Vitamin D, zinc and glutamine: Synergistic action with OncoTherad immunomodulator in interferon signaling and COVID­19 (Review).

Coronavirus disease 2019 (COVID­19), caused by severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2), was identified in December, 2019 in Wuhan, China. Since then, it has continued to spread rapidly in numerous countries, while the search for effective therapeutic options persists. Coronaviruses, including SARS­CoV­2, are known to suppress and evade the antiviral responses of the host organism mediated by interferon (IFN), a family of cytokines that plays an important role in antiviral defenses associated with innate immunity, and has been used therapeutically for chronic viral diseases and cancer. On the other hand, OncoTherad, a safe and effective immunotherapeutic agent in the treatment of non­muscle invasive bladder cancer (NMIBC), increases IFN signaling and has been shown to be a promising therapeutic approach for COVID­19 in a case report that described the rapid recovery of a 78­year­old patient with NMIBC with comorbidities. The present review discusses the possible synergistic action of OncoTherad with vitamin D, zinc and glutamine, nutrients that have been shown to facilitate immune responses mediated by IFN signaling, as well as the potential of this combination as a therapeutic option for COVID­19.

Evaluation of a dry therapeutic urinary diet and concurrent administration of antimicrobials for struvite cystolith dissolution in dogs.

BACKGROUND: Struvite urolithiasis with bacterial urinary tract infection (UTI) is commonly reported in dogs; few data exist to describe successful dissolution protocols in dogs with naturally occurring disease. We hypothesized that a dry therapeutic urinary diet combined with targeted antimicrobial therapy can effectively dissolve presumptive struvite cystolithiasis in dogs with naturally occurring urease-producing bacterial UTI. RESULTS: Ten dogs with presumed infection-induced struvite cystolithiasis based on lower urinary tract signs (LUTS), radiodense cystoliths, and urease-producing bacterial UTI were enrolled. At enrollment, antimicrobials and dry therapeutic urinary diet were dispensed. In addition to lack of radiographic resolution of urolithiasis, dogs with persistent clinical signs were considered non-responders. There was no significant difference in pH between responders and non-responders; USG was significantly higher in the responder group. Recheck visits continued until radiographic dissolution or failure was documented. Five of the 10 dogs achieved radiographic dissolution of cystolithiasis within a median of 31 days (range 19-103). In the other 5 dogs, surgical urolith removal was necessary due to persistent LUTS (3 dogs within 2 weeks) or lack of continued dissolution noted radiographically (1 dog with numerous cystoliths failed at day 91; 1 dog failed by day 57 with questionable owner compliance). CONCLUSIONS: Dissolution of urinary tract infection induced struvite cystoliths can be accomplished in some dogs fed this dry therapeutic urinary diet in conjunction with antimicrobial therapy. Case selection could increase the likelihood of successful dissolution; however, if calcium phosphate is present, this could also prevent stone dissolution. If clinical signs persist despite diet and antimicrobials, stone removal is advised.

Successful medical management of pseudomembranous cystitis in three cats with lower urinary tract obstruction.

CASE REPORT: The present case series describes the clinical course and outcome of three cats diagnosed with pseudomembranous cystitis. This is an uncommon presentation of lower urinary tract obstruction but can be easily be identified by ultrasonography, revealing severe bladder wall thickening and thin hyperechoic luminal strips. The condition can be secondary to severe bacterial urinary tract infection. All cats were successfully treated with medical management only, mainly based on antimicrobials and individualised supportive therapy. CONCLUSION: Further evaluation of this condition is necessary in order to determine potential underlying aetiologies, pathophysiological mechanisms and the most appropriate standardised treatment.

Preventive and therapeutic effects of sodium bicarbonate on melamine-induced bladder stones in mice.

The actual preventive and therapeutic effects of alkalinizing urine on melamine-induced bladder stones (cystolith) are not completely known. Using an ideal model, two experiments were conducted in Balb/c mice. The mice were fed a normal diet in controls and a melamine diet in the other groups. The first day was set as experiment-day 1. In "Experiment 1", either low-/mid-/high-dose sodium bicarbonate (SB) or sterile water was administered by intragastric perfusion (once daily) to the mice for 14 days. Relative to the model group, the mean pH of the urine in the SB groups was significantly elevated at 3 h after SB administration, with a significant decrease in cystolith incidence on experiment-day 14. In "Experiment 2", on experiment-day 12, the melamine diet was replaced by a normal diet in 4 groups with melamine withdrawal (MW). Meanwhile, either mid-/high-dose SB or sterile water was administered by intragastric perfusion (once) to the mice in the corresponding groups. On experiment-day 12, after an additional 8 h, the cystolith incidence was significantly reduced in the high-SB, MW + mid-SB and MW + high-SB groups than in the model group. In conclusion, low urinary pH is one of the main determinants of the formation of melamine-associated stones, urinary alkalinization can be achieved by a proper dose of oral SB, and SB acts to prevent and treat melamine-induced cystoliths in mice.

