Low-dose Oral Cyclosporine Research Articles

Study on safety and efficacy of low dose oral cyclosporine for the treatment of prurigo nodularis in Bangladeshi population

Prurigo nodularis (PN) is a disease with multiple itching nodules situated chiefly on the extremities. The disease is often persistent and the therapy is refractory. Oral cyclosporine used in moderate to severe psoriasis has shown modest improvement in the skin lesions with significant side effects. The drug is recently used in the treatment of PN with variable efficacy. The present study was therefore intended to investigate whether low dose oral cyclosporine can be preferred as an effective and safe therapy for Prurigo nodularis. This quasi-experimental study was conducted in the Department of Dermatology and Venereology of Community Based Medical College Hospital, Mymensingh, Bangladesh, over a period of 6 months between July 2016 to December 2016. A total of 96 clinically diagnosed cases of prurigo nodularis attending at the above mentioned places were consecutively included in the study. After evaluation of the baseline clinical and laboratory features of the patients, oral cyclosporine was given as 2 mg/kg/day for consecutive 12 weeks. A female preponderance was observed in the study with female to male ratio being 7:3. The putative etiological factors present among the patients were a history of frequent mosquito bite (43.8%), anaemia (28%), hypertension (27.1%) bronchial asthma (22.9%), family history of PN (29.2%) and family history of atopy (24%). The nodules were mainly distributed in front of the lower limbs followed by upper limbs and trunk. In terms of nodule characteristics, 33.3% were excoriated, 38.5% were palpable, 26% flattened, 28.1% infected and 35.4% pruritic nodules In the present study, majority (87.5%) of the patients became free from visible lesions after 12 weeks of treatment with cyclosporine. Serum IgE and total eosinophil count reduced significantly after treatment than those before treatment (177.5 vs. 91.6 U/mL, p < 0.001 and 0.5 vs. 0.3 k/μL, p < 0.001 respectively. However, 8.2% of the patients exhibited albuminuria during the course of treatment. Most of the patients of Prurigo Nodularis after 12 weeks of treatment with low-dose oral cyclosporine became free from the lesions without any significant side-effects.
 CBMJ 2018 January: Vol. 07 No. 01 P: 16-23

Adverse effects of low-dose systemic cyclosporine therapy in high-risk penetrating keratoplasty.

The purpose of this study was to investigate the adverse effects of low-dose oral cyclosporine (CsA) therapy following high-risk corneal transplantation. The medical records from 88 subjects who had undergone high-risk penetrating keratoplasties and had been administered oral CsA were retrospectively analyzed. High risk was defined as a history of graft rejection, three or more quadrants of vascularization, or the presence or history of intraocular inflammation. An initial CsA dose of 3-5 mg/kg per day was given for 3-7 days, followed by 2.5-3.5 mg/kg per day for approximately 1 month. The concentration of CsA was maintained at the target trough level of 120-150 ng/ml for at least 6 months or until serious complications developed. The relationship between the cumulative dose and duration of CsA administration and the adverse systemic effects, including the frequency of herpes keratitis, was evaluated. The incidence of herpes keratitis in the study subjects was compared with the incidence in 185 patients who had not received CsA therapy following penetrating keratoplasty. The mean survival time of the grafts was 33.6 months. Adverse effects occurred in 81.8 % of subjects. Hypertension, elevated liver enzyme levels, elevated serum creatinine level, and decreased absolute neutrophil count (ANC) were observed in 14.8, 6.8, 5.7, and 5.7 % of subjects, respectively. Simvastatin-induced rhabdomyolysis also developed in one case. Some patients exhibited minor complications, with gastrointestinal problems and hypertrichosis recorded in 5.7 and 3.4 % of subjects, respectively. Hypertension and hepatotoxicity most frequently occurred after 4 to 8 weeks of medication, while ANC decrease and nephrotoxicity generally developed after 24 weeks of treatment, with incidence related to the cumulative dose. Herpes keratitis occurred more frequently (31.8 %) in the CsA-treated subjects than in subjects that did not receive CsA therapy (p = 0.005). Most of the adverse effects were reversed after discontinuation of CsA therapy. The results of this study suggest that low-dose oral CsA therapy may induce various adverse effects, the most common of which are herpes keratitis and hypertension.

