Oral Administration Of Cyclosporine Research Articles

Oral immunosuppressants improve pregnancy outcomes in women with idiopathic recurrent miscarriage: A meta-analysis.

Reports said immunotherapy is effective for the treatment of idiopathic recurrent miscarriage (RM). Immunotherapy is invasive, and lymphocyte therapy carries some risk of infection. Oral immunosuppressants have the advantages of simple administration and convenience; however, there is no statistical analysis of whether they can improve pregnancy outcomes in patients with idiopathic RM. Six databases were searched for studies on oral immunosuppressants and RM; 374 articles were identified. There were two oral immunosuppressants, cyclosporine A and prednisone; two studies were on cyclosporine A and three studies were on prednisone for RM. In total, 554 RM patients were included in this analysis, including 357 patients who received oral immunosuppressive agents and 197 patients who received basic treatment, placebo, or no treatment. Oral administration of cyclosporine A or prednisolone increases live birth rate (OR=3.6, 95% CI: 2.1-6.15, p<0.00001) and ongoing pregnancy rate (OR=8.82, 95% CI: 2.91-26.75, p=0.0001) in patients with idiopathic RM. Drug use reduced miscarriage rate (OR=0.21, 95% CI: 0.08-0.52, p=0.0007); however, there was significant heterogeneity (I2 =73%) and a moderate-to-severe risk of bias. There was no effect on premature birth rate (OR=2.26, 95% CI: 0.96-5.31, p=0.06). This meta-analysis cannot provide a reference for the duration of medication treatment because the selected studies had inconsistent durations. We did a statistical analysis and found that oral immunosuppressants (including cyclosporine A or prednisolone) can improve pregnancy outcomes in patients with idiopathic RM, increase live birth rate and ongoing pregnancy rate, and reduce miscarriage rate.

T cell function is dispensable for intracranial aneurysm formation and progression.

Given the social importance of intracranial aneurysm as a major cause of a lethal subarachnoid hemorrhage, clarification of mechanisms underlying the pathogenesis of this disease is essential for improving poor prognosis once after rupture. Previous histopathological analyses of human aneurysm walls have revealed the presence of T cells in lesions suggesting involvement of this type of cell in the pathogenesis. However, it remains unclear whether T cell actively participates in intracranial aneurysm progression. To examine whether T cell is involved in aneurysm progression, intracranial aneurysm model of rat was used. In this model, aneurysm is induced by increase in hemodynamic force loaded on bifurcation site of intracranial arteries where aneurysms are developed. Deficiency in T cells and pharmacological inhibition of T cell function were applied to this model. CD3-positive T cells were present in human aneurysm walls, whose number was significantly larger compared with that in control arterial walls. Deficiency in T cells in rats and pharmacological inhibition of T cell function by oral administration of Cyclosporine A both failed to affect intracranial aneurysm progression, degenerative changes of arterial walls and macrophage infiltration in lesions. Although T cells are detectable in intracranial aneurysm walls, their function is dispensable for macrophage-mediated inflammation and degenerative changes in arterial walls, which presumably leads to intracranial aneurysm progression.

Two Cases of Toxic Epidermal Necrolysis Associated with Deflazacort Therapy in Nephrotic Syndrome: Successfully Treated with Cyclosporine A

Toxic epidermal necrolysis (TEN) is a rare, acute, serious, and potentially fatal skin disease, in which cell death causes the epidermis to separate from the dermis. It is thought to be a hypersensitivity complex that affects the skin and mucous membranes, and is caused by certain medications, infections, genetic factors, underlying immunologic disease, or more rarely, cancers. We report two cases of TEN associated with deflazacort (DFZ), a derivative of prednisolone, used in the first episode of nephrotic syndrome (NS). The skin eruption appeared on the 4th and 5th weeks after DFZ administration, while NS was in remission. The widespread lesions were managed by intensive supportive treatment, discontinuation of DFZ, and oral administration of cyclosporine. Both patients showed a rapid improvement in symptoms of TEN without any complications or relapse of NS. Key words: Toxic epidermal necrolysis; Deflazaocrt; Cyclosporine; Nephrotic syndrome

Early non-steady-state population pharmacokinetics of oral cyclosporine in renal transplant recipients.

