Effect of Cyclosporin A on prostacyclin synthesis by vascular tissue

Neild, Gh; Rocchi, G.; Imberti, Luisa; Fumagalli, Fabio; Brown, Zarin; Remuzzi, Giuseppe; Williams, D G

doi:10.1016/0049-3848(83)90090-7

Cited by 107 publications

(41 citation statements)

References 17 publications

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“…Cyclosporine causes an increase in vasoconstrictors and platelet proaggregators (endothelin and thromboxane A2) and a concomitant decrease in vasodilators and inhibitors of platelet aggregation (prostacyclin and nitric oxide) (11,(30)(31)(32). PGI2-stimulating factor is low or depleted in CNI-TMA, resulting in low levels of PGI2, a potent vasodilator and inhibitor of platelet aggregation (33).…”

Section: Pathogenesis and Clinical Presentationmentioning

confidence: 99%

Outcome of Plasma Exchange Therapy in Thrombotic Microangiopathy After Renal Transplantation

Karthikeyan

Parasuraman

Shah

et al. 2003

American Journal of Transplantation

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Thrombotic microangiopathy (TMA) in renal transplant recipients is commonly associated with calcineurin inhibitors (CNIs), though several factors such as vascular rejection, viral infections and other drugs may play a contributory role. We report a series of 29 patients with TMA, all of whom were on CNIs. Though plasma exchange (PEx) is widely used to treat TMA, therapeutic guidelines are not well defined. All our patients were treated with PEx and discontinuation of CNIs. Thrombotic microangiopathy was diagnosed at a median of 7 days post-transplant. The mean decrease in Hgb and platelets during TMA was 66% and 64%, respectively, and peak serum creatinine during TMA was 7.4 ± 2.9 mg%. Mean duration of PEx therapy was 8.5 (range 5-23) days. Recovery of platelet count to 150K/mcL and Hgb to 8-10 g/dL were used as endpoints for PEx. Twenty-three/29 (80%) patients recovered graft function after PEx. Twenty/23 (87%) patients who recovered were placed back on CNl. Nineteen/20 (95%) patients tolerated reinstitution of CNl without recurrence of TMA. In post-transplant TMA, PEx was associated with a graft salvage rate of 80%, reversal of hematological changes can be used as the endpoint for PEx therapy and CNl can be reintroduced without risk of recurrence in the majority of patients.

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Section: Pathogenesis and Clinical Presentationmentioning

confidence: 99%

Outcome of Plasma Exchange Therapy in Thrombotic Microangiopathy After Renal Transplantation

Karthikeyan

Parasuraman

Shah

et al. 2003

American Journal of Transplantation

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“…CsA has been shown to cause direct vascular endothelial damage Correspondence: Dr H Tezcan, North Idaho Cancer Center, 700 Ironwood Drive, Coeur d'Alene, ID 83814, USA Received 18 July 1997; accepted 13 August 1997 and to alter the ratio of thromboxane to prostacyclin production resulting in procoagulant activity. [18][19][20][21][22][23][24] Since patients who develop neurologic symptoms attributable to CsA without microangiopathic changes and those who develop TTP are frequently early post-transplant, discontinuing CsA may be associated with development of severe GVHD. The introduction of FK506 into clinical use has allowed substitution of FK506 for CsA in patients developing TTP following BMT and solid organ transplantation.…”

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confidence: 99%

Severe cerebellar swelling and thrombotic thrombocytopenic purpura associated with FK506

Tezcan

Zimmer

Fenstermaker

et al. 1998

Bone Marrow Transplant

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Summary:Two patients with CsA-associated neurotoxicity developed severe cerebellar swelling and thrombotic thrombocytopenic purpura after switching to FK506 and high-dose corticosteroids. The prodrome of CsAassociated neurotoxicity, TTP and hypertension while receiving FK506, and high-dose corticosteroids could all be implicated in the development of this syndrome. Close monitoring of patients receiving FK506 and highdose corticosteroids, for the development of TTP is warranted. Early radiological examination should also be considered in such patients to allow early surgical intervention. Keywords: cerebellar swelling; TTP; FK506; cyclosporine neurotoxicity; steroids Common side-effects of cyclosporin A (CsA) include renal dysfunction, hypertension and tremors.1,2 Rare severe neurotoxicity including ataxia and occipital blindness is also reported. [3][4][5][6] This syndrome resembles thrombotic thrombocytopenic purpura (TTP). There are numerous case reports of TTP following BMT. [7][8][9][10][11][12][13] Clinical manifestations include: hypertension, edema, renal failure, neurologic changes and microangiopathic hemolytic anemia. Although the syndromes are both associated with CsA use, the presence or absence of microangiopathic hemolytic anemia can distinguish them. 14 Treatment of CsA neurotoxicity consists of discontinuing the drug, correcting electrolyte abnormalities and controlling hypertension. 3,13,15 Neurologic changes typically resolve within 48 h of discontinuing CsA. In contrast, patients with TTP have a much poorer outcome despite discontinuing CsA, often requiring intensive support.14 Although ideal management is unclear, it appears that plasma exchange alone 16 or combined with protein immunoadsorption may be effective modes of therapy. and to alter the ratio of thromboxane to prostacyclin production resulting in procoagulant activity. [18][19][20][21][22][23][24] Since patients who develop neurologic symptoms attributable to CsA without microangiopathic changes and those who develop TTP are frequently early post-transplant, discontinuing CsA may be associated with development of severe GVHD. The introduction of FK506 into clinical use has allowed substitution of FK506 for CsA in patients developing TTP following BMT and solid organ transplantation. 25 However, the safety of this approach is not well established as there are now reports of FK506-induced TTP following BMT and solid organ transplantation. 26-28 Case 1A 28-year-old male with Hodgkin's disease received an HLA-matched unrelated donor BMT 2 years after relapsing following an autologous BMT. Conditioning was with thiotepa and carboplatin. He received low-dose intravenous heparin as hepatic veno-occlusive disease (VOD) prophylaxis. GVHD prophylaxis consisted of cyclosporine, methotrexate and methylprednisolone. On day +8, he developed hyperbilirubinemia (primarily direct), associated with an elevated CsA level of 514 (normal range, 250-450). CsA was held and restarted at one-third the previous dose on day +10. On day +11, he developed cort...