Low-dose cyclosporin improves the health-related quality of life in Japanese psoriasis patients dissatisfied with topical corticosteroid monotherapy

Psoriasis greatly impacts the health-related quality of life of patients, including any dermatological conditions that are listed in the dermatology life quality index (DLQI). We investigated the relationships between DLQI and the degree of patient satisfaction using questionnaires among psoriasis patients treated only with topical corticosteroids. Patients who were dissatisfied with topical corticosteroids alone and agreed to receive cyclosporin were given low-dose oral cyclosporin. We assessed changes of the DLQI and the psoriasis area and severity index (PASI) scores in patients dissatisfied with treatment during the period of cyclosporin addition. Of 32 enrolled patients, 17 reported dissatisfaction with the current treatment of topical corticosteroids alone. There was a significantly positive correlation between the degree of patient satisfaction questionnaires and the DLQI of these 32 patients. Among the 17 dissatisfied patients, 12 patients agreed to receive additional cyclosporin therapy and five did not. The 12 patients who started on cyclosporin had a significantly lower PASI after 12 weeks than they did at baseline. The DLQI improved significantly after 12 weeks in the cyclosporin-treated patients. The 12 patients who agreed to receive cyclosporin showed a significantly lower DLQI at 12 weeks compared to the five patients who declined the addition of cyclosporin to their treatment. Assessing the degree of patient satisfaction with therapy using a questionnaire could be useful for improving clinical interventions in psoriasis patients. Low-dose oral cyclosporin could be effective in patients who are dissatisfied with topical corticosteroid treatment alone.

Clinical Outcome and Pharmacokinetics After Addition of Low-Dose Cyclosporine to Methotrexate: A Case Study of Five Patients with Treatment-Resistant Inflammatory Bowel Disease

This study reports the clinical outcome, toxicity, and methotrexate pharmacokinetics after the addition of low-dose cyclosporine to methotrexate in patients with ulcerative colitis or Crohn's disease. Three patients with steroid-refractory ulcerative colitis and two patients with steroid refractory Crohn's disease who failed monotherapy with subcutaneous methotrexate 25 mg/week for 16 weeks were treated with the combination of methotrexate and low-dose oral cyclosporine (3 mg/kg/day) for an additional 16 weeks. Clinical response was measured with the Inflammatory Bowel Disease Questionnaire (IBDQ) score. Concentrations of erythrocyte methotrexate, plasma methotrexate, and plasma 7-hydroxymethotrexate were also determined. Both patients with Crohn's disease withdrew from the study for toxicity (headaches, seizure). The three patients with ulcerative colitis experienced clinical improvement with a mean increase in the IBDQ score from 164 to 190 points, p = 0.01. The mean serum creatinine in the three patients who completed the study increased from 0.9 mg/dL at baseline to 1.2 mg/dL at week 16, p = 0.04. One patient developed hypertension. There was no significant change from baseline in the concentrations of erythrocyte methotrexate, plasma methotrexate, and plasma 7-hy-droxymethotrexate. Combination therapy with methotrexate and low-dose oral cyclosporine did not alter methotrexate pharmacokinetics and resulted in high rates of cyclosporine-associated toxicity.

Clinical outcome and pharmacokinetics after addition of low-dose cyclosporine to methotrexate: a case study of five patients with treatment-resistant inflammatory bowel disease.

This study reports the clinical outcome, toxicity, and methotrexate pharmacokinetics after the addition of low-dose cyclosporine to methotrexate in patients with ulcerative colitis or Crohn's disease. Three patients with steroid-refractory ulcerative colitis and two patients with steroid refractory Crohn's disease who failed monotherapy with subcutaneous methotrexate 25 mg/week for 16 weeks were treated with the combination of methotrexate and low-dose oral cyclosporine (3 mg/kg/day) for an additional 16 weeks. Clinical response was measured with the Inflammatory Bowel Disease Questionnaire (IBDQ) score. Concentrations of erythrocyte methotrexate, plasma methotrexate, and plasma 7-hydroxymethotrexate were also determined. Both patients with Crohn's disease withdrew from the study for toxicity (headaches, seizure). The three patients with ulcerative colitis experienced clinical improvement with a mean increase in the IBDQ score from 164 to 190 points, p = 0.01. The mean serum creatinine in the three patients who completed the study increased from 0.9 mg/dL at baseline to 1.2 mg/dL at week 16. p = 0.04. One patient developed hypertension. There was no significant change from baseline in the concentrations of erythrocyte methotrexate, plasma methotrexate, and plasma 7-hydroxymethotrexate. Combination therapy with methotrexate and low-dose oral cyclosporine did not alter methotrexate pharmacokinetics and resulted in high rates of cyclosporine-associated toxicity.

