tacrolimus and Peripheral-Nervous-System-Diseases

Neurologic itch is defined as pruritus resulting from any dysfunction of the nervous system. Itch arising due to a neuroanatomic pathology is seen to be neuropathic. Causes of neuropathic itch range from localized entrapment of a peripheral nerve to generalized degeneration of small nerve fibers. Antipruritic medications commonly used for other types of itch such as antihistamines and corticosteroids lack efficacy in neuropathic itch. Currently there are no therapeutic options that offer relief in all types of neuropathic pruritus, and treatment strategies vary according to etiology. It is best to decide on the appropriate tests and procedures in collaboration with a neurologist during the initial work-up. Treatment of neuropathic itch includes general antipruritic measures, local or systemic pharmacotherapy, various physical modalities, and surgery. Surgical intervention is the obvious choice of therapy in cases of spinal or cerebral mass, abscess, or hemorrhagic stroke, and may provide decompression in entrapment neuropathies. Symptomatic treatment is needed in the vast majority of patients. General antipruritic measures should be encouraged. Local treatment agents with at least some antipruritic effect include capsaicin, local anesthetics, doxepin, tacrolimus, and botulinum toxin A. Current systemic therapy relies on anticonvulsants such as gabapentin and pregabalin. Phototherapy, transcutaneous electrical nerve stimulation, and physical therapy have also been of value in selected cases. Among the avenues to be explored are transcranial magnetic stimulation of the brain, new topical cannabinoid receptor agonists, various modes of acupuncture, a holistic approach with healing touch, and cell transplantation to the spinal cord.

Topics: Acupuncture Therapy; Amines; Anesthetics, Local; Anticonvulsants; Antipruritics; Botulinum Toxins, Type A; Calcineurin Inhibitors; Cannabinoid Receptor Agonists; Capsaicin; Cyclohexanecarboxylic Acids; Doxepin; Gabapentin; gamma-Aminobutyric Acid; Humans; Neuromuscular Agents; Peripheral Nervous System Diseases; Phototherapy; Physical Therapy Modalities; Pregabalin; Pruritus; Tacrolimus; Transcranial Magnetic Stimulation; Transcutaneous Electric Nerve Stimulation

Topics: Anti-HIV Agents; Anticonvulsants; Antineoplastic Agents; Antitubercular Agents; Cisplatin; Dose-Response Relationship, Drug; Early Diagnosis; Humans; Immunosuppressive Agents; Paclitaxel; Peripheral Nervous System Diseases; Phenytoin; Tacrolimus; Thalidomide; Vincristine

No clinical techniques induce restoration of neurological losses following spinal cord trauma. Peripheral nerve damage also leads to permanent neurological deficits, but neurological recovery can be relatively good, especially if the ends of a transected nerve are anastomosed soon after the injury. The time until recovery generally depends on the distance the axons must regenerate to their targets. Neurological recovery following the destruction of a length of a peripheral nerve requires a graft to bridge the gap that is permissive to, and promotes, axon regeneration. But neurological recovery is slow and limited, especially for gaps longer than 1.5 cm, even using autologous peripheral nerve grafts. Without a reliable means of bridging long nerve gaps, such injuries commonly result in amputations. Promoting extensive neurological recovery requires techniques that simultaneously provide protection to injured neurons and increase the numbers of neurons that extend axons, while inducing more rapid and extensive axon regeneration across long nerve gaps. Although conduits filled with various materials enhance axon regeneration across short nerve gaps, pure sensory nerve graft remains the gold standard for use across long nerve gaps, even though they lead to only limited neurological recovery. Consistent results demonstrate that several immunosuppressive agents enhance the number of axons and the rate at which they regenerate. This review examines the roles played by immunosuppressants, especially FK506, with primary focus on its role as a neuroprotectant and neurotrophic agent, and its potential clinical use to promote improved neurological recovery following peripheral nerve and spinal cord injuries.

