Pharmacokinetic Considerations with the Use of Antiepileptic Drugs in Patients with HIV and Organ Transplants

Purpose of Review

Antiepileptic drugs are frequently administered to patients with HIV infection or in recipients of organ transplants. The potentially serious drug-drug interactions between the “classic” antiepileptic drugs, antiretrovirals, and immunosuppressants have been extensively studied. Evidence-based information on the second and third generation of antiepileptic drugs is almost non-existent. The purpose of this review is to analyze the pharmacokinetic profile of these newer agents to assess their potential for drug interactions with antiretrovirals and immunosuppressants.

Recent Findings

As a group, the newer generations of antiepileptic drugs have shown a more favorable drug interaction potential compared to the “classic” ones. A group of moderate enzyme-inducing drugs includes eslicarbazepine acetate, oxcarbazepine, rufinamide, and topiramate. These drugs are not as potent inducers as the “classic” drugs but may potentially decrease the serum concentrations of some antiretrovirals and immunosuppressants. Antiepileptic drugs with no or minimal enzyme-inducing properties include brivaracetam, gabapentin, lacosamide, lamotrigine, levetiracetam, perampanel, pregabalin, and vigabatrin.

Summary

The newer generations of antiepileptic drugs have expanded the therapeutic options in patients with HIV infection or organ transplants.

     

Fibrate and statine myopathy

Fibrates and statines are useful in preventing arteriosclerosis and thromboembolic events. However, they should be administered with caution.The risk of fibrate/statine myopathy, the most common side effect of fibrate/statine therapy, increases with dosage, combination of a fibrate with a statine,hypothyroidism, renal insufficiency, and intake of cytochrome P450 inhibitors. In case of clinical signs of a fibrate/statine myopathy such as proximal myalgias, stiffness,weakness, and dark urine, appropriate investigations should be initiated. If they establish the diagnosis of fibrate/statine myopathy, lipid lowering drugs should be immediately withdrawn. If rhabdomyolysis is present, prompt and adequate therapy is required.Though muscle abnormalities are rare side effects, fibrate/statine therapy should be regularly monitored with regard to clinical and laboratory alterations.The new "superstatines" rosuvastatine and pitavastatine reduce serum cholesterol more effectively than the established statines, but it is not known if they also have fewer muscular side effects than established statines.     

A clinician's approach to modulate disease activity in MS

All multiple sclerosis (MS) patients should have their treatment profile carefully evaluated as to disease control, optimal therapy, and adverse side effects at every clinical visit, with the goal of safely minimizing disease activity. There is a general consensus among clinicians that therapy should be initiated early in the course of the disease and should be continued indefinitely unless disease activity continues, intolerable side effects develop, patient transitions to a primary progressive course, or more effective and safer drugs become available. Patients for whom treatment is delayed should be seen at least every 6 months, and therapy should be initiated if new disease activity is found. Magnetic resonance imaging is the most practical laboratory test currently available for monitoring ongoing tissue injury and is useful when evaluating the efficacy of a given therapy. Four immunomodulators and 2 immunosuppressants are currently approved for the treatment of relapsing or secondary progressive forms of MS; in addition, various immunosuppressive or immunomodulating drugs have been used off-label, alone or in combination, in clinical practice. Many issues remain to be resolved in attempting to modulate disease activity in MS patients. Consequently, the art of medicine and clinical judgment become important aspects of MS patient care.     

A case of Beh?et's disease associated with myopathy during cyclosporin treatment]

A 46-year-old male was admitted to the Department of Neurology complaining of gait disturbance. He was given a diagnosis of Beh?et's disease and placed on colchicine (0.5-1.0 mg/day) for 7 months without improvement. Subsequently cyclosporin (290 mg/day) was added this regimen. However, 7 months after initiation of combined colchicine/cyclosporin therapy serum creatine kinase (CK) rose to 1,255 U/l. On admission, neurological examination revealed generalized muscle atrophy with predominant proximal muscle weakness and decreased deep tendon reflexes. No myalgia was noted. Laboratory tests demonstrated anemia, liver dysfunction, chronic renal failure and an elevated serum CK level. The plasma cyclosporin concentration was 220 ng/dl, which is within therapeutic limits. Motor unit potentials in electromyography of bilateral quadriceps muscles were generally of short duration and reduced amplitude. A biopsy of quadriceps muscle showed variability in the size of type 2 fibers and scattered small vacuoles. Some of the vacuoles resembled rimmed vacuoles. These vacuoles were stained positively for acid phosphatase. Electronmicroscopy revealed that these vacuoles contained dense bodies, myeloid bodies, and glycogen particles. Collectively suggesting that these structures are autophagic vacuoles. Cyclosporin was reduced to 200 mg/day with unchanged colchicine dose and bromocriptine, which potentiates cyclosporin effects, was started. Gradual recovery from muscle weakness ensued. These findings suggest that cyclosporin contributed to the pathogenesis of this myopathy. On increase in use of cyclosporin, one should consider the possibility of myopathy as one of its side effects especially in combination therapy with myotoxic drugs such as colchicine.     