Comparative effectiveness and safety of oral azathioprine and low-dose oral cyclosporin in maintenance of the response in patients with acute, steroid-resistant,ulcerative colitis who initially responded to intravenous cyclosporin

Comparative effectiveness and safety of oral azathioprine and low-dose oral cyclosporin in maintenance of the response in patients with acute, steroid-resistant,ulcerative colitis who initially responded to intravenous cyclosporin

The use of combined intravenous pulse methylprednisolone and low-dose oral cyclosporin A in the treatment of corneal graft rejection: Addendum to previous report

The use of combined intravenous pulse methylprednisolone and low-dose oral cyclosporin A in the treatment of corneal graft rejection: Addendum to previous report

Addition of low-dose oral cyclosporine in severe ulcerative colitis--pharmacokinetics and clinical outcome report of twelve cases.

Addition of low-dose oral cyclosporine in severe ulcerative colitis--pharmacokinetics and clinical outcome report of twelve cases.

Clinical response does not correlate with intestinal or blood cyclosporine concentrations in patients with Crohn's disease treated with high dose oral cyclosporine: [formula omitted], WJ Tremaine, GM Lawson. Mayo Clinic, Rochester, MN

High-dose ( >5 mg/kg/d) oral cyclosporine may be effective treatment for Crohn's disease, whereas low-dose oral cyclosporine ( < or = 5 mg/kg/d) is not. This study determined the correlation between blood and intestinal tissue cyclosporine concentrations and clinical response in patients with Crohn's disease treated with cyclosporine 8 mg/kg/day.Twelve patients with inflammatory Crohn's disease were treated for 6 wk with oral cyclosporine 8 mg/kg/day, adjusted to a whole blood cyclosporine concentration (chromatography) of 200-300 ng/ml. Response was determined by the Crohn's disease activity index. Cyclosporine was measured in intestinal tissue biopsies obtained by colonoscopy at week 6 (chromatography).Eight patients responded and four did not respond. There were no significant differences between the responders and nonresponders in the mean whole blood or intestinal tissue cyclosporine concentrations. Similarly, there were no significant correlations between change in the Crohn's disease activity index score (baseline to week 6) and whole blood or intestinal tissue cyclosporine concentrations. Cyclosporine side effects, including nephrotoxicity and peroneal nerve palsy, were common.Clinical response did not correlate with whole blood or intestinal tissue cyclosporine concentrations in patients treated with high-dose cyclosporine for Crohn's disease. Cyclosporine side effects, including a significant decrease in renal function, were common.

Acute reversible central nervous system toxicity associated with low-dose oral cyclosporine therapy

Cyc1osporine isan immunosuppressant drug that has been used to prevent rejection of transplanted organs for more than a decade. More recently, cyc1osporine has been used inthe treatment ofcutaneousdiseases suchaspyodermagangrenosum (PG)1-7 that have been unresponsive to other therapies. We describe the occurrence of acute, reversible central nervous system (eNS) toxicity in a patient treated with low-dose oral cyclosporine for PG.