This study aimed to evaluate the change in the pharmacokinetics (PK) of cyclosporine in the non-steady-state period in the first week after renal transplantation; the factors influencing this change, including genetic variability; and the time point concentration that correlated best with drug exposure. Data were obtained from 69 patients, and PK studies were conducted on postoperative days (PODs) 2, 3, and 7. Samples were taken pre-dose and at 1, 2, 3, 4, 6, 8, and 12 hours after drug administration. MDR1, CYP3A4, and CYP3A5 were genotyped. A population PK analysis and correlational analysis between the concentration at each time point and the area under the time–concentration curve were performed. A two-compartment model with first-order absorption was chosen. The rate and extent of drug absorption showed a significant increase on POD3, followed by a slight decrease on POD7. Until POD3, 8 hours post-dose was the single time point concentration that correlated best with drug exposure and 3 hours was the best time point on POD7. In both analyses, the MDR1 genotype showed potential as a factor influencing PK change. We conclude that oral administration of cyclosporine and dose adjustment based on a single concentration measurement might result in unexpected drug exposure during this early posttransplantation period.

Quantile Normalization Approach for Liquid Chromatography— Mass Spectrometry-based Metabolomic Data from Healthy Human Volunteers

In metabolomic research, it is important to reduce systematic error in experimental conditions. To ensure that metabolomic data from different studies are comparable, it is necessary to remove unwanted systematic factors by data normalization. Several normalization methods are used for metabolomic data, but the best method has not yet been identified. In this study, to reduce variation from non-biological systematic errors, we applied 1-norm, 2-norm, and quantile normalization methods to liquid chromatography-mass spectrometry (LC-MS)-based metabolomic data from human urine samples after oral administration of cyclosporine (high- and low-dose) in healthy volunteers and compared the effectiveness of the three methods. The principal component analysis (PCA) score plot showed more obvious groupings according to the cyclosporine dose after quantile normalization than after the other two methods and prior to normalization. Quantile normalization is a simple and effective method to reduce non-biological systematic variation from human LC-MS-based metabolomic data, revealing the biological variance.

Effects of powdered whole grapefruit and metoclopramide on the pharmacokinetics of cyclosporine in dogs

To determine whether oral administration of metoclopramide or a commercially available powdered whole grapefruit (PWG) nutraceutical in combination with cyclosporine enhances systemic availability of cyclosporine in dogs. 8 healthy mixed-breed dogs in part 1 and 6 of these 8 dogs in part 2. Cyclosporine pharmacokinetics were determined over the course of 24 hours after oral administration of cyclosporine (5 mg/kg) alone, cyclosporine with metoclopramide (0.3 to 0.5 mg/kg), cyclosporine with 2 g of PWG, or cyclosporine combined with both metoclopramide and 2 g of PWG by use of a Latin square crossover study with a 14-day washout period between treatments. Sixty days later, 6 of the 8 dogs were given 10 g of PWG followed by cyclosporine, and pharmacokinetic parameters were compared with those previously obtained after administration of cyclosporine alone. Although metoclopramide or coadministration of metoclopramide and 2 g of PWG had no effect on the pharmacokinetic parameters of cyclosporine, compared with results for cyclosporine alone, the higher (10-g) dose of PWG resulted in 29% faster mean time to maximal plasma cyclosporine concentration, 54% larger area under the curve, and 38% lower apparent oral clearance. Adjustment of the cyclosporine dose may not be needed when metoclopramide is coadministered orally to prevent common adverse effects of cyclosporine. Powdered whole grapefruit has the potential to reduce the required orally administered dose of cyclosporine but only when PWG is used in an amount (at least 10 g) that is currently not cost-effective.

Conversion from Calcineurin Inhibitors to Sirolimus Maintenance Therapy in Renal Allograft Recipients with Risk Factors