Topics: Animals; Axons; Drug Administration Schedule; Humans; Immunophilins; Immunosuppressive Agents; Ischemia; Nerve Regeneration; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Spinal Cord Injuries; Tacrolimus

FK506 (tacrolimus, Prograf is an immunosuppressant drug that also has profound neuroregenerative and neuroprotective actions independent of its immunosuppressant activity. The separation of these properties has led to the development of non-immunosuppressant derivatives that retain the neurotrophic activity. This review focuses on the peripheral nerve actions of these compounds following mechanical injury (nerve crush or transection with graft repair) and in models of inflammatory neuropathies. Whereas FK506 may be indicative for the treatment of inflammatory neuropathies where its immunosuppressive action would be advantageous, non-immunosuppressant derivatives represent a new class of potential therapeutic agents for the treatment of human neurological conditions in general. Moreover, these studies have led to the discovery of a novel mechanism whereby these compounds activate intrinsic neuroregenerative and neuroprotective pathways in the neuron.

Topics: Animals; Axons; Graft Survival; Humans; Immunophilins; Inflammation; Models, Neurological; Nerve Crush; Nerve Degeneration; Nerve Regeneration; Neuroprotective Agents; Peripheral Nervous System Diseases; Tacrolimus; Wound Healing

Peripheral neuropathy after bone marrow transplantation can produce motor disability with significant morbidity and mortality, particularly when the neuropathy occurs within the first few months of the transplant. Most of these severe neuropathies have demyelinating features on electrophysiologic tests and histopathology, characteristic of immunologically-mediated neuropathies. The specific immune mechanism is uncertain. It is possible that cyclosporin, FK-506, and interferon-alpha may all trigger immunologically mediated neuropathies in rare patients. Transplants in patients with pre-existing demyelinating neuropathy may result in abrupt exacerbation of the neuropathy. Other causes of severe neuropathies include high-dose cytosine arabinoside and critical illness polyneuropathy. Less severe neuropathies with primarily sensory deficits may result from etoposide conditioning, thalidomide treatment for graft-versus-host disease, and the chemotherapeutic agents cisplatin and paclitaxel when used at high-dose with peripheral stem cell support. When encountering patients with disabling motor neuropathies, transplant physicians must identify (with the aid of nerve conduction tests) those neuropathies that are likely to be immunologically mediated and then empirically add or alter immunosuppressant therapies. Unfortunately, experience has been too limited to suggest specific regimens or the optimal sequence of immunosuppressant therapies.

Topics: Bone Marrow Transplantation; Cyclosporine; Cytarabine; Demyelinating Diseases; Humans; Immunosuppressive Agents; Interferon-alpha; Peripheral Nervous System Diseases; Tacrolimus; Time Factors

Previous investigations have shown that plasma selenium concentrations are significantly lower in patients with established chronic graft nephropathy (CGN) than in healthy transplant controls. The aims of this study were to determine when in the transplant process low selenium concentrations become apparent and to explore the relationship between selenium levels and risk factors for CGN.. Plasma selenium concentrations were measured in 40 patients (20 receiving cyclosporin, 20 receiving tacrolimus) undergoing transplantation. Samples were obtained immediately before transplantation and at 3, 6 and 12 months after transplantation.. A low plasma selenium concentration was found in 30 patients at the time of transplantation but this had normalized in the majority of patients by 3 months. Plasma selenium concentrations at 3, 6 and 12 months were significantly higher than baseline values for both treatment arms, but were significantly lower at 3 months in patients who experienced either clinical acute rejection (CAR) or cytomegalovirus (CMV) infection during the preceding months.. Low plasma selenium concentrations are common at the time of transplantation but appear to normalize thereafter. The identification of low selenium levels in patients who experience CAR or CMV (two important risk factors for clinically apparent CGN) suggests that the relationship between selenium and CGN warrants further investigation.

Topics: Adolescent; Adult; Aged; Cadaver; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Peripheral Nervous System Diseases; Selenium; Tacrolimus

