Positive neuropathic sensory symptoms as endpoints in diabetic neuropathy trials.
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Clinical Trials as Topic↗
Biomedical subjects
S C Apfel
Publications and source records attributed to S C Apfel.
Neurotrophic factor therapy--prospects and problems.
Over the past 15 years neurotrophic factors have generated considerable excitement for their potential as therapy for a wide variety of degenerative neurological disorders, for which there is currently no treatment. The first part of this period was marked by the discovery, characterization, and cloning of many new growth factors, and by successful testing of these factors in animal models of neurological disease. In recent years the biotechnology industry and pharmaceutical industry have attempted to replicate the success of the animal studies in clinical trials. Although some studies have demonstrated moderate efficacy, for the most part the clinical trials have been less successful at demonstrating the therapeutic efficacy of this new class of drugs. For example, nerve growth factor appeared to be efficacious in two phase II clinical trials for peripheral neuropathy, but failed in a large scale phase III trial. Ciliary neurotrophic factor, brain derived neurotrophic factor and insulin like growth factor-1 have all been tested in clinical trials for the treatment of amyotrophic lateral sclerosis, with at best, variable indications of efficacy. Nevertheless, there are still many reasons to be optimistic that some of these agents may be useful clinically. Many technical and pharmacological issues remain to be adequately addressed, before neurotrophic factors can live up to their potential. Our collective experience with them has re-adjusted previously wild expectations, so that they are now much more realistic. This is necessary and beneficial for the maturation of this field of study.
Alzheimer Disease↗
Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group.
CONTEXT: Nerve growth factor is a neurotrophic factor that promotes the survival of small fiber sensory neurons and sympathetic neurons in the peripheral nervous system. Recombinant human nerve growth factor (rhNGF) has demonstrated efficacy as treatment for peripheral neuropathy in experimental models and phase 2 clinical trials. OBJECTIVE: To evaluate the efficacy and safety of a 12-month regimen of rhNGF in patients with diabetic polyneuropathy. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial conducted from July 1997 through May 1999. SETTING: Eighty-four outpatient centers throughout the United States. PATIENTS: A total of 1019 men and women aged 18 to 74 years with either type 1 or type 2 diabetes and a sensory polyneuropathy attributable to diabetes. INTERVENTIONS: Patients were randomly assigned to receive either rhNGF, 0.1 microg/kg (n = 504), or placebo (n = 515) by subcutaneous injection 3 times per week for 48 weeks. Patients were assessed at baseline, 12 weeks, 24 weeks, and 48 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was a change in neuropathy between baseline and week 48, demonstrated by the Neuropathy Impairment Score for the Lower Limbs, compared between the 2 groups. Secondary outcome measures included quantitative sensory tests using the CASE IV System, the Neuropathy Symptom and Change questionnaire, the Patient Benefit Questionnaire (PBQ), and a global symptom assessment, as well as nerve conduction studies and occurrence of new plantar foot ulcers. Patients also were evaluated for presence of adverse events. RESULTS: Among patients who received rhNGF, 418 (83%) completed the regimen compared with 461 (90%) who received placebo. Administration of rhNGF was safe, with few adverse events attributed to treatment apart from injection site pain/hyperalgesia and other pain syndromes. However, neither the primary end point (P =.25) nor most of the secondary end points demonstrated a significant benefit of rhNGF. Exceptions were the global symptom assessment (P =.03) and 2 of 32 comparisons within the PBQ, which showed a modest but significant benefit of rhNGF (P =.05 for severity of pain in the legs and P =.003 for 6-month symptoms in the feet and legs). CONCLUSION: Unlike previous phase 2 trials, this phase 3 clinical trial failed to demonstrate a significant beneficial effect of rhNGF on diabetic polyneuropathy. JAMA. 2000;284:2215-2221.
Activities of Daily Living↗
Neurotrophic factors and pain.
Neurotrophic factors have been shown to play significant roles in the transmission of physiologic and pathologic pain. Nerve growth factor appears to be particularly important. It is crucial for the development of sympathetic and small fiber sensory neurons that serve as nociceptors. It stimulates the expression and release of neuropeptides involved in pain transmission, and interacts with cellular and molecular mediators of inflammation. Blockade with nerve growth factor antiserum demonstrates the critical role of the growth factor in mediating inflammatory hyperalgesia. Administration of nerve growth factor to rodents results in the rapid onset of hyperalgesia. Although the exact mechanism is unknown, several possibilities have been proposed. In clinical trials for the treatment of Alzheimer disease and peripheral neuropathy, induction of pain has been the major adverse event. When administered intracebrebroventricularly, a dull constant back pain resulted. Subcutaneous injection of nerve growth factor induces injection site hyperalgesia, as well as generalized myalgias and arthralgias. Whether the mechanisms underlying these adverse events are identical to those associated with the hyperalgesia in rodents is unknown. In addition to nerve growth factor, other growth factors, such as brain-derived neurotrophic factor and glial cell-derived neurotrophic factor, may be involved in pain pathways. Their precise roles are still being defined, but evidence suggests that they may have particular relevance to neuropathic pain. Understanding the role all these factors play may change the way we approach the treatment of pain in general, and neuropathic pain in particular.