Background: The efficacy and safety of conversion treatment with sirolimus in renal transplant recipients using the calcineurin inhibitor (CNI) with one or more risk factors was evaluated. Methods: Ninety-three renal transplant recipients were prospectively enrolled. CNIs(CsA and FK506) as main immunosuppressant were converted to SRL immunosuppressant protocol. Rapid conversion with si-rolimus was performed in all patients. The CNI withdrawal was in 2 weeks. At 4 hours after oral administration of cyclosporin A or tacrolimus, the patients took sirolimus. Initial dose of sirolimus was 6 mg, and repeated maintenance dose is 1.0 - 2.0 mg/d. The first concentration of sirolimus was detected at 5 - 7 days after first oral administration, and the target concentration was 6 - 10 μg/L. Results: The symptoms were markedly improved in patients with CNI induced renal toxicity and CNI induced liver toxicity, and the concentration of sirolimus were maintained at (5.1 ± 1.2) μg/L. Serum creatinine levels decreased from (297.72 ± 150.28) μmol/L to (123.76 ± 44.2) μmol/L, and the liver function were recovery in 24 (92.3%) patients. 9 patients with high glucose returned to normal, and 2 patients were improved. Serum creatinine levels decreased more than 25% of primary level in 17 patients, and the effective rate was 51.5%. 10 patients with tumor were appeared 6 - 43 months after renal transplantation, no recurrence was found in 8 of them and 2 patients were dead. Acute rejections were occurred in 3 patients at 6 months after conversion treatment. The complications were included hyperlipidemia and proteinuria. 3 patients were dead, 6 patients returned to dialysis treatment, and 2 patients were removal of grafts. At 3 years after conversion treatment, the survival rates of patients and grafts were 90.9% and 75.8%, respectively. Conclusion: The conversion treatment with SRL and MMF may be a better option for the renal transplant recipients using the CNI with risk factors appeared.

Management of Living Donor Liver Transplant Patients Using Twice-Daily 4-Hour Intravenous Cyclosporine Therapy

Oral administration of cyclosporine (CsA) is the currently favored route in most liver transplant centers. From October 1998 to January 2008, 86 living donor liver transplantations (LDLTs) were performed in 85 patients (46 adults and 39 children) at our institution. Seventy-three patients received tacrolimus (Tac), and 12 intravenous CsA twice daily at a dose of 3 mg/kg/d as a 4-hour continuous infusion. Thirteen of 73 Tac-based patients were switched to CsA because of side effects. Five were switched to intravenous CsA because they were unable to take the drug orally because of severe Tac-related complications. The remaining eight patients switched to oral CsA. We evaluated patients (11 adults and three children), including 12 with induction therapy and two with conversion therapy within 2 weeks of LDLT. The patients were given a 4-hour intravenous infusion of CsA at an initial dose of 3 mg/kg/d. Stable and adequate blood CsA concentrations were achieved by 4-hour intravenous CsA administration. Among several factors, only graft-to-recipient weight ratio ( r = .743, P < .0001) showed significant correlations with initial blood CsA concentration. No adverse effects were observed after intravenous CsA. No patients developed biopsy-proven acute cellular rejection (ACR) during intravenous CsA administration, whereas two patients had histopathologically diagnosed episodes of ACR after conversion from intravenous to oral CsA. Our findings suggest that immediate administration of a 4-hour intravenous infusion of CsA at an initial dose of 3 mg/kg/d is practical and effective for routine clinical use.

253. An AAV Vector-Mediated Gene Transfer into Canine Skeletal Muscle

Duchenne muscular dystrophy (DMD) is an X-linked, lethal muscle disorder caused by mutations in the dystrophin gene (14 kb cDNA). An adeno-associated virus (AAV) vector-mediated gene transfer is one of attractive approaches to the treatment of DMD, but it has a limitation in insertion size up to 4.9 kb. We recently demonstrated that the AAV vector-mediated micro-dystrophin cDNA transfer could ameliorate dystrophic phenotypes in skeletal muscles of dystrophin-deficient mdx mice (Mol Ther 10: 821-828, 2004). For clinical application, it is important to examine therapeutic effects and the safety issue in larger animal models, such as dystrophic dogs. We established a colony of beagle-based canine X-linked muscular dystrophy in Japan (Exp Anim. 52: 93-97, 2003). To investigate transduction efficiency in canine skeletal muscle using an AAV vector, we injected the AAV vector encoding the LacZ gene driven by a CMV promoter (1.0-2.0 |[times]| 1013 vg/ml, 100-500 |[mu]|l/muscle) into skeletal muscles of normal dogs. |[beta]|-galactosidase (|[beta]|-gal) was expressed only in few fibers at 2 weeks after the injection, and not detected at 4 or 8 weeks after the injection. Instead, large numbers of mononuclear cells appeared around |[beta]|-gal-expressing fibers. To clarify mechanisms of low transduction and cellular infiltration in canine muscle after transfer of the AAV vector, we examined viral infectivity in vitro, cytotoxicity and immune responses of AAV vector transduction in vivo. First, we infected the AAV vector into canine primary myotubes. This in vitro study showed that the AAV vector could allow higher transgene expression in canine myotubes than in murine ones. Second, we tested whether injection of AAV particles elicit cytotoxicity or not. When a promoter-less AAV vector expressing no transgene (5 |[times]| 1012 vg/muscle) was injected into canine muscle, almost no infiltrating cells was observed in injected muscle. Third, we investigated immune responses. A lot of CD4- or CD8-positive cells were detected in clusters of infiltrating cells, together with elevated serum level of anti-|[beta]|-gal IgG. To confirm low transduction depending on immune response, dogs received daily oral administration of cyclosporine (20 mg/kg/day) from |[ndash]|5 day of the introduction of the AAV vector. Immunosuppression largely but not completely improves transduction efficiency of the AAV vector. These results suggest that AAV vector-mediated gene transfer elicits stronger immune responses in canine muscle, but immune responses against transgene products can not thoroughly explain the phenomenon. Cellular toxicity of transgene products might also participate in these infiltrations, while cytotoxicity and immunity of the AAV particles themselves can be negligible based on the result of a promoter-less AAV vectors. It is indispensable to know the molecular background of excess immune responses and cellular toxicity in canine models to establish AAV vector-mediated gene transfer in dystrophic patients.