Neurotoxicity is a significant clinical side effect of immunosuppressive treatment used in prophylaxis for rejection in solid organ transplants. This study aimed to provide insights into the mechanisms underlying neurotoxicity in patients receiving immunosuppressive treatment following renal transplantation. Clinical and neurophysiological assessments were undertaken in 38 patients receiving immunosuppression following renal transplantation, 19 receiving calcineurin inhibitor (CNI) therapy and 19 receiving a calcineurin-free (CNI-free) regimen. Groups were matched for age, gender, time since transplant and renal function and compared to normal controls (n = 20). The CNI group demonstrated marked differences in nerve excitability parameters, suggestive of nerve membrane depolarization (p < 0.05). Importantly, there were no differences between the two CNIs (cyclosporine A or tacrolimus). In contrast, CNI-free patients showed no differences to normal controls. The CNI-treated patients had a higher prevalence of clinical neuropathy and higher neuropathy severity scores. Longitudinal studies were undertaken in a cohort of subjects within 12 months of transplantation (n = 10). These studies demonstrated persistence of abnormalities in patients maintained on CNI-treatment and improvement noted in those who were switched to a CNI-free regimen. The results of this study have significant implications for selection, or continuation, of immunosuppressive therapy in renal transplant recipients, especially those with pre-existing neurological disability.

Topics: Adult; Aged; Calcineurin Inhibitors; Cross-Sectional Studies; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Peripheral Nervous System Diseases; Tacrolimus

Topics: Amiodarone; Anti-Arrhythmia Agents; Anti-HIV Agents; Antibodies, Monoclonal; Anticonvulsants; Antineoplastic Agents; Antiprotozoal Agents; Antirheumatic Agents; Antitubercular Agents; Colchicine; Gout Suppressants; Humans; Immunosuppressive Agents; Infliximab; Interferon-alpha; Metronidazole; Peripheral Nervous System Diseases; Phenytoin; Tacrolimus

Accumulating evidence indicates that in addition to its immunosuppressant properties, FK506 (tacrolimus), an FDA-approved molecule, promotes nerve regeneration. However, the neuroprotective and neurotrophic effects of this molecule on sensitive fiber regeneration have never been studied. In order to fill this gap in our knowledge, we assessed the therapeutic potential of FK506 in a rat model of peripheral nerve repair. A 1-cm segment of left peroneal nerve was cut out and immediately autografted in an inverted position. After surgery, the animals were treated with FK506 (1.2 mg/kg/d) via an osmotic pump and compared to untreated animals. Recovery of use of the injured leg was assessed weekly for 12 weeks using a walking track apparatus and a camcorder. At the end of this period, motor and metabosensitive responses of the regenerated axons were recorded and histological analysis was performed. We observed that FK506 significantly: (1) increased the diameter of regenerated axons in the distal portion of the graft; (2) improved the responses of sensory neurons to metabolites such as potassium chloride and lactic acid; and (3) induced a fast-to-slow-fiber-type transition of the tibialis anterior muscle. Taken together, these data indicate that FK506 potentiates metabosensitive nerve fiber regeneration. Pharmacological studies of various dosages and concentrations of FK506 are required before recommending this drug for therapeutic treatment of nerve injuries.

Topics: Animals; Disease Models, Animal; Growth Cones; Immunosuppressive Agents; Lactic Acid; Male; Muscle Fibers, Fast-Twitch; Nerve Regeneration; Peripheral Nerve Injuries; Peripheral Nerves; Peripheral Nervous System Diseases; Peroneal Nerve; Potassium Chloride; Rats; Rats, Sprague-Dawley; Recovery of Function; Sensory Receptor Cells; Tacrolimus; Treatment Outcome

A 57-year-old male patient in the first remission of acute erythroid leukemia underwent reduced-intensity umbilical cord blood transplantation. He developed grade III acute graft-versus-host disease (GVHD) on day 29. Although the acute GVHD was resolved with tacrolimus and steroid therapy, weakness developed in the left upper extremity on day 59. Neurological examination demonstrated asymmetric muscular weakness of the extremities with the proximal part of the left upper extremity being markedly affected. Neurophysiological studies suggested that this was due to immune-mediated demyelinating neuropathy. Intravenous immunoglobulin (IVIG) therapy was administered at a dose of 0.4 g/kg/day for 5 days and worsening of clinical symptoms ceased. While the patient developed diarrhea and chronic GVHD of the skin and cytomegalovirus (CMV) antigenemia was repeatedly positive, neurological exacerbation was stabilized. Neurological symptoms did not immediately improve after the second and third dose of IVIG. Approximately 50 days after the third dose of IVIG, neurological symptoms improved with the gradual resolution of diarrhea and CMV reactivation. Although the pathophysiology of polyneuropathies after allo-SCT is not well understood, some reports suggest an association with GVHD or alloreactive T cell expansion following antecedent infection. This case provides valuable information regarding the pathophysiology of peripheral neuropathy following allo-SCT.