Enzyme induction with antiepileptic drugs: Cause for concern?

Several commonly prescribed antiepileptic drugs (AEDs)—including phenobarbital, phenytoin, and carbamazepine—stimulate the synthesis of a broad range of monooxygenase and conjugating enzymes. These agents are well known to reduce the duration and action of many lipid‐ and non–lipid‐soluble drugs, including anticoagulants, cytotoxics, analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contraceptives, psychoactive drugs, immunosuppressants, and of course, other AEDs. This process, therefore, may be associated with a number of clinical problems including higher cancer mortality, progressive AIDS, transplant rejection, and unwanted pregnancy. Withdrawal of enzyme‐inducing AEDs will increase the concentration of induced drugs, bringing with it substantial risk of toxicity if doses are not concomitantly reduced. Yet the potential widespread adverse health consequences of these interactions, both with AED initiation and withdrawal, remain largely underappreciated. Furthermore, induction also affects enzymes involved in endogenous metabolic pathways, and can alter bone biochemistry, gonadal steroids, and lipid markers. Therefore, enzyme‐inducing AEDs may contribute to the development of a number of comorbidities, including osteoporosis, sexual dysfunction, and vascular disease. This process continues as long as the patient takes the inducer. Modern AEDs that do not possess this property have similar efficacy for the common epilepsies. Accordingly, perhaps consideration should be given to starting treatment with, or even switching patients to, non–enzyme‐inducing AEDs.     

Treatment of myasthenia gravis with mycophenolate mofetil: a case report

We report a patient with myasthenia gravis (MG) who had marked clinical benefit in response to treatment with mycophenolate mofetil as documented by serial quantitative measures of strength and muscle fatigue. Our patient had experienced either adverse side effects or a suboptimal response to the usual immunosuppressive agents used in MG. Mycophenolate mofetil was used in combination with cyclosporine and prednisone and allowed for significant reductions in dosage of these immunosuppressants. We conclude that mycophenolate mofetil deserves further study as a therapeutic agent in MG. In particular, its role as a steroid-sparing agent and as a drug to be used in combination immunotherapy in more severe or refractory cases of MG should be investigated.     

Statins and the neuromuscular system: a neurologist's perspective

Statins intolerance is mainly due to their side effects on the neuromuscular system (primarily muscle). It has become an important issue because of the major cardiovascular risk reduction of this class of drugs. However, the facts related to these side effects are sometimes under‐recognized or controversial. A literature review of the recent developments in the field is given. The clinical definition of statin myopathy and its presentation are not suitable for the myology field. Management and prevention are not validated. More genetic risk factors need to be established. Neurologists should become more involved in statin intolerance evaluation and management.     

Immunosuppressive / immunomodulating therapies in myasthenia gravis-at present and in the near future

Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission that is primarily caused autoantibodies specific to the neuromuscular junction and is characterized by fatigability and weakness of the striated muscles. Immunosuppression is the mainstay of treatment for MG, and patients with MG are currently treated with immunomodulating or immunosuppressive agents. This review summarizes the current situation and perspective of medical therapy for MG, focusing on mechanisms of action and clinical application of corticosteroids and different classes of immunomodulating or immunosuppressive drugs used for MG. Immunosuppressive treatment is indicated for patients with disabling weakness, not sufficiently managed with cholinesterase inhibitors. Prednisolone (PSL) is used in the great majority of patients. Tacrolimus and cyclosporine are the first-line immunosuppressants, whereas azathioprine is a conventional but less frequently used medication in Japan. The incidence of late- and elderly-onset MG is reported to be increasing. The risk of complications in corticosteroid treatment appears to depend on drug dosage, treatment duration, and patients' characteristics, and the serious side effects should be increased in late- and elderly- onset MG. Although nonspecific, current immunosuppressive treatment is highly effective in most MG patients, the need for prolonged administration and unwanted effects are still relevant limitations to its use.     