Myasthenia gravis with thymus hyperplasia and pure red cell aplasia

A case of myasthenia gravis (MG) with thymus hyperplasia and pure red cell aplasia (PRCA) is reported. A 57-year-old woman was diagnosed as having MG and was treated with thymectomy 26 years ago. The histology of the resected thymus was thymic lymphoid follicular hyperplasia. She developed rapidly progressive anemia and a bone marrow examination revealed PRCA. Her hematological results improved with oral administration of cyclosporine A. Cases of MG, thymoma and PRCA have been reported in the literature. We report the first case of MG without thymoma and PRCA.

244. Successful AAV Vector-Mediated Gene Transfer into Canine Skeletal Muscle Required Suppression of Excess Immune Responses

Duchenne muscular dystrophy (DMD) is an X-linked, lethal muscle disorder caused by a mutation in the dystrophin gene (14 kb cDNA). An adeno-associated virus (AAV) vector-mediated gene transfer is one of attractive approaches to the treatment of DMD, but it has a limitation in insertion size up to 4.9 kb. To find a short but functional dystrophin cDNA, we have previously constructed three micro-dystrophin cDNAs, and generated transgenic (Tg) dystrophin-deficient mdx mice expressing micro-dystrophin. Among them, CS1-Tg mdx mice showed lowest levels of serum creatine kinase, complete amelioration of muscle pathology, and nearly full restoration of contractile force (BBRC. 293:1265, 2002). We also showed that muscle-specific MCK promoter in AAV vector could drive longer expression of the LacZ gene than the CMV promoter in skeletal muscle (Gene Ther. 23:1576, 2002). Furthermore, we constructed the AAV2 vector expressing ΔCS1 micro-dystrophin driven by MCK promoter, and demonstrated that AAV vector-mediated ΔCS1 transfer could ameliorate dystrophic phenotypes in mdx muscles (7th ASGT Annual Meeting 2004, in submission). For the application of this strategy to DMD patients, however, it is necessary to examine therapeutic effects and the safety issue in larger animal models, such as dystrophic dogs. We recently established a colony of beagle-based canine X-linked muscular dystrophy in Japan (Exp. Anim. 52: 93, 2003). When the AAV vector encoding the LacZ gene driven by a CMV promoter was introduced into skeletal muscles of dogs, β-galactosidase (β-gal) was expressed only in few fibers of injected muscle after 2 weeks of injection. No β-gal-positive fiver was detected in canine muscle at 4 and 8 weeks post-injection. Instead, large numbers of mononuclear cells appeared around β-gal-expressing fibers in injected muscle. To clarify mechanisms of low transduction and cellular infiltration in canine muscle after transfer of AAV vector, we examined viral infectivity, cytotoxicity and immune responses. First, we infected AAV vector into canine primary myotubes. This in vitro study showed that AAV vector could allow higher transgene expression in canine myotubes than in murine ones. Second, we tested whether injection of AAV particle elicit cytotoxicity or not. When the AAV vector expressing no transgene was injected into canine muscle, almost no infiltrating cells was observed in injected muscle. Third, we investigated immune responses. A lot of CD4- or CD8-positive cells were detected in clusters of infiltrating cells, together with elevated serum level of anti-β-gal IgG. To confirm low transduction depending on immune response, dogs received daily oral administration of cyclosporine (20 mg/kg/day) from -5 day of the introduction of the AAV vector. Immunosuppression considerably improved transduction efficiency by an AAV vector introduction in canine muscle. These results suggested that AAV vector-mediated gene transfer elicited stronger immune responses in canine muscle, and it was necessary to know the molecular background of excess immune responses and to find the way to minimize and suppress immune responses.