IMMUNOSUPPRESSIVE PROPERTIES OF THE BENZOTHIAZEPINE CALCIUM ANTAGONISTS DILTIAZEM AND CLENTIAZEM, WITH AND WITHOUT CYCLOSPORINE, IN HETEROTOPIC RAT HEART TRANSPLANTATION

In vitro studies have shown that calcium channel blockers (CCB) exert inhibitory effects on immunocompetent cells but conflicting results have been reported as to the translation of these effects into significant in vivo immunosuppression. In this study we evaluated the effects of the benzothiazepine-like calcium blockers diltiazem and clentiazem, given alone or associated with cyclosporine on survival improvement of heterotopic rat heart transplants. Inbred male rats of the Lewis strain were used as recipients and Wistar-Furth as donors. Following abdominal implantation of the graft, recipients were randomly divided into 9 groups (n = 5). Group 1 were control isografts (Lew-Lew); group 2 were control allografts (WFu-Lew), and group 3 were allografts treated with low-dose oral cyclosporine 2 mg/kg/day. Groups 4 and 5 were allografts treated with oral diltiazem 0.25 and 2.50 mg/kg/day. Groups 6 and 7 were treated with oral clentiazem, 0.25 and 2.50 mg/kg/day. Groups 8 and 9 consisted of allografts receiving low-dose cyclosporine with either diltiazem or clentiazem 2.50 mg/kg/day, all drugs were administered daily by gavage. Graft function was monitored by transabdominal palpation, and rejection was considered to be complete when no contraction of the graft could be detected. Mean survival time of untreated allografts was 6.4 +/- 0.5 days. Cyclosporine alone increased the mean survival time to 10.6 +/- 2.7 days (P < 0.05 vs. group 2). At all doses studied, diltiazem and clentiazem significantly increased mean survival time of allografts, clentiazem being slightly more potent than diltiazem. In addition, the observed beneficial effects of the benzothiazepine-like calcium channel blockers were dose-dependent. When combined with cyclosporine, diltiazem and clentiazem interacted synergistically (mean survival time increased to 16.8 +/- 3.4 days for diltiazem and 15.8 +/- 1.4 days for clentiazem). These results demonstrate that the benzothiazepine-like calcium channel blockers, as opposed to phenylalkylamines or dihydropyridines, afford significant immunosuppression when used alone. These observations, and the fact that they beneficially interact with cyclosporine, suggest that the benzothiazepine-like calcium antagonists should be considered the drugs of choice when CCBs are to be selected in transplanted patients.

Elevation of fasting serum lipids in patients treated with low-dose cyclosporine for severe plaque-type psoriasis: An assessment of clinical significance when viewed as a risk factor for cardiovascular disease

Hyperlipidemia has received little attention as a side effect of cyclosporine therapy for severe psoriasis. We report changes in fasting serum lipids in patients treated with low-dose oral cyclosporine for psoriasis and discuss their significance. Twenty-two patients with severe, recalcitrant, plaque-type psoriasis were treated with cyclosporine, 5 mg/kg/day, for 12 to 16 weeks. Fasting serum lipid levels (triglycerides, cholesterol, and high-density lipoproteins) were measured at 2-week intervals. The mean serum triglyceride level increased from 117.8 +/- 11.7 mg/dl before initiation of therapy to 183.9 +/- 31.4 mg/dl after 2 weeks of treatment, without further significant change during the remainder of the study (p less than 0.007). A significant elevation of serum cholesterol from 207.1 +/- 8.1 mg/dl initially to 247.4 +/- 10.2 mg/dl after 2 weeks of treatment occurred (p less than 0.001) and persisted with continued cyclosporine therapy. No consistent alteration in high-density lipoprotein was noted (p less than 0.42). Serum lipids should be closely monitored in psoriasis patients receiving intermediate or long-term therapy with cyclosporine, especially in the presence of elevated baseline values.

Long-Term Treatment of Crohnʼs Disease with Cyclosporine

Low-dose oral cyclosporine was used to maintain remission in patients with Crohn's disease. In seven patients, cyclosporine was used as a steroid-sparing agent; in 14 it was given for refractory active disease as an adjunct to conventional treatment, and then continued as maintenance treatment. Cyclosporine was given at an initial dose of 5 mg/kg reduced by 1 mg/kg at 2-month intervals until a maintenance dose of 2 mg/kg was reached. Of the seven patients in whom cyclosporine was used as a steroid-sparing agent, six had a relapse. Remission was achieved in seven of the refractory active group, but cyclosporine was withdrawn because of side effects in six of the patients in this group. Of the seven patients who had achieved remission, six subsequently had a relapse. Therefore, 12 of 14 patients (86%) in remission had a relapse despite cyclosporine maintenance. Ten of these (83%) had a relapse at a cyclosporine dose of 2 or 3 mg/kg. Cyclosporine levels at relapse (median, 74 ng/ml) were lower than the mean levels over the first 6 weeks of treatment (median, 130 ng/ml; p = 0.02). Our data do not support the use of cyclosporine to maintain remission in Crohn's disease.