Zinc disc implantation model of urinary bladder calculi and humane endpoints.

The zinc disc implantation-induced urinary bladder calculi model in the rat is commonly used for preclinical evaluation of the antiurolithiatic activity of test compounds. Certain published reports state that relatively long durations for which zinc discs must be implanted in the bladders of rats. Hence, there is a need to refine this model. These investigations aimed to determine whether long-term studies using the zinc disc implantation model provide any additional data that affect the final outcomes of the study. In this study, we evaluated the effects of a well-known antiurolithiatic polyherbal drug, Cystone, for different treatment durations of 10, 20 and 48 days postimplantation. Our results indicate that even the shortest duration of 10 days is sufficient to reveal antiurolithiatic effects of a test drug. Hence, in the zinc disc implantation-induced urinary bladder calculi model, the study duration is proposed to be minimized so as to reduce the distress caused to the rats due to long-term exposure to the implant. Further, it is suggested that the growth of the bladder calculi can be monitored by taking X-ray radiographs of the bladder deposits to decide the time to terminate the study. Use of preformed calcium oxalate crystal instead of zinc discs, as suggested in earlier reports by others, may also be considered to avoid the sacrifice of rats at the end of the study.

Effects of low-molecular-weight polyguluronate sulfate on experimental urolithiasis in rats.

Urinary macromolecules, especially glycosaminoglycans (GAGs), have attracted great interest as promising inhibitors of urinary stone formation. As an analogue of GAGs, low-molecular-weight polyguluronate sulfate (LPGS) with strong polyanionic nature was prepared by chemical modification of brown algae extract. The effects of LPGS both on ethylene glycol-induced nephrolithiasis and Zinc disc implant-induced urinary bladder stone formation in Wistar rats were evaluated, and its acute toxicity in Kunming mice and Wistar rats were also investigated. The contents of renal oxalate and calcium in ethylene glycol-induced nephrolithiasic rats were decreased significantly from 5.01 +/- 0.96 to 3.26 +/- 1.31 mumol/g kidney (P < 0.01) and 20.11 +/- 4.60 to 11.83 +/- 3.54 mumol/g kidney (P < 0.01), respectively, after oral administration of LPGS at dose-level of 100 mg/kg. The renal crystal depositions and histopathological changes were reduced also. The formation of zinc disc implant-induced urinary bladder stones in rats was inhibited considerably after oral administration of LPGS at dose-levels of 50 mg/kg (P < 0.05) and 100 mg/kg (P < 0.01). The intravenous LD(50) and the oral maximum tolerance value of LPGS in mice are 6.29 and 25 g/kg, and in rats are 2.25 and 10 g/kg, respectively. These data show that LPGS has significant prevention effects both on nephrolithiasis and urinary bladder stone formation in rats, and negligible oral toxicity both in mice and rats. LPGS is a safe and promising drug candidate for the prevention of urolithiasis.

Effect of extract of Phyllanthus niruri on crystal deposition in experimental urolithiasis.

Phyllanthus niruri (Pn) is a plant that has been shown to interfere in the growth and aggregation of calcium oxalate (CaOx) crystals. In the present study we evaluated the effect of Pn on the preformed calculus induced by introduction of a CaOx seed into the bladder of male Wistar rats. Pn treatment (5 mg/ rat/day) was initiated immediately or 30 days after CaOx seeding and thus in the presence of a preformed calculus. Animals were sacrificed 50 or 70 days after surgery. The resulting calculi were weighed and analyzed by X-ray diffraction, stereomicroscopy and scanning electronic microscopy. Precocious Pn treatment reduced the number (75%, P < 0.05) and the weight (65%, P < 0.05) of calculi that frequently exhibited a matrix-like material on its surface, compared to the untreated CaOx group. In contrast, Pn treatment in the presence of a preformed calculus did not prevent further calculus growth; rather, it caused an impressive modification in its appearance and texture. Calculi from Pn-treated animals had a smoother, homogeneous surface compared to the spicule shape of calculi found in the untreated CaOx group. XRD analysis revealed the precipitation of struvite crystals over the CaOx seed and Pn did not change the crystalline composition of the calculi. This suggests that Pn interfered with the arrangement of the precipitating crystals, probably by modifying the crystal-crystal and/or crystal-matrix interactions. Results suggest that Pn may have a therapeutic potential, since it was able to modify the shape and texture of calculi to a smoother and probably more fragile form, which could contribute to elimination and/or dissolution of calculi.

