Chronic Administration Of Cyclosporine Research Articles

Drug-Induced Gingival Overgrowth: The Effect of Cyclosporin A and Mycophenolate Mophetil on Human Gingival Fibroblasts.

Drug-induced gingival overgrowth may occur after a chronic administration of three classes of systemic drugs: Anticonvulsants, immunosuppressants, and calcium channel blockers. This study aimed to investigate how cyclosporin A and mycophenolate mophetil (immunosuppressive drugs) could interfere with human gingival fibroblasts functions, leading to gingival enlargement. Human gingival fibroblasts derived from the tissue of a 60-year-old female were cultured in a DMEME medium. A stock solution with 1 mg/mL of mycophenolate and 1 mg/mL of cyclosporine were prepared and dissolved in a DMEM medium to prepare a serial dilution at the concentrations of 5000, 2000, 1000, 500, and 100 ng/mL, for both treatments. Cell viability was measured using the PrestoBlue™ Reagent Protocol. Quantitative real-time RT-PCR was performed in order to analyze the expression of 57 genes coding for gingival fibroblasts “Extracellular Matrix and Adhesion Molecules”. Mycophenolate and cyclosporine had no effect on fibroblast cell viability at 1000 ng/mL. Both the treatments showed similar effects on the expression profiling of treated cells: Downregulation of most extracellular matrix metalloproteases genes (MMP8, MMP11, MMP15, MMP16, MMP24) was assessed, while CDH1, ITGA2, ITGA7, LAMB3, MMP12, and MMP13 were recorded to be upregulated in fibroblasts treated with immunosuppressive drugs. It has been demonstrated that gingival overgrowth can be caused by the chronic administration of cyclosporin A and mycophenolate mophetil. However, given the contrasting data of literature, further investigations are needed, making clear the possible effects of immunosuppressive drugs on fibroblasts.

Chronic Administration of Cyclosporine A Changes Expression of BDNF and TrkB in Rat Hippocampus and Midbrain

Neurotrophins, including the brain-derived neurotrophic factor (BDNF), are essential for regulating neuronal differentiation in developing brains. BDNF and its receptor tyrosine kinase receptor B (TrkB) are involved in neuronal signaling, survival and plasticity. Cyclosporine A (CsA) is a potent immunosuppressive agent which prevents allograft rejection in organ transplantation and various immunological diseases. We investigated whether chronic administration of CsA decreases BDNF gene expression in rats, and the influence of CsA on mRNA levels of TrkB receptors was also examined. For 30 days of CsA (10 mg/kg/day) administration, the expression of BDNF and TrkB mRNA was significantly decreased in the hippocampus and midbrain, but there was no significant difference in the cortex. CsA (0, 1, 5 10, 15 ug/ml) down-regulated BDNF and TrkB gene expression through cultured SH-SY5Y cells, as did all-trans retinoic acid (ATRA), and there was no effect on cell viability. These experimental results indicate that suppression of the BDNF and TrkB mRNA, protein level of BDNF expression in the hippocampus and midbrain may be related to altered behavior observed following chronic administration of CsA. A common mechanism of adverse effects of CsA induced depressive symptoms may involve neurotoxicity mediated by down-regulation of brain BDNF and TrkB.

Drug‐Drug Interaction After Single Oral Doses of the Furanocoumarin Methoxsalen and Cyclosporine

Furanocoumarins increase the bioavailability of drugs that are CYP3A4 substrates. A possible interaction of methoxsalen with cyclosporine was evaluated in 12 healthy volunteers following oral administration of 40 mg methoxsalen, 200 mg cyclosporine, or a combination of both in a randomized crossover study. Methoxsalen increased area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of cyclosporine by 29% (range, -20% to 172%; P < .05) and 8% (range, -10% to 26%; P < .05), respectively, compared to cyclosporine alone. The AUC geometric means ratio (95% confidence interval) for cyclosporine plus methoxsalen/cyclosporine alone was 1.14 (1.02, 1.27), and treatments were therefore not bioequivalent. Methoxsalen causes a clinically significant interaction with cyclosporine in some susceptible individuals. The reasons for susceptibility and the clinical implications for chronic cyclosporine administration have not been established. Caution is recommended in combination therapy, and more frequent monitoring of cyclosporine plasma levels and clinical monitoring is advised.