Topics: Acute Disease; Cord Blood Stem Cell Transplantation; Graft vs Host Disease; Humans; Immunoglobulins, Intravenous; Leukemia, Erythroblastic, Acute; Male; Middle Aged; Peripheral Nervous System Diseases; T-Lymphocytes; Tacrolimus; Transplantation Conditioning

In this study, we have evaluated neuroprotective effect of an immunosuppressant immunophilin ligand, FK506, in the sciatic nerve injury model in rats. FK506 was injected to the sciatic nerve transected 3-month-old female Wistar rats (2 mg/kg/day starting 1 day prior to sciatic nerve injury up to 7 day post operation). Equal number of sciatic nerve transected animals served as injured untreated controls. The contralateral side served as respective control. L4-L5 region of the spinal cord was removed on day 1, 3, 7, 14, 21, and 28, post operation and then processed for cryo-sectioning and paraffin sectioning. The cryocut sections were used for immunohistochemistry for localizing all microglia (using anti-Iba-1) and MHC-II expressing microglia (with OX-6). The physical dissector method was applied on Nissl stained paraffin sections for absolute motor neuron counting in the L4-L5 region of spinal cord. FK506 treated animals presented 88.7% neuronal survival while the injured alone had 79.12%, which is significantly less than the treated animals. FK506 caused early proliferation of microglia at 1 and 3 days post operation. FK506 also significantly restricted transformation of these cells in to phagocytes. Colocalization of activated microglia by anti-Iba-1 and OX-6 antibodies, confirms that the MHC-II expressing cells in injured spinal cord are none other than microglial cells and MHC-II expressing cells are significantly less in treated as compared to untreated injured animals. We propose that immunosuppression is one of the main mechanisms by which FK506 protects the central neurons following peripheral injury.

Topics: Animals; Cell Proliferation; Cell Survival; Cytoprotection; Drug Evaluation, Preclinical; Female; Immunosuppression Therapy; Immunosuppressive Agents; Microglia; Neurons; Neuroprotective Agents; Peripheral Nervous System Diseases; Phenotype; Rats; Rats, Wistar; Sciatic Nerve; Tacrolimus

Tacrolimus is used widely for immunosuppression following transplantation. It has rarely been linked to the development of peripheral neuropathy. However, one study also reported improvement in peripheral neuropathy after tacrolimus use. We have reported herein two patients who developed chronic sensorimotor polyneuropathy after tacrolimus use following renal transplantation. One patient had an unusual presentation with bilateral facial and extremity weakness and a relapsing course. The other patient presented with focal sensory symptoms in one hand. Electrophysiological studies confirmed widespread, predominantly demyelinating or axonal polyneuropathy. We concluded that patients on tacrolimus should be carefully monitored for symptoms suggestive of peripheral neuropathy.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neural Conduction; Peripheral Nervous System Diseases; Polyneuropathies; Postoperative Complications; Tacrolimus

The calcineurin inhibitors (CIs) cyclosporine A and tacrolimus are essential for graft-versus-host disease prophylaxis but are associated with adverse effects, including neurotoxicity. We report a case of irreversible CI-induced neuropathic pain following allogeneic hematopoietic stem cell transplantation. The patient developed dysesthesia, electric shock-like pain, and severe itching followed by intractable analgesic-resistant pain in the lower extremities. There were no abnormal radiographic findings, and there was no improvement with a reduction of CI dosage or with administration of a calcium channel blocker. These clinical findings are similar to but inconsistent with CI-induced musculoskeletal pain syndromes previously reported in organ transplantation.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Pain; Peripheral Nervous System Diseases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radiography; Tacrolimus; Transplantation, Homologous