Drug-induced myopathies

PURPOSE OF REVIEW: Drug-induced muscle disorders are important causes of morbidity, but the risk-benefit profile of the incriminated drugs must be put into perspective. This review highlights some recent advances on statin-induced and antiretroviral drug-induced myopathies and calls attention to some less familiar myotoxic disorders. RECENT FINDINGS: In statin myopathy, reduction of coenzyme Q has been discussed as a key mechanism. However, data on coenzyme Q concentration and mitochondrial dysfunction in muscle of these patients are not conclusive. The first two controlled trials on coenzyme Q supplementation in statin myopathy have yielded contradictory results and do not support a routine supplementation. In human immunodeficiency virus infection, the advent of highly active antiretroviral therapy has led to a shift from virus-related to drug-induced morbidity. The knowledge of these distinct syndromes allows rational management. In addition, an omnium-gatherum is presented with recent findings on drug-induced dermatomyositis, tendinopathy, rhabdomyolysis, and local myotoxicity. These latter topics are intended to direct attention to less familiar but still clinically relevant myotoxic events. SUMMARY: Statin myotoxicity may be prevented in many cases by anticipation of drug-drug interactions. On the contrary, undue withdrawal of statins owing to minor myalgias should be avoided. A large and appropriately powered trial is required to finally determine whether supplementation of coenzyme Q can mitigate statin myopathy. The identification of individual genetic risk factors for myotoxicity is a key challenge for future pharmacogenomic research.     

A review of the treatment of primary headaches. Part II: Tension-type headache

This paper reviews pharmacological and other approaches currently used to treat tension-type headache (TTH), and examines aspects of the classification and pathogenesis of this common complaint Accurate diagnosis is essential before treatment is prescribed and should involve complete history taking, thorough neurological examination and evaluation of possible associated factors. The most frequently used drugs for the acute treatment of TTH are non-steroidal anti-inflammatory drugs (NSAIDs) of which only some have been shown to be efficacious in placebo-controlled trials. Amitriptyline remains the first choice treatment for prophylaxis. Other antidepressants, muscle relaxants and benzodiazepines may be used, but few have been evaluated adequately in placebo-controlled trials. Biofeedback and relaxation training, demonstrated efficacious by controlled studies, may be used when the aim is to avoid the side effects of pharmacological treatment.     

The DMD gene and therapeutic approaches to restore dystrophin

Duchenne muscular dystrophy (DMD) is a severe X-linked disease characterized by progressive muscle weakness. It is caused by a variety of DMD gene pathogenic variations (large deletions or duplications, and small mutations) which leads to the absence or to a decreased amount of dystrophin protein. The allelic Becker muscular dystrophy is characterized by later onset and milder muscle involvement, and other rarer phenotypes might also be associated, such as dilated cardiomyopathy, cognitive impairment, and other neurological signs. Following the identification of the genetic cause and the disease pathophysiology, innovative personalized therapies emerged. These can be categorized into two main groups: (1) therapies aiming at the restoration of dystrophin at the sarcolemma; (2) therapeutics dealing with secondary consequences of dystrophin deficiency. In this review we provide an overview about DMD genotype-phenotype correlation, and on main approaches to restore dystrophin as stop codon read-through, exon skipping, vector-mediated gene therapy, and genome-editing strategies, some of these are based on approved orphan drugs. Finally, we present the clinical potential of novel strategies combining therapies to correct the genetic defect and other approaches, targeting secondary downstream pathological cascade due to dystrophin deficiency.     

A review of the treatment of primary headaches. Part II: Tension-type headache.