Curcumin, a diferuloylmethane, attenuates cyclosporine-induced renal dysfunction and oxidative stress in rat kidneys

BackgroundIn India, Curcumin (CMN) is popularly known as "Haldi", and has been well studied due to its economic importance. Traditional Indian medicine claims the use of its powder against biliary disorders, anorexia, coryza, cough, diabetic wounds, hepatic disorder, rheumatism and sinusitis. This study was designed to examine the possible beneficial effect of CMN in preventing the acute renal failure and related oxidative stress caused by chronic administration of cyclosporine (CsA) in rats. CMN was administered concurrently with CsA (20 mg/kg/day s.c) for 21 days. Oxidative stress in kidney tissue homogenates was estimated using thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) content, superoxide dismutase (SOD), and Catalase (CAT). Nitrite levels were estimated in serum and tissue homogenates.ResultsCsA administration for 21 days produced elevated levels of TBARS and marked depletion of renal endogenous antioxidant enzymes and deteriorated the renal function as assessed by increased serum creatinine, Blood Urea Nitrogen (BUN) and decreased creatinine and urea clearance as compared to vehicle treated rats. CMN markedly reduced elevated levels of TBARS, significantly attenuated renal dysfunction increased the levels of antioxidant enzymes in CsA treated rats and normalized the altered renal morphology.ConclusionIn conclusion our study showed that CMN through its antioxidant activity effectively salvaged CsA nephrotoxicity.

Multiple papillomavirus‐associated epidermal hamartomas and squamous cell carcinomasin situin a dog following chronic treatment with prednisone and cyclosporine

A 4-year-old, spayed female toy fox terrier developed multiple epidermal hamartomas and squamous cell carcinomas in situ following chronic immunosuppressive therapy with prednisone and cyclosporine for management of an immune-mediated nonregenerative anaemia. Immunohistochemical staining was positive for papillomavirus antigen within both benign (n = 19) and malignant (n = 8) cutaneous lesions that developed during a 3-year period of observation, with positive staining most often seen in keratinocytes in the granular cell layer. Treatment of the papillomavirus infection with interferon-alpha was discontinued after 2 weeks because of diarrhoea and a further increase in liver enzymes. The cutaneous lesions of this dog persisted and new lesions developed during the year following discontinuation of both cyclosporine and prednisone. This is the first reported case of papillomavirus-associated squamous cell carcinoma in situ developing in a dog following chronic administration of cyclosporine and prednisone.

Immunophilin ligands FK506 and cyclosporine A improve neurologic and histopathologic outcome after transient spinal cord ischemia in rabbits

We comparatively evaluated the protective effect of the immunophilin ligands cyclosporine A (INN: ciclosporin), FK506, and rapamycin on the spinal cord in a rabbit model of transient ischemia. Both cyclosporine A and FK506 inhibit calcineurin, whereas rapamycin does not. Thirty-six male New Zealand White rabbits were divided into the following 6 groups: group C, 15 minutes of spinal cord ischemia; group FK, FK506 (1 mg/kg) administered 30 minutes before ischemia; group CsA, cyclosporine A (30 mg/kg) administered 30 minutes before ischemia; group CsA-C, chronic administration of cyclosporine A (20 mg/kg) for 9 days before ischemia; group R, rapamycin (1 mg/kg) administered 30 minutes before ischemia; and group R+FK, rapamycin (1 mg/kg) administered 20 minutes before FK506 pretreatment (1 mg/kg). Group CsA-C was added because the drug does not readily cross the blood-brain barrier. Neurologic function was evaluated by Johnson's 5-point scale at 8, 24, and 48 hours after ischemia, and histopathology was assessed 48 hours after ischemia. At 24 and 48 hours after ischemia, the Johnson score was better in groups FK (4.0 +/- 1.1), R+FK (3 +/- 1.1), and CsA-C (2.7 +/- 1.2) than in group C (0.8 +/- 1.2). Numbers of morphologically intact anterior horn cells were higher in groups FK (31.3 +/- 9.9), R+FK (23.2 +/- 4.5), and CsA-C (18.3 +/- 6.8) than in group C (6.3 +/- 4.3). FK506 and chronic administration of cyclosporine A, but not rapamycin, protect the spinal cord from transient ischemia. Although these results are compatible with inhibition of calcineurin in the mechanism of neuroprotective action of these drugs, other effects through different pathways cannot be excluded before further study.