Cyclosporine in dermatology

Cyclosporine is a potent immunosuppressive agent with no appreciable effect on the bone marrow and a selective inhibitory effect on helper T cells. Oral cyclosporine was first used to prevent organ rejection but also has been reported to be effective in other disorders. In cutaneous diseases that respond to oral cyclosporine helper T cells appear to be involved in their pathogenesis. This article reviews the cutaneous diseases that have been treated with cyclosporine and its pharmacology and side effects. Two significant adverse side effects are renal dysfunction and hypertension, both of which are reversible when short-term low-dose (less than 5 mg/kg per day) oral cyclosporine is discontinued. Lymphoma is unlikely in an otherwise healthy patient who has received low-dose oral cyclosporine for limited periods. The use of oral cyclosporine in any patient should be carefully considered in terms of the risk/benefit ratio and needs to be carried out under close medical supervision. In view of the limited experience with cyclosporine in dermatology, whenever possible its use should be confined to formal clinical studies with established protocols and guidelines. Further controlled studies need to be performed to evaluate the efficacy of low-dose cyclosporine in many dermatoses and its side-effect profile, particularly over the long term.

Low dose cyclosporin a therapy in chronic posterior uveitis

Nine patients with chronic posterior endogenous uveitis of varying aetiology, not satisfactorily controlled with systemic corticosteroids alone, were treated with low dose oral Cyclosporin A (mean maintenance dose 4.0 +/- 1.1 mg/kg/day). Six of the nine patients also continued to receive oral prednisolone (15 mg/day or less). During a follow up period of 6-30 (mean 17) months, seven have shown sustained visual improvement. Nephrotoxicity was the major side effect with serum creatinine concentration (mean +/- 1SD) rising from 91 +/- 7 mumol/l to 115 +/- 13 mumol/l (0.01 less than p less than 0.05) after the first twelve months of treatment. Other observed side effects have included taste disturbance, hypomagnesaemia, and hypertension. Cyclosporin A treatment is of value in the management of severe intraocular inflammation, unresponsive to conventional therapy, but the optimum duration of therapy remains to be established and nephrotoxicity is the major dose limiting effect.

OKT‐3 monoclonal antibody for severe acute renal allograft rejection

We treated 12 renal transplant recipients (9 cadaveric and 3 1‐haploidentical) demonstrating severe rejection with OKT‐3 monoclonal antibody. Rejection was confirmed by fine needle aspirate (FNA) or needle biopsy, or both. All had initial immunosuppression induction with low dose oral cyclosporine (CyA) (10 mg/kg/d) and alternate‐day reducing dose prednisone. Of the 12 patients, 10 received OKT‐3 for steroid resistant rejection (SRR), and 2 as primary treatment for accelerated acute rejection (ARR). Eight of 10 SRR and 1 of 2 ARR responded initially. Four of 8 SRR responders had recurrent rejections within 5 d of discontinuing their OKT‐3: 2 responded to traditional high‐dose steroids, 2 required nephrectomy. Seven of 12 transplants (58%) still function after 5 to 10 months – 6 with SRR, 1 with ARR. In 3 of 4 SRR and 1 ARR who did not experience a recurrent rejection, azathioprine (AZA) had been added electively to CyA immediately on discontinuing the OKT‐3. Patients who did not respond to OKT‐3, or re‐rejected on discontinuing the OKT‐3, had histological evidence or interstitial hemorrhage and endothelial intimal reaction. A blastogenic reaction on FNA on completion of OKT‐3 favored recurrent rejection. Three of the first 4 patients had fulminant herpetic and fungal infections. Subsequent patients were treated prophylactically with oral acyclovir and mycostatin and had no further infection. We suggest that (1) OKT‐3 with antimicrobial prophylaxis is safe and effective for SRR, (2) needle biopsy and serial FNA may be predictive of response of recurrent rejections, (3) the addition of AZA to CyA on completion of OKT‐3 may prevent recurrent rejection.