Acrylamide (AC) is a known industrial neurotoxic chemical that has been recently found in carbohydrate-rich foods cooked at high temperatures. Repeated AC administration produces a pronounced neuropathy characterized by flaccid paralysis and ataxia and represents a well-established animal model of progressive axonal loss. AC also elicits prominent morphologic alterations (e.g., eccentrically placed nuclei, infolding of the nuclear membrane, accumulations of dense bodies, and clusters of smooth endoplasmic reticulum (SER) associated with numerous microtubules) in cerebellar Purkinje cells that may contribute to the pronounced ataxia in these animals. Here, we examined the neuroprotective action of FK506 (tacrolimus) in male and female rats given daily intraperitoneal injections of AC (30 mg/kg) for 4 weeks. Daily subcutaneous injections of FK506 (2 mg/kg/day) dramatically reduced the behavioral signs of neuropathy (i.e., paralysis and ataxia), markedly protected against axonal loss (by 82% and 73% in the tibial nerves of male and female rats, respectively), and reduced the pathologic changes in Purkinje cells. In a separate study, subcutaneous injections of FK506 (2 or 10 mg/kg) for 2 weeks markedly increased heat shock protein-70 (Hsp-70) immunostaining in sensory neurons, motor neurons, Purkinje cells, and other regions of the brain (in particular, the amygdala) from nonintoxicated and AC-intoxicated rats compared to controls. In contrast, AC-intoxicated animals not given FK506 demonstrated reduced Hsp-70 staining. Thus, the ability of FK506 to increase Hsp-70 expression may underlie its neuroprotective action. We suggest that compounds capable of eliciting a heat shock response may be useful for the treatment of human neuropathies.

Topics: Acrylamide; Amygdala; Animals; Cerebellum; Drug Administration Routes; Drug Administration Schedule; Female; Heat-Shock Response; HSP70 Heat-Shock Proteins; Immunosuppressive Agents; Male; Motor Activity; Neurons; Neuroprotective Agents; Peripheral Nerves; Peripheral Nervous System Diseases; Proto-Oncogene Proteins c-fos; Purkinje Cells; Rats; Rats, Sprague-Dawley; Sex Factors; Tacrolimus

Antiretroviral toxic neuropathy is the most common neurological complication of human immunodeficiency virus infection. This painful neuropathy not only affects the quality of life of human immunodeficiency virus-infected patients but also severely limits viral suppression strategies. We have developed an in vitro model of this toxic neuropathy to better understand the mechanism of neurotoxicity and to test potential neuroprotective compounds. We show that among the dideoxynucleosides, ddC appears to be the most neurotoxic, followed by ddI and then d4T. This reflects their potency in causing neuropathy. AZT, which does not cause a peripheral neuropathy in patients, does not cause significant neurotoxicity in our model. Furthermore, in this model, we show that the immunophilin ligand FK506 but not cyclosporin A prevents the development of neurotoxicity by ddC, as judged by amelioration of ddC-induced "neuritic pruning," neuronal mitochondrial depolarization, and neuronal necrotic death. This finding suggests a calcineurin-independent mechanism of neuroprotection. As calcineurin inhibition underlies the immunosuppressive properties of these clinically used immunophilin ligands, this holds promise for the neuroprotective efficacy of nonimmunosuppressive analogs of FK506 in the prevention or treatment of antiretroviral toxic neuropathy.

Topics: Animals; Cell Death; Cells, Cultured; Ganglia, Spinal; HIV Infections; Mitochondria; Neurons, Afferent; Neuroprotective Agents; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Inhibitors; Schwann Cells; Tacrolimus

Poor functional recovery after peripheral nerve injury is attributable, at least in part, to chronic motoneuron axotomy and chronic Schwann cell (SC) denervation. While FK506 has been shown to accelerate the rate of nerve regeneration following a sciatic nerve crush or immediate nerve repair, for clinical application, it is important to determine whether the drug is effective after chronic nerve injuries. Two models were employed in the same adult rats using cross-sutures: chronic axotomy and chronic denervation of SCs. For chronic axotomy, a chronically (2 months) injured proximal tibial (TIB) was sutured to a freshly cut common peroneal (CP) nerve. For chronic denervation, a chronically (2 months) injured distal CP nerve was sutured to a freshly cut TIB nerve. Rats were given subcutaneous injections of FK506 or saline (5 mg/kg/day) for 3 weeks. In the chronic axotomy model, FK506 doubled the number of regenerated motoneurons identified by retrograde labeling (from 205 to 414 TIB motoneurons) and increased the numbers of myelinated axons (from 57 to 93 per 1000 microm2) and their myelin sheath thicknesses (from 0.42 to 0.78 microm) in the distal nerve stump. In contrast, after chronic denervation, FK506 did not improve the reduced capacity of SCs to support axonal regeneration. Taken together, the results suggest that FK506 acts directly on the neuron (as opposed to the denervated distal nerve stump) to accelerate and promote axonal regeneration of neurons whose regenerative capacity is significantly reduced by chronic axotomy.