[Can selective alpha-blockers help the spontaneous passage of the stones located in the uretero-bladder junction?]. / Pot ajuta alfa-blocantele selective eliminarea calculilor ureterali aflati la jonctiunea uretero-vezicala?

The majority of ureteral stones at presentation in hospital are located within the distal ureter. Knowing that only half of the stones 4 to 5.9 mm will pass spontaneously, we tried to see: if we can facilitate this elimination for the stones smaller than 8 mm by selectve alpha-blockers (alfuzosin and tamsulosin) which induce relaxation of the smooth muscle of uretrotrigonal area and if there is any difference between these two drugs, concerning efficiency and tolerance. The inclusion criteria for each group were: stone size between 4 and 8 mm--even patients with steinstrasse--and previous, at least 2 weeks of expulsion treatment with nonsteroidal antiinflammatory and antispasmodic agents and Rowatinex. The results were encouraging: almost all the patients eliminated the stones without any pain in the first 5-10 days of treatment (only two patients from alfuzosin group did not tolerate this drug). We believe that both alfuzosin and tamsulosin have a crucial impact in spontaneous painless elimination of the stones smaller than 8 mm located in the uretero-bladder junction.

The effect of Phyllanthus niruri on urinary inhibitors of calcium oxalate crystallization and other factors associated with renal stone formation.

OBJECTIVE: To evaluate the effect of an aqueous extract of Phyllanthus niruri (Pn), a plant used in folk medicine to treat lithiasis, on the urinary excretion of endogenous inhibitors of lithogenesis, citrate, magnesium and glycosaminoglycans (GAGs). MATERIALS AND METHODS: The effect of chronic (42 days) administration of Pn (1.25 mg/mL/day, orally) was evaluated in a rat model of urolithiasis induced by the introduction of a calcium oxalate (CaOx) seed into the bladder of adult male Wistar rats. The animals were divided into four groups: a sham control (16 rats); a control+Pn (six); CaOx+water instead of Pn (14); and CaOx+Pn (22). Plasma and urine were collected after 42 days of treatment for biochemical analysis and the determination of urinary excretion of citrate, magnesium and GAGs. The animals were then killed and the calculi analysed. RESULTS: The creatinine clearance or urinary and plasma concentrations of Na+, K+, Ca2+, oxalate, phosphate and uric acid were unaffected by Pn or the induction of lithiasis. Treatment with Pn strongly inhibited the growth of the matrix calculus and reduced the number of stone satellites compared with the group receiving water. The calculi were eliminated or dissolved in some treated animals (three of 22). The urinary excretion of citrate and magnesium was unaffected by Pn treatment. However, the mean (sd) urinary concentration of GAGs was significantly lower in rats treated with CaOx+Pn, at 5.64 (0.86) mg/g creatinine, than when treated with CaOx + water, at 11.78 (2.21) mg/g creatinine. In contrast, the content of GAGs in the calculi was higher in the CaOx + Pn rats, at 48.0 (10.4) g/g calculus, than in the CaOx + water group, at 16.6 (9.6) g/g calculus. CONCLUSION: These results show that Pn has an inhibitory effect on crystal growth, which is independent of changes in the urinary excretion of citrate and Mg, but might be related to the higher incorporation of GAGs into the calculi.

Attenuation of oxalate-induced nephrotoxicity by eicosapentaenoate-lipoate (EPA-LA) derivative in experimental rat model.