Cyclosporine and bromocriptine-induced suppressions of CYP3A1/2 and CYP2C11 are not mediated by prolactin

The purpose of this study was to determine if the suppression of hepatic CYP3A1/2 (cytochrome P450 3A1/2) and CYP2C11 (cytochrome P450 2C11) by cyclosporine is mediated by prolactin. Male intact rats were given subcutaneous doses of either 15 mg/kg/day of cyclosporine or 1 ml/kg/day of cyclosporine vehicle concomitantly with one of the following: 500 mg/kg prolactin, 1 ml/kg prolactin vehicle, 4 mg/kg bromocriptine, or 1 ml/kg bromocriptine vehicle for 14 days. Protein expressions were measured using Western blot analysis and activities were measured using an in vitro testosterone hydroxylation assay. The administration of prolactin did not significantly alter CYP3A1/2 protein expression. Hypoprolactinemia, produced by bromocriptine, caused a significant suppression of CYP3A1/2 activity levels when bromocriptine was administered alone and in combination with cyclosporine ( P<0.001, P<0.05; respectively). However, the cause of the suppression by bromocriptine was likely not the result of lowering prolactin levels. Bromocriptine administration also lowered CYP2C11 protein expression and activity, while prolactin administration had virtually no effect on CYP2C11. Chronic cyclosporine administration caused a 140% increase in prolactin area under the curve (AUC) ( P<0.001). Bromocriptine caused a significant decline in endogenous prolactin secretion, however, concurrent cyclosporine administration did not recover these levels. Overall, while both cyclosporine and bromocriptine, separately, can significantly alter the fate of hepatic P450 enzymes, the suppression is likely not due to an alteration in prolactin levels.

Chronic cyclosporine administration induces renal P-glycoprotein in rats

The effect of cyclosporine doses on renal P-glycoprotein expression was examined. Rats were given cyclosporine orally at 2, 10, 30 mg/kg/day or subcutaneously at 1, 5, 15 mg/kg/day for 28 days with or without 14 days of additional vehicle dosing. Following cyclosporine dosing, renal function and P-glycoprotein expression were measured. Renal function was reduced in rats receiving oral cyclosporine and the highest subcutaneous dose, 15 mg/kg/day. Western blot analysis showed that cyclosporine administered orally at 10 and 30 mg/kg/day and subcutaneously at 15 mg/kg/day induced significantly renal P-glycoprotein expression. After discontinuation of cyclosporine, renal P-glycoprotein returned to pre-dosing levels in oral groups, whereas the return was incomplete in subcutaneous groups. These results indicate that cyclosporine induces renal P-glycoprotein overexpression a dose-dependent manner.

THE ROLE OF RENAL SYMPATHETIC NERVES IN EXPERIMENTAL CHRONIC CYCLOSPORINE NEPHROPATHY

Sympathetic nervous system hyperactivity has been postulated to play a major role in the intense intrarenal vasospasm and hypertension provoked by cyclosporine. It has been argued that the denervated renal allograft may be partially protected from the tubulointerstitial fibrosis associated with chronic cyclosporine administration compared with innervated kidneys in extrarenal transplantation. Utilizing a model of chronic cyclosporine nephropathy in which striped fibrosis develops in the uninephrectomized salt-depleted rat, the effect of renal denervation on renal structure and function was examined. Sprague-Dawley rats maintained on a low-salt diet underwent uninephrectomy and contralateral renal denervation or sham denervation, followed by cyclosporine 15 mg/kg daily by injection. After 21 days, glomerular filtration was markedly depressed and linear zones of tubular atrophy and interstitial fibrosis had developed compared with vehicle-treated control animals (P<0.001). However, there was no significant difference in either renal function or structure between denervated and sham-operated animals treated with cyclosporine. We conclude that renal sympathetic neural hyperactivity is not important in the development of chronic cyclosporine nephropathy.