Topics: Animals; Axons; Axotomy; Cell Count; Chronic Disease; Denervation; Female; Fluorescent Dyes; Immunosuppressive Agents; Injections, Subcutaneous; Motor Neurons; Nerve Regeneration; Peripheral Nervous System Diseases; Peroneal Nerve; Rats; Rats, Sprague-Dawley; Schwann Cells; Tacrolimus; Tibial Nerve; Time Factors

This retrospective study describes the outcome in 53 patients who had immunosuppressive treatment changed from cyclosporine (CSP) to tacrolimus for resistant acute GVHD (n = 23), hemolytic uremic syndrome (HUS) (n = 13) or CSP-associated neurotoxicity (n = 17). Tacrolimus was administered at doses of 0.03 mg/kg/day intravenously or 0.12 mg/kg/day orally in divided doses, as tolerated. Median time of conversion to tacrolimus after transplant was day 47. Nineteen patients had treatment changed to tacrolimus for resistant acute GVHD grades III or IV, with the median day of conversion being day 49 after transplant. Two of 20 evaluable patients had a complete resolution of GVHD after changing treatment to tacrolimus, with 18 showing no improvement. Eleven evaluable patients had therapy changed to tacrolimus for CSP-associated neurotoxicity at a median of 36 days after transplant. Eight patients had resolution of neurotoxicity and three had partial improvement. Eleven evaluable patients had therapy changed to tacrolimus for HUS at a median of 46 days after transplant. One patient had complete resolution of HUS and 10 showed no response. Side-effects related to tacrolimus included renal toxicity (34%), neurotoxicity (15%) and HUS (9%). Nine (17%) patients remain alive, including six patients who had therapy changed to tacrolimus for CSP-associated neurotoxicity. While often successful for dealing with neurotoxicity, only a rare patient improved after therapy was changed from CSP to tacrolimus for HUS or resistant acute GVHD.

Topics: Acute Disease; Adolescent; Adult; Bone Marrow Transplantation; Child; Child, Preschool; Cyclosporine; Drug Resistance; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Peripheral Nervous System Diseases; Retrospective Studies; Tacrolimus; Transplantation, Homologous; Treatment Outcome

The presence of severe and mild neurotoxicity in our pediatric renal transplant recipients treated with tacrolimus was determined by chart review (severe neurotoxicity) and patient survey (mild neurotoxicity). 14 patients were studied (mean age 15 yr, 5 month, +/- 4.4 yr). 1 patient experienced seizures, felt to be related to malignant hypertension. No other episode of severe neurotoxicity was documented. Most patients (12/14) reported at least one mild neurologic symptom, and half stated their symptoms were present at least 'most of the time'. The most frequent complaints were myalgias (7/14, 50%) and tremors (7/14, 50%) followed by fatigue (5/14, 38%). Severe neurotoxicity may be relatively infrequent in pediatric renal transplant patients treated with tacrolimus. Milder neurologic complaints may be commonly seen in this population, but in general are not severe enough to cause discontinuation of tacrolimus.

Topics: Adolescent; Adult; Child; Evaluation Studies as Topic; Eye; Fatigue; Follow-Up Studies; Headache; Humans; Hyperesthesia; Hypertension, Malignant; Immunosuppressive Agents; Kidney Transplantation; Muscle, Skeletal; Pain; Peripheral Nervous System Diseases; Retrospective Studies; Seizures; Sleep Initiation and Maintenance Disorders; Tacrolimus; Tremor

Topics: Demyelinating Diseases; Humans; Liver Diseases; Liver Transplantation; Male; Middle Aged; Peripheral Nervous System Diseases; Tacrolimus

Topics: Adult; Humans; Male; Middle Aged; Peripheral Nervous System Diseases; Tacrolimus