were characterized by a daily urinary KIM -1 excretion, comparable to animals with IF-induced chronic cystitis. The histopathological analysis confirmed cystitis in all animals treated with either CP or IF (groups 1,2,4,5), while no altered kidney microscopic morphology, compared to respective control groups A and B, was observed in those rats. Conclusions: The study confirmed the proximal tubular dysfunction in rats with both cyclophosphamide- and ifosfamide-induced cystitis, which was reflected by an increased urinary KIM-1 excretion. The disturbance was more emphasized in CP-treated animals, especially in those ones treated with the single, high CP dose. The functional tubulopathy was not accompanied by a structural kidney damage in rats treated with either CP or IF.