This paper reviews pharmacological and other approaches currently used to treat tension-type headache (TTH), and examines aspects of the classification and pathogenesis of this common complaint. Accurate diagnosis is essential before treatment is prescribed and should involve complete history taking, thorough neurological examination and evaluation of possible associated factors. The most frequently used drugs for the acute treatment of TTH are non-steroidal anti-inflammatory drugs (NSAIDs) of which only some have been shown to be efficacious in placebo-controlled trials. Amitriptyline remains the first choice treatment for prophylaxis. Other antidepressants, muscle relaxants and benzodiazepines may be used, but few have been evaluated adequately in placebo-controlled trials. Biofeedback and relaxation training, demonstrated efficacious by controlled studies, may be used when the aim is to avoid the side effects of pharmacological treatment.     

Increase in muscular pain threshold following low frequency-high intensity peripheral conditioning stimulation in humans

The effects of low frequency-high intensity transcutaneous and intramuscular electrical nerve stimulation (TENS and IENS, respectively) on ipsilateral muscular pain threshold were studied in healthy volunteers. The combined effects of TENS (or IENS) and vibration as well as the effects of TENS applied to contralateral regions were also investigated. Muscular pain threshold was evaluated by the subjects' verbal reports in response to electrical stimulation (wire electrodes) of the vastus medialis muscle and by the appearance of blink response (startle reaction) without habituation. TENS was generally applied to the skin overlying the same muscle, and in some instances to the skin overlying the contralateral vastus medialis or triceps muscle. IENS was performed through the same electrodes used for inducing muscular pain. Vibration was applied to the tendon of ipsilateral quadriceps femoris muscle. TENS consistently induced marked and long-lasting elevations of ipsilateral muscular pain threshold. Comparable results were obtained by IENS. TENS and vibration performed simultaneously induced increases in muscular pain threshold, which were greater than those obtained with each individual conditioning stimulation. TENS proved to be capable of enhancing muscular pain threshold even when applied to contralateral regions; however, these effects were smaller and of shorter duration. The results provide evidence that low frequency-high intensity TENS (or IENS) are effective in raising muscular pain threshold and support the hypothesis that this type of stimulation brings supraspinal control systems into action through the activation of group III afferent fibres.     

New therapies in muscular dystrophies

Muscular dystrophies are a group of hereditary muscle disorders that often result in severe disability. Curative therapy is not yet available for muscular dystrophies (MD). In the near future, it is not expected that gene-replacement therapy will be available. Other strategies to decrease the rate of muscle necrosis and to increase strength in patients are necessary. Therefore the interest in symptomtic drug treatment has recently increased. A few trials have been performed on different types of muscular dystrophies, and some have generated postive results on muscle strength or muscle mass. We review the state of the art in therapy of MD and summarize the drugs that have been used and the evidence and results of such clinical trials.     

Vincristine and bortezomib cause axon outgrowth and behavioral defects in larval zebrafish

Peripheral neuropathy is a common side effect of a number of pharmaceutical compounds, including several chemotherapy drugs. Among these are vincristine sulfate, a mitotic inhibitor used to treat a variety of leukemias, lymphomas, and other cancers, and bortezomib, a 26S proteasome inhibitor used primarily to treat relapsed multiple myeloma and mantle cell lymphoma. To gain insight into the mechanisms by which these compounds act, we tested their effects in zebrafish. Vincristine or bortezomib given during late embryonic development caused significant defects at both behavioral and cellular levels. Intriguingly, the effects of the two drugs appear to be distinct. Vincristine causes uncoordinated swimming behavior, which is coupled with a reduction in the density of sensory innervation and overall size of motor axon arbors. Bortezomib, in contrast, increases the duration and amplitude of muscle contractions associated with escape swimming, which is coupled with a preferential reduction in fine processes and branches of sensory and motor axons. These results demonstrate that zebrafish is a convenient in vivo assay system for screening potential pharmaceutical compounds for neurotoxic side effects, and they provide an important step toward understanding how vincristine and bortezomib cause peripheral neuropathy.     