Chronic administration of cyclosporine A does not impair memory retention in rats.

Cyclosporine A (CsA) is the treatment of choice for patients undergoing organ as well as neural transplantation. CsA immunosuppression is associated with neurological and motor alterations in transplant recipients as well as in normal or hemiparkinsonian rats. We investigated possible impairments of memory retention in CsA-treated rats to determine direct effects of CsA on the dementing illness inherent in most neurodegenerative disorders. Rats receiving chronic treatment with CsA at a dose of 10 mg kg-1, i.p., daily for 26 days, as used in neural transplants for animal models of neurodegenerative disorders did not significantly differ from vehicle-treated rats, and even appeared slightly improved, in retention of a passive avoidance task. This present observation parallels recent studies demonstrating 'neuroprotective' effects of CsA in addition to its immunosuppressive effects.

Coronary vasomotor responses in cyclosporine-treated piglets

Chronic treatment with cyclosporine A (Cx) seems to produce a decreased ability of the endothelium to secrete nitric oxide. However, its effect on the coronary arterial system remains controversial. Therefore, coronary arteries isolated from piglets treated by intramuscular injections of Cx (10 mg/kg/day, IM, for 22 days) were studied in organ baths and compared with those isolated from control animals (IM injections of the Cx solvent). Depolarization-induced contractions (KCl 120 mM) were similar in both groups, whereas the acetylcholine-induced contractions (percent of 120 mM KCl) were enhanced: The area under the curve (AUC) was 245 +/- 51 in the Cx group versus 110 +/- 15 in the control group (p < 0.05). Removal of the endothelium did not significantly modify the acetylcholine-induced contractions in both groups and, therefore, did not attenuate the enhanced responsiveness to acetylcholine in the Cx group. On unrubbed rings contracted with prostaglandin F2 alpha, the endothelium-dependent relaxations from serotonin (in the presence of 1 microM ketanserin) were reduced: The AUC was 479 +/- 24 in the Cx group versus 385 +/- 22 in the control group (p < 0.02). Larger AUC values were also found for bradykinin and substance P in the Cx group: 158 +/- 18 versus 55 +/- 17 (in the control group, p < 0.01) and 198 +/- 8 versus 145 +/- 12 (p < 0.01), respectively. Nevertheless, no alteration in calcium ionophore-induced relaxations was observed: The AUC was 217 +/- 10 in the Cx group and 224 +/- 18 in the control group (NS). Indomethacin incubation (10 microM) did not prevent the impairment in endothelium-dependent relaxations and did not attenuate the cyclosporine-induced augmentation of acetylcholine-induced contractions. Thus, chronic administration of cyclosporine to piglets impairs the coronary endothelial function and produces functional changes in smooth muscle cells. These alterations may play a role in the occurrence of cardiac graft vasculopathy.

Inhibition of ileal bile acid transport by cyclosporin A in rat

Chronic administration of cyclosporin A may induce cholestasis and this effect has been attributed to impaired hepatic bile salt synthesis, metabolism and transport. We investigated the effect of cyclosporin A on intestinal absorption of bile acids in the ileum of rat. Ileal bile acid absorption was measured by in vivo intestinal perfusion with cyclosporin A and the solvent Cremophor EL. During ileal perfusion with 25 microM glycocholic acid, the concentration of 2.8 mM cyclosporin A inhibited intestinal bile acid absorption on average by 34%. Additional experiments were performed with everted gut sacs of the distal ileum to evaluate active absorption. A dose and time dependent inhibition of the active intestinal absorption of bile acids was found, with a 50% transport inhibition at an average cyclosporin A concentration of 2.69 mmol L-1. Thus, cyclosporin A inhibits the active intestinal absorption of bile acids which may influence bile acid synthesis, turnover and secretion and may contribute to cyclosporin A induced cholestasis.