Hyperoxaluria is one of the major risk factors for the formation of urinary calcium oxalate stones. Calcium oxalate crystals and their deposition have been implicated in inducing renal tubular damage. Lipoic acid (LA) and eicosapentaenoic acid (EPA) have been shown to ameliorate the changes associated with hyperoxaluria. This prompted us to investigate the nephroprotectant role of EPA-LA, a new derivative, in vivo in hyperoxaluric rats. Elevation in the levels of calcium, oxalate and phosphorus, the stone-forming constituents, were observed in calculogenic rats as a manifestation of crystal deposition. Tubular damage to the renal tissue was assessed byassaying the excretion of marker enzymes in the urine. Damage to the tubules was indicated by increased excretion of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transferase (gamma-GT), beta-Glucuronidase (beta-GLU) and N-Acetyl beta-D glucosaminidase (NAG). Fibrinolytic activity was found to be reduced. Administration of EPA, LA and EPA-LA reduced the tubular damage and decreased the markers of crystal deposition markedly, which was substantiated by the reduction in weight of bladder stone formed. Our results highlight that EPA-LA is the most effective drug in inhibiting stone formation and mitigating renal damage caused by oxalate toxicity, thus confirming it as a nephroprotectant. Further work in this direction is warranted to establish the therapeutic effectiveness of this new derivative.

Spontaneous expulsion of large vesicle calculi in a woman with paraparesis.

INTRODUCTION: Urolithiasis is a common but preventable complication of Spinal Cord Disorders (SCD). CASE REPORT: We report a 25-year-old woman with paraparesis who spontaneously passed two large calculi perurethra without pain and developed urethral scarring. Detrusor hyperreflexia, absence of sensations and lack of sphincter tone could have contributed to painless expulsion of the large calculi in this patient. CONCLUSION: Dysuria, a prominent symptom of urolithiasis may not be present in subjects with SCD. Awareness about urolithiasis among health professionals involved in the care of SCD patients is necessary for prevention and early intervention.

Inhibition of calcium oxalate urolithiasis in a rat model of lithogenesis using bisphosphonates.

Bisphosphonates bind renal calculi and inhibit calcium oxalate crystal growth in vitro. We evaluated their ability to inhibit calcium oxalate urolithiasis in a lithogenic rat model. Male Sprague-Dawley rats (four groups, eight rats each) were fed 1.0% ethylene glycol in their drinking water for 6 weeks. All rats had implantation of a 50- to 60-mg zinc pellet in their urinary bladder at the beginning of the 6-week period. The control group received no treatment. The other three groups received six weekly intraperitoneal injections of one of three bisphosphonates: pamidronate (APD), clodronate (CLO), or methylene diphosphonate (MDP). At the end of 6 weeks, the zinc pellet was retrieved and weighed; the kidneys were sectioned and stained to evaluate inflammation, tubular dilation, and crystal deposition; and blood and urine samples were analyzed for calcium and creatinine. There were no detectable biochemical differences between the control and the treatment groups. Zinc pellets removed from control animals had a significantly greater increase in weight secondary to crystal deposition than those from the treatment groups (mean 28.4% for control v 18.9%, 15.3%, and 18.6%, respectively, for animals given APD, CLO, and MDP). The control animals also had significantly higher scores for inflammation, tubular dilation, and crystal deposition than animals treated with MDP and CLO. Older and newer-generation bisphosphonates have an inhibitory effect on calcium oxalate urolithiasis that is demonstrable at relatively infrequent dosing intervals in vivo. More frequent dosing or higher doses may allow greater inhibition of stone formation.

Efeitos do tratamento cronico de ratos com o extrato de Chamaecrista nictans Irwin and Barneby na eliminacao de calculos renais / Effects of chronic treatment of rats with Chamaecrista nictans Irwin and barneby on eliminition of renal calculli

Chamaecrista nictans subs. patellaria var. ramosa Irwin and Barneby (Cassia patellaria DC), tambem conhecida pelo nome popular de peninha, e uma erva daninha originaria do Brasil cujo cha e utilizado na medicina popular para eliminacao de calculos renais. O ensaio farmacologico foi feito a fim de testar o efeito do tratamento cronico com extrato fluido da planta, na urolitiase experimental em ratos atraves da inducao de calculo vesical. Os resultados indicam que o extrato fluido da peninha nao apresentou atividade antilitiasica no modelo experimental testado

Efficacy of a novel injectable cephalosporin, Cefclidin, on the experimental complicated urinary tract infections with urinary stones caused by Pseudomonas aeruginosa and Proteus mirabilis.