Flare-up reaction on murine contact hypersensitivity: III. Effect of staphylococcal enterotoxin B

Staphylococcal enterotoxin B (SEB), a bacterial superantigen, is known as an immunomodulator because it activates an extremely large number of T-cells, and induces the production of large amounts of cytokines. In this study, we examined the effects of SEB on the contact hypersensitivity reaction (CHR). BALB/c mice were first sensitized through haptens applied to the back, and CHR was then induced through challenge to the left ear using the same haptens. SEB was administered intravenously 4 weeks later, causing a flare-up, peaking at 24 h post-administration, in the left ear that had previously exhibited CHR. This flare-up reaction was hapten non-specific, and was inhibited by anti-mouse tumor necrosis factor (TNF)-α antibodies. The flare-up was also suppressed by the oral administration of cyclosporin A prior to the administration of SEB. These results suggest that SEB induces a flare-up of CHR via the production of TNF-α.

Evaluation of pharmacokinetic interaction between cyclosporin A and probucol in rats.

The purpose of this study was to clarify the mechanism of pharmacokinetic interaction between cyclosporin A and probucol in clinical cases. The whole blood concentration of cyclosporin A was measured after oral administration of cyclosporin A with or without probucol in rats. Cyclosporin A was administered as three types of solutions: the contents of the conventional formulation (Sandimmun capsule) diluted with corn oil and the contents of the new microemulsion preconcentrate formulation (Neoral capsule) diluted with saline or corn oil. The solubility of cyclosporin A and another lipophilic agent tacrolimus in water with or without probucol was also measured. The area under the blood concentration-time curve (AUC) after the administration of Sandimmun (corn oil) and Neoral (corn oil) was significantly decreased to 26% and 41% of the control by coadministration of probucol. However in the case of Neoral (saline), it was unchanged. The terminal elimination rate constant was not affected by probucol in any type of cyclosporin A solution. The solubility of cyclosporin A or tacrolimus in water dropped to 49% or 16% of the respective control in the presence of probucol. The interaction between cyclosporin A and probucol is caused by the decreased absorption of cyclosporin A partly based on the lowered solubility in the presence of probucol.

Studies on the cyclosporin A loaded stearic acid nanoparticles

Stearic acid nanoparticles were prepared in this study by melt-homogenization to investigate the possibility of them as a new kind of drug carrier system. Some physicochemical properties of stearic acid nanoparticles were studied and morphology examined by transmission electron microscope. Cyclosporin A as a model drug was then encapsulated into stearic acid nanoparticles. Following the establishment of high performance liquid chromatography assay for cyclosporin A analysis in stearic acid nanoparticles or blood samples, the encapsulation ratio of cyclosporin A to stearic acid nanoparticles was estimated and pharmacokinetics as well as bioavailability of cyclosporin A stearic acid nanoparticles after oral administration to Wistar rats were studied, using the Sandimmun Neoral® (an available microemulsion system of cyclosporin A) as a reference. The mean diameter of cyclosporin A stearic acid nanoparticles was 316.1 nm, while the encapsulation ratio of cyclosporin A to stearic acid nanoparticles reached to 88.36%. It was demonstrated by IR spectra and differential scanning calorimetry that there was no chemical reaction occurred between the cyclosporin A and stearic acid. The relative bioavailability of cyclosporin A stearic acid nanoparticles over reference was nearly 80%, and the time to reach maximum concentration ( T max) of cyclosporin A after oral administration of cyclosporin A stearic acid nanoparticles was delayed significantly than the reference, suggesting an obvious sustained release effect. The stearic acid nanoparticles might be a very potential drug carrier.

Cyclosporin pharmacokinetics in the elderly.