Effects of cyclosporine at the hypothalamic-pituitary axis in pituitary-grafted young female rats

This work was designed to investigate the effects of cyclosporine on prolactin secretion by an ectopically grafted heterologous pituitary gland, and on the hypothalamic content of norepinephrine, dopamine and serotonin. The administration of cyclosporine prevented the augmentation in plasma prolactin levels which occurred following an ectopic graft of a litter-mate pituitary gland. In contrast, in sham-operated rats, cyclosporine increased prolactin levels on day 8 of treatment. Both pituitary grafting and cyclosporine treatment in sham-operated rats decreased hypothalamic norepinephrine content. In grafted rats, cyclosporine returned hypothalamic norepinephrine to normal. Hypothalamic serotonin content decreased 8 days after pituitary grafting but increased to the values of control animals after cyclosporine administration. Cyclosporine treatment for 2 and 8 days increased serotonin content in sham-operated animals. As expected, the hypothalamic dihydroxphenylacetic acid/dopamine index increased after pituitary grafting and administration of cyclosporine for 8 days resulted in a further increase. Cyclosporine administration for 2 days, however, decreased this index to the values observed in control animals while drug treatment of control rats for 8 days decreased the dihydroxyphenylacetic acid/dopamine index. In vitro release of prolactin from the ectopic gland was markedly decreased in animals treated with cyclosporine for 2 days and this effect was less evident in 8-day treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporin A induces glomerular endothelial cell injury in vitro

The chronic administration of cyclosporin A (CyA) could be associated with renal arteriolar damage. Endothelial cell injury is considered to be the first event in this pathological change. Bovine glomerular endothelial cells (GEN) were used to investigate whether CyA induces microvascular injury in vitro. The damage induced by CyA was demonstrated by cell detachment from the culture plate and cell lysis as characterized by the increase in lactate dehydrogenase (LDH) at the same time after CyA treatment. One mumol/L of CyA induced detachment of GEN within 3 h and lysis after 6 h. Cyclosporin A-induced GEN lysis appeared in a dose and time-dependent manner. These results indicate that GEN are vulnerable to CyA exposure, suggesting that GEN damage might be related to CyA-mediated glomerular injury.

The effect of chronic administration of cyclosporin A on phenytoin pharmacokinetic parameters in the rat

The potential for a drug interaction between cyclosporin A and phenytoin was investigated in rats. Rats were treated daily for 14 days with cyclosporin A (50mg/Kg, s.c.) and on the day of the experiment phenytoin (10mg/Kg) was administered intravenously. The mean residence time, the elimination half-life and the volume of distribution at steady state were significantly higher in the cyclosporin A-treated group than in the control group. However, total body clearance was similar in both groups. Plasma levels of urea, aspartate aminotransferase (AST) and glucose were significantly higher in the cyclosporin A-treated group than the control group. It was concluded that the observed changes could have been, at least in part, due to an inhibitory effect of cyclosporin A on liver drug metabolizing enzymes and/or liver and kidney damage.

Chronic administration of cyclosporin A induces a decrease in hepatic excretory function in man.

Chronic administration of cyclosporin A may induce cholestasis in a few patients. The purpose of this study was to examine the effect of chronic administration of cyclosporin A on serum bile acid levels, serum bilirubin concentration, and bromosulfophthalein plasmatic fractional clearance. Twenty heart-transplanted patients with normal serum alanine aminotransferase activity receiving cyclosporine A during a mean duration of 33 months (range 7-54) were compared to 20 matched kidney-transplanted patients with normal serum alanine aminotransferase receiving azathioprine for a mean duration of 34 months (range 6-72). As compared to azathioprine-treated patients, patients treated with cyclosporin A had an increase in serum bile acid levels of 32% (P < 0.01), an increase in serum bilirubin concentration of 100% (P < 0.001), and a decrease in bromosulfophthalein plasmatic fractional clearance of 60% (P < 0.001). These results suggest that cyclosporin A induces a decrease in hepatic excretory function in man.