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“…10 Animal studies have, however, demonstrated that CsA can induce endothelial damage by interfering with prostacyclin and promoting platelet aggregation. 11,12 This or other processes could potentially allow CsA to penetrate the bloodbrain barrier and exert its toxic effect. From the available data, however, it is evident that the precise pathophysiology of CsA neurotoxicity has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Fatal outcome due to cyclosporine neurotoxicity with associated pathological findings

Gopal

Thorning

Back

1999

Bone Marrow Transplant

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Summary:We present a case of death likely to be directly due to cyclosporine (CsA) neurotoxicity. To date, there have been no reports of deaths directly due to CsA neurotoxicity, nor has an associated histological lesion been described independent of confounding processes. A 54-year-old male received an HLA-matched-unrelated BMT for CML. He developed progressive encephalopathy and on day ؉79 had a generalized seizure. All CSF studies were negative for infectious causes. MRI revealed diffuse, symmetrical white matter abnormalities located in the occipital sub-cortex, thalamus, mid brain, pons, and cerebellum which were typical of CsA toxicity. The patient died of central respiratory failure within 72 h of discontinuing CsA. Autopsy revealed diffuse patchy white matter edema and astrocytic injury without evidence of axonopathy, demyelination, microvascular injury, or infectious/inflammatory process. This case demonstrates previously undescribed lethal CsA neurotoxicity and may reveal an associated primary pathological lesion. Keywords: cyclosporine; neurotoxicity; MRI; CML; allogeneic bone marrow transplant Neurological complications cause morbidity and mortality in up to 37% of patients following allogeneic bone marrow transplantation. 1 Case reports and retrospective case series implicate CsA neurotoxicity as a significant contributor to these complications. 1,2 This toxicity can range from the most common finding of tremors to the most severe syndrome of seizures, visual disturbances, and radiographically characteristic white matter abnormalities often involving the occipital lobes. 2,3 This distinguishable clinical and radiographic syndrome, however, has not been reported to be directly fatal. [2][3][4] Here, we present a patient with typical CsA CNS neurotoxicty, a fatal outcome, and no other overt cause of death. We also describe the previously unreported Case reportPhiladelphia chromosome-negative CML was diagnosed in June 1996 in a 54-year-old male with adult onset diabetes. In July 1997, while still in chronic phase, he received an HLA-identical unrelated allogeneic BMT following CY/TBI conditioning. He was treated with routine GVHD prophylaxis consisting of CsA/MTX according to the Seattle regimen. 5 Engraftment (Ͼ500 neutrophils) occurred on day ϩ20, and platelet requirements ceased after day ϩ22. His post-transplant course was notable for the development of acute skin GVHD on day ϩ26 not requiring increased immunosuppression and symptomatic biopsyproven upper gastrointestinal GVHD on day ϩ65 requiring treatment with methylprednisolone (1 mg/kg i.v. twice daily).After complaining of intermittent 'blurred vision' for several days, he was noted by his wife to be confused on day ϩ78. Neurological examination and routine laboratory studies were normal. The following day he was increasingly somnolent. Deep tendon reflexes were symmetrical but plantar reflexes were absent. Otherwise, sensory/motor and cranial nerve examinations were normal. On day ϩ79 he had a single generalized tonic-clonic seizure that was...

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Effect of Cyclosporin A on prostacyclin synthesis by vascular tissue

Cited by 107 publications

References 17 publications

Outcome of Plasma Exchange Therapy in Thrombotic Microangiopathy After Renal Transplantation

Outcome of Plasma Exchange Therapy in Thrombotic Microangiopathy After Renal Transplantation

Severe cerebellar swelling and thrombotic thrombocytopenic purpura associated with FK506

Fatal outcome due to cyclosporine neurotoxicity with associated pathological findings

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