Cyclosporin is an immunosuppressant used in organ transplantation and selected autoimmune diseases such as rheumatoid arthritis. In both these indications, the elderly represent an important and growing segment of the patient population. Cyclosporin is primarily eliminated via biotransformation by cytochrome P450 (CYP)3A in the gut wall and liver. Additionally, P-glycoprotein (mdr-1) located in the gastrointestinal epithelium can affect affect blood drug concentrations after oral administration of cyclosporin, presumably by counter-transporting the drug from the systemic circulation back into the gastrointestinal lumen. Theoretically, age-related alterations in either of these pathways could affect cyclosporin disposition in the elderly. These general pharmacological considerations together with the narrow therapeutic index of cyclosporin between minimally immunosuppressive concentrations and those associated with adverse events, underscore the need for dedicated pharmacokinetic studies in the elderly. Single dose studies have demonstrated that cyclosporin pharmacokinetics are not different in healthy elderly individuals compared with healthy young adults, nor is the between-subject variability in pharmacokinetic parameters more heterogenous in healthy elderly individuals. Similarly, there were no apparent differences in cyclosporin disposition in elderly patients with rheumatoid arthritis compared with healthy young and elderly individuals. Whether pharmacokinetic variability may be increased in elderly patients has not been rigorously addressed and requires investigation in a larger patient population for a definitive conclusion. A population pharmacokinetic study of cyclosporin in organ transplant patients, including elderly allograft recipients up to 75 years of age, did not identify age as a covariable influencing cyclosporin pharmacokinetics. Hence, the available pharmacokinetic data in the elderly do not reveal any major differences from the disposition characterised in younger individuals. It is generally recognised that the elderly are more prone to drug-related adverse experiences and are at greater risk for drug-drug interactions secondary to polypharmacy. The former factor may underlie, in part, the increased incidence of renal adverse events reported in patients with rheumatoid arthritis over 65 years of age receiving cyclosporin. Clinical experience with cyclosporin in elderly organ transplant recipients has not revealed a tolerability profile remarkably different from those in younger patients. Polypharmacy may have specific relevance for elderly patients treated with cyclosporin since this agent is a substrate of both CYP3A and P-glycoprotein, both of which are important in the elimination of many commonly used drugs. This implies that the clinician prescribing cyclosporin for an elderly patient must exercise a heightened awareness for potential drug-drug interactions which could affect the pharmacokinetics of cyclosporin. Based on the available cyclosporin pharmacokinetic data in adults, no age-related administration adaptations appear necessary for its use in the elderly.

Systemic and regional hemodynamics in cyclosporin A hypertension in the rat

SUMMARY: This study examined the hemodynamic effects of 21 days oral administration of cyclosporin A (CyA) in the male Wistar rat. Forty rats were randomly divided into four groups (n=10). Group 1: Sham (olive oil 1 mL/kg/day by gavage) with cardiac output (CO) measurement. Group 2: CyA (CyA 15 mg/kg/day in olive oil by gavage) with CO measurement. Group 3: Sham as for group 1 with regional flow measurements. Group 4: CyA as for group 2 with regional flow measurements. Systolic blood pressure was measured every fourth day. After 21 days mean arterial blood pressure was measured by intra‐arterial cannulation, and CO, and renal, mesenteric, and hindquarter blood flows (RBF, MBF, and HBF) were determined using transonic small animal flowmeters. Total peripheral resistance (TPR) and regional resistances were calculated. Oral CyA produced a sustained rise in systolic blood pressure. Olive oil did not affect blood pressure. CyA increased TPR (P&lt;0.05), renal vascular resistance (RVR, P&lt;0.01) and MBF (P&lt;0.01), decreased RBF (P&lt;0.01), but did not change CO, HBF, mesenteric or hindquarter vascular resistance. We conclude that chronic oral administration of CyA produces hypertension with a hemodynamic profile characterized by rises in TPR and RVR without changes in CO or mesenteric or hindquarter vascular resistances in the Wistar rat.

Decrease in oral bioavailability of cyclosporin A by coadministration of probucol in rats.

To assess the pharmacokinetic interaction of cyclosporin A with probucol, we administered cyclosporin A (10 mg/kg body weight) to rats orally or intravenously with or without pretreatment of probucol (10 mg/animal, daily for 8 days). The whole blood cyclosporin A concentration-time curves after oral administration showed a 34% reduction in peak concentration and a 30% decrease in area under the blood concentration-time curve (AUC) by administration of probucol. No apparent change in elimination half-life or volume of the central compartment was observed with the treatment of probucol. After intravenous administration of cyclosporin A, the blood levels could be described by a two-compartment open model. No differences were observed in the AUC, elimination half-life or total clearance of cyclosporin A by the pretreatment of probucol. Calculated bioavailability following oral administration of cyclosporin A decreased by 33% with the treatment of probucol. These results suggest that probucol may not profoundly influence the disposition of cyclosporin A. Coadministration of probucol could decrease the fraction of absorbed cyclosporin A after oral administration.