The sodium retaining effects of cyclosporine

The effect of chronic cyclosporine administration on volume regulation was studied in mongrel dogs. Dogs received either cyclosporine (20 mg/kg/day p.o.; N = 7) or vehicle (N = 6) while being maintained on a constant sodium diet. Dogs had measurement of baseline vasoactive hormones. Daily sodium excretion was determined. Following eight days of drug administration, dogs were anesthetized, pre-volume expansion data was collected, and dogs underwent a one hour, 10% body weight 0.9% saline volume expansion. Daily sodium balance was +8.6 +/- 2.2 mEq in the cyclosporine group versus 0.4 +/- 1.8 mEq (P less than 0.05) in the control group after 8 days. Prior to acute volume expansion, aldosterone was 22.5 +/- 7.1 ng% in the cyclosporine group versus 4.7 +/- 0.7 ng% in controls (P less than 0.05). ANF was suppressed in the animals receiving cyclosporine. In response to volume expansion, the cyclosporine group demonstrated an attenuation of maximum urine flow by 56%, fractional excretion of sodium by 52%, and electrolyte free water clearance by 75% when compared to controls (P less than 0.05). We demonstrate that chronic cyclosporine administration activates the renin-angiotensin-aldosterone system, suppresses circulating ANF, and results in chronic sodium retention. Additionally, cyclosporine attenuates the natriuretic and diuretic response to acute volume expansion.

Effect of chronic administration of cyclosporin A on hepatic uptake and biliary secretion of bromosulfophthalein in rat

Cyclosporin A (CyA) decreases bile flow and bile salt secretion in the rat. The purpose of this study was to examine the influence of CyA on the hepatic transport of bromosulfophthalein (BSP). Male Sprague-Dawley rats were injected with CyA at the daily dose of 10 mg/kg (treated animals) or solvent (controls) during three weeks. Hepatic uptake of BSP (assessed by the plasma disappearance curve of the dye) and biliary secretion during infusions (95.5 and 178 nmol/min/100 g) were examined in both groups. Administration of CyA resulted in a decrease in both bile flow and BSP biliary secretion at the two infusion rates used. BSP plasma disappearance rate was significantly lower in treated animals than in controls. Conjugation of the dye was unaffected by CyA. There was no modification in ALT activity or in liver histology. These data show that chronic administration of CyA in rats decreases both hepatic uptake and biliary secretion of BSP. Thus, the inhibitory effect of CyA on biliary secretion is not limited to bile salts but also is observed with other cholephilic substances.

Acute cyclosporine-induced renal vasoconstriction: lack of effect of theophylline

Both acute and chronic administration of cyclosporine A (CSA) lead to renal vasoconstriction, but the mechanism is not fully understood. The present studies were designed to explore the possible role of adenosine in acute CSA-induced renal vasoconstriction in rats. Six groups of anesthetized Sprague-Dawley rats were studied using standard clearance techniques: group 1 rats were controls; groups 2, 4, and 6 received CSA intravenously at 20, 30, and 40 mg.h-1.kg body wt-1, respectively; groups 3 and 5 were identical to groups 2 and 4 except that a priming injection of theophylline was given (56 mumol/kg body wt) and theophylline was included in the intravenous infusate (0.56 mumol.min-1.kg body wt-1). CSA produced acute and concentration-dependent reductions in renal plasma flow (left kidney) and in the clearances of p-aminohippuric acid and inulin (both kidneys). Except in group 6, these changes were observed in the absence of a decrease in arterial blood pressure, demonstrating that CSA produced an acute and concentration-dependent increase in renovascular resistance. Theophylline not only failed to block CSA-induced renal vasoconstriction, if anything, it potentiated it. Because theophylline is an adenosine receptor antagonist, these findings contradict the hypothesis that adenosine mediates acute CSA-induced renal vasoconstriction.

Chronic administration of cyclosporin a induces a decrease in hepatic excretory function in man. A study in heart transplanted patients with normal liver biochemistry

Chronic administration of cyclosporin a induces a decrease in hepatic excretory function in man. A study in heart transplanted patients with normal liver biochemistry