We evaluated the effects of a novel cephalosporin, cefclidin (CFCL) and imipenem (IPM), on the eradication of bacteria from the urine, bladder stones and the kidneys, and also on the prevention of the infection stone formations, in our polymicrobial urinary tract infection model of rats associated with bladder stones using IMP-sensitive or IPM-resistant Pseudomonas aeruginosa and Proteus mirabilis as a causative pathogen. CFCL completely eradicated P. mirabilis from the urine and the stone in the short-term regimen (5 days). CFCL completely eradicated both IPM-sensitive P. aeruginosa and P. mirabilis from the urine, the stones and the kidneys as compared to IPM in the long-term regimen (11 days), reflecting the superior antibacterial activity of CFCL. CFCL also significantly prevented the development of infection stones as compared to IPM in the long-term regimen. There was no significant difference in the blood urea nitrogen (BUN) values between the CFCL or IPM-treated and the non-treated groups. The cumulative recovery rate of unchanged CFCL reached 47.3% of the total dosage (20 mg/kg) within 8 hours.

Evaluation of Ammannia baccifera Linn. for antiurolithic activity in albino rats.

Ethanolic extract of A. baccifera was tested for its antiurolithic activity in male albino rats. Urinary stones were induced by implantation of zinc discs in the urinary bladder. The stones formed were mainly of magnesium ammonium phosphate with traces of calcium oxalate. Ethanolic extract of A. baccifera (2g/kg/day, po) was found to be effective in reducing the formation of stones as also in dissolving the pre-formed ones. There was a significant increase in the urinary excretion of calcium, magnesium and oxalate, four weeks after implantation of zinc discs. Treatment with A. baccifera has significantly reduced calcium and magnesium levels in the prophylactic group while it has reversed the levels of these ions to normal values in the curative group.

Canine cystinuria: an extended study on the effects of 2-mercaptopropionylglycine on cystine urolithiasis and urinary cystine excretion.

A clinical study covering 1 to 6 years was undertaken during which 25 cystinuric dogs were orally treated with 2-mercaptopropionylglycine (2-MPG). The drug was effective at dissolving uroliths at a dose of approximately 40 mg kg-1 body weight. In 15 dogs with bladder uroliths, complete urolith dissolution was achieved on 9/17 occasions (53%). When 2-MPG was administered prophylactically at 30 mg/kg body weight, uroliths did not reform in 14 dogs (56%). In four dogs, uroliths re-formed during treatment, but dissolved when the dose of 2-MPG was raised to 40 mg kg-1 body weight. Six dogs were surgically treated, and in two of these animals the uroliths were found to consist of magnesium ammonium phosphate. Euthanasia was performed on six dogs during the study; three because of recurrent uroliths with urethral obstruction, and three because of aging. In one dog, uroliths were present in the bladder throughout the study. The purpose of the study was to propose a new strategy for individual treatment of cystinuric dogs. This was accomplished by measuring the urinary free cystine concentration and the mixed cysteine-2-MPG disulphide in a subgroup of 15 of the 25 dogs. To evaluate cystine excretion, morning samples of urine were used, and the cystine concentration was related to the creatinine concentration. For dose adjustment it was difficult to evaluate the effect of 2-MPG on urinary cystine excretion, especially when cystine uroliths were present. However, this variable was studied in order to identify dogs with a strong tendency for urolith formation during 2-MPG treatment. In some cases, urinary cystine excretion returned to normal with time, and in three dogs, 2-MPG treatment could be stopped after 1.5 to 3.5 years. In spite of no further treatment, urinary cystine was almost undetectable up to 2 years later, and the dogs did not develop any new uroliths. It was concluded that 2-MPG is a satisfactory alternative treatment for cystinuric dogs. It has a good prophylactic effect, shown as a change in the rate of urolith formation from on average 6 months before to 17 months during 2-MPT treatment. The drug was shown to have few side effects, and the dog owner drug compliance can be followed by measurement of the mixed 2-MPG-cysteine disulphide.

Relationships between some lithogenetic factors and vitamin B6-status in idiopathic calcium lithiasis.

Several researchers have shown that a reduced intake of vitamin B6 can induce increased oxalate urinary excretion leading to a higher incidence of calcium oxalate stones. Furthermore, the treatment with pyridoxine in patients with urinary stones and high oxalate excretion has led to contradictory results as the excretion of oxalate was either decreased, unchanged or increased. To verify if these divergent results were linked to a different B6 status of the patients undergoing the treatment, we studied the vitamin B6 and the main lithogenetic factor levels in patients with idiopathic calcium lithiasis as compared to normal subjects. The results showed that a high oxalate excretion is not necessarily coupled with a low vitamin B6 status and viceversa. However, some stone formers present a non homogeneous vitamin pattern that could be the consequence of an abnormal vitamin B6 metabolism.