Botulinum toxin in migraine prophylaxis

Migraine is a chronic headache disorder manifesting in attacks lasting 4-72 hours. Characteristics of headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea, photophobia and phonophobia. The migraine aura is a complex of neurological symptoms, which occurs just before or at the onset of migraine headache. Botulinum toxin A represents a completely new option for patients with chronic pain conditions. Numerous retrospective open-label chart reviews and 4 double-blind, placebo-controlled studies have demonstrated that botulinum toxin type A is significantly effective in migraine prophylaxis and reduces the frequency, severity, and disability associated with migraine headaches. Studies have generally reported a good and consistent efficacy. The differential therapeutic use of botulinum toxin appears to be worth attempting in migraine patients with the following characteristic features: (1) Muscular stress as migraine trigger, e. g., in craniocervical dystonia, pericranial painful muscular trigger points or tender points, oromandibular dysfunction, (2) concurrent chronic tension-type headache with the aggravating factors of muscular stress or oromandibular dysfunction, (3) chronic migraine with frequent migraine attacks on more than 15 days per month for longer than 3 months and if other therapeutic options have been either ineffective or have not been tolerated. The use of the agent does not cause CNS side effects. Migraine patients in particular, often suffer greatly, as a result of the adverse effects of the drugs used, from fatigue, dizziness, reduced concentration, loss of appetite, weight gain, hair loss and changes in libido. These side effects are not known in association with botulinum toxin A. To date, neither organic damage nor allergic complications have been reported. Thus, both the tolerability and the safety of this therapeutic measure are high. The mode of action by which botulinum toxin is effective in migraine prophylaxis is not fully understood and is under investigation. Currently, a number of other randomized, placebo-controlled, clinical trials are being conducted to evaluate the efficacy, optimal dosing, and side-effect profile of botulinum toxin type A in the prophylaxis of migraine and other headache entities.     

Compartmentalized microfluidic culture platform to study mechanism of paclitaxel-induced axonal degeneration

Chemotherapy induced peripheral neuropathy is a common and dose-limiting side effect of anticancer drugs. Studies aimed at understanding the underlying mechanism of neurotoxicity of chemotherapeutic drugs have been hampered by lack of suitable culture systems that can differentiate between neuronal cell body, axon or associated glial cells. Here, we have developed an in vitro compartmentalized microfluidic culture system to examine the site of toxicity of chemotherapeutic drugs. To test the culture platform, we used paclitaxel, a widely used anticancer drug for breast cancer, because it causes sensory polyneuropathy in a large proportion of patients and there is no effective treatment. In previous in vitro studies, paclitaxel induced distal axonal degeneration but it was unclear if this was due to direct toxicity on the axon or a consequence of toxicity on the neuronal cell body. Using microfluidic channels that allow compartmentalized culturing of neurons and axons, we demonstrate that the axons are much more susceptible to toxic effects of paclitaxel. When paclitaxel was applied to the axonal side, there was clear degeneration of axons; but when paclitaxel was applied to the soma side, there was no change in axon length. Furthermore, we show that recombinant human erythropoietin, which had been shown to be neuroprotective against paclitaxel neurotoxicity, provides neuroprotection whether it is applied to the cell body or the axons directly. This observation has implications for development of neuroprotective drugs for chemotherapy induced peripheral neuropathies as dorsal root ganglia do not possess blood-nerve-barrier, eliminating one of the cardinal requirements of drug development for the nervous system. This compartmentalized microfluidic culture system can be used for studies aimed at understanding axon degeneration, neuroprotection and development of the nervous system.     

Neurobiological perspective of spasticity as occurs after a spinal cord injury

In this review we use the term spasticity to mean the generation of abnormal patterns of forces that are generated involuntarily. It is clear that spasticity can have both detrimental and beneficial effects on the neuromuscular system of the affected individuals. Muscle spasticity routinely occurs after a spinal cord injury and other neurological disorders. Although often studied as if there was a single mechanism associated with this phenomenon, it is clear that there are multiple mechanisms having both neural and muscular components, particularly when such terms also are applied to other neuromotor disorders. The aims of this review are to describe the neural and muscular adaptations that are associated with spasticity, highlight the major possible mechanisms producing spasticity, and discuss the role of selected pharmacological interventions in controlling spasticity. Spasticity appears to be related to altered membrane channel and receptor properties that are primarily associated with an increase in the excitability of spinal neurons, resulting in abnormal (in the intensity and combination of muscles activated) contractions that are generated involuntarily. While most of the efforts to understand the etiology of spasticity have focused on motoneurons, it is likely that spinal interneurons play a central role as well as the mechanical properties of muscle fibers and associated connective tissues. A number of pharmacological interventions have been used in attempts to suppress spasticity with varying results, but concomitant with suppressed muscle activation, there can be significant side effects including a reduction in the control of movement.