Efficacy and side effects of cyclosporin A in nephrotic syndrome of childhood.

The efficacy and side effects of the oral administration of cyclosporin A (Cyc-A) were investigated in 13 children with the nephrotic syndrome. Two of these children were steroid-dependent, 9 were resistant to steroids, and 2 displayed frequent relapses. The diagnosis of 6 patients was mesangioproliferative glomerulonephritis (MezPGN), of another 6 mesangiocapillary glomerulonephritis, and of 1 minimal change disease. Cyc-A was administered for 6 months at a dosage of 7 mg/kg/day with continual monitoring of the serum levels. At the end of the treatment period, 7 of the patients (53.8%) had a total remission, 5 (38.4%) a partial remission, and 1 (7.8%) did not respond to treatment. While total remission was achieved in 4 patients who had responded well to steroids, this was true for only 3 (33.3%) of the 9 patients who had not benefited from steroids. The effects and side effects of Cyc-A on histopathological morphology were also investigated by means of posttreatment biopsies. While histopathological improvement was seen in 3 patients with MezPGN, there was evidence of deterioration in 1 patient with MLH.

Treatment of dextran sulfate sodium-induced murine colitis by intracolonic cyclosporin

The use of oral and intravenous cyclosporin represents a significant advance in the therapy of refractory inflammatory bowel diseases (IBD). However, oral administration of cyclosporin is fraught with improper delivery of cyclosporin to the colon for its topical action. Because of unpredictable metabolism by cytochrome P-450 IIIA, the targeted blood level for systemic effect is not reached at low doses. Furthermore, the doses that have been used for therapy of IBD have been shown to induce several adverse side effects. Thus, an alternate method of delivering cyclosporin to the colon is desirable. In this study, the effect of intracolonically administered cyclosporin was tested for its efficacy to heal mucosal erosions in dextran sulfate sodium (DSS)-induced colitis in mice. Both acute and chronic colitis was induced by feeding female Swiss-Webster mice with 5% DSS (30,000-40,000 mol wt) for five or seven days, respectively. Therapy was advocated prophylactically, prophylaxis plus therapy and therapeutically during the acute and chronic phase of the disease and therapeutically during the chronic phase of the disease. Intracolonic cyclosporin given prophylactically showed adverse effects by increasing the damage to the colonic mucosa. However, intracolonic cyclosporin given therapeutically in 2.5, 5, and 10 mg/kg after the induction of colitis resulted in dramatic responses in terms of reducing the disease activity and histologic scores, corroborated by complete histological resolution compared to oral cyclosporin given at identical doses. Intracolonic cyclosporin (5 mg/kg) was also very effective in reducing the chronic inflammation. The results of this study highlight the application of this animal model for therapeutic research. Furthermore, cyclosporin administered as an enema provides a new stratagem for the therapy of IBD because of its rapid onset of action at very low doses without the risk inherent in oral or systemic administration.

Alopecia universalis treated with oral cyclosporine A and prednisolone: immunologic studies.

Alopecia universalis is a refractory condition. Although the cause of this disease is unknown, immunologic abnormalities have recently been suspected. Thus, we treated six cases of refractory alopecia universalis with immunotherapy. Oral administration of cyclosporine A (2.5 mg/kg) and prednisolone (5 mg/day) resulted in marked symptomatic improvement. Cyclosporine A did not produce any side effects because the administered dosage was relatively low. At present, more than 6 months after the cessation of treatment, recurrence of alopecia has not been seen. Oral administration of low-dose cyclosporine A and prednisolone is considered to be an effective treatment for this disease. Immunologic examination of peripheral blood demonstrated improvement of immunologic function. In particular, CD8-positive T cells, NK cells, and C3, which had been reduced, were increased. A reduction in active CD4 cells, eosinophils, and circulating immune complexes was observed. Histology with fluorescent antibodies showed T-cell infiltration around the hair matrixes. This phenomenon was no longer observed after treatment. These improvements in immunologic function were seen in parallel with the resolution of the clinical symptoms, indicating that immunologic abnormalities are related to this disease.