Animals↗
Managing the neurotoxicity of paclitaxel (Taxol) and docetaxel (Taxotere) with neurotrophic factors.
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Animals↗
Introduction to diabetic neuropathy.
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Diabetic Neuropathies↗
Neurotrophic factors in the therapy of diabetic neuropathy.
A large number of neurotrophic factors that exert effects on specific neuronal populations in the peripheral nervous system have been discovered. Some of these factors may prove useful for the treatment of diabetic peripheral neuropathy. Among the most promising are members of the neurotrophin gene family (nerve growth factor [NGF], brain-derived neurotrophic factor, neurotrophin [NT]-3, and NT-4/5), insulin-like growth factor (IGF)-I and IGF-II, and glial cell-derived neurotrophic factor. Of these, NGF and the IGFs have been tested most extensively in animal models of diabetic neuropathy, with encouraging results. Recombinant human nerve growth factor (rhNGF) has been tested in phase II clinical trials for treatment of patients with diabetes, and the results have been encouraging. Phase III trials of rhNGF have been completed, and clinical trials of other neurotrophic factors are likely to be conducted in the next few years.
Brain-Derived Neurotrophic Factor↗
Nerve regeneration in diabetic neuropathy.
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Animals↗
Neurotrophic factors in peripheral neuropathies: therapeutic implications.
Neurotrophic factors are proteins which promote the survival of specific neuronal populations. Many have other physiological effects on neurons such as inducing morphological differentiation, enhancing nerve regeneration, stimulating neurotransmitter expression, and otherwise altering the physiological characteristics of neurons. These properties suggest that neurotrophic factors are highly promising as potential therapeutic agents for neurological disease. Neurotrophic factors will most likely be applied to the peripheral nervous system initially, since there are fewer problems for large proteins to gain access to peripheral neurons. Many of the most intensively studied factors are active in the peripheral nervous system. These include the neurotrophins (nerve growth factor, brain derived neurotrophic factor, neurotrophin-3, neurotrophin-4/5), the insulin like growth factors, ciliary neurotrophic factor, and glial cell derived neurotrophic factor and its related proteins. The biology of these factors and their receptors in the peripheral nervous system is reviewed here. We also review data suggesting that abnormal availability of some factors may contribute towards the pathogenesis of certain types of peripheral neuropathy. Finally, the pre-clinical data suggesting that individual factors might be effective in treating neuropathy is reviewed, along with data relating to possible side effects of neurotrophic factor therapy. Several factors have already entered clinical trials with variable success. The data from these trials is reviewed as well.
Animals↗
Neurotrophic factors and diabetic peripheral neuropathy.
Recent evidence from animal models of diabetes and human diabetic subjects suggests that the reduced availability of neurotrophic factors may contribute to the pathogenesis of diabetic peripheral neuropathy (DPN). Of these proteins, nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin (NT-3) and NT-4/5 appear to be important for the development and maintenance of peripheral neurons, but others, including insulin-like growth factors (IGFs), may also be involved. Studies with NGF, NT-3, IGF-I and IGF-II both in vitro and in animal models of neuropathies (including DPN) suggest that these factors ameliorate nerve degeneration. Recombinant human NGF is the first neurotrophic factor to enter clinical trials for DPN and is currently being tested in two phase III studies.
Animals↗
Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group.
BACKGROUND: Preclinical studies have demonstrated that nerve growth factor may prevent or reverse peripheral neuropathy. We have therefore tested the effects of recombinant human nerve growth factor in patients with diabetic polyneuropathy. METHODS: A total of 250 patients with symptomatic diabetic polyneuropathy randomly received either placebo or one of two doses of recombinant human nerve growth factor for 6 months. Patients were assessed for symptoms and signs of polyneuropathy before and after treatment. RESULTS: Compared with placebo, recombinant human nerve growth factor led to significant improvement after 6 months of treatment, as measured by the sensory component of the neurologic examination, two quantitative sensory tests, and the impression of most subjects that their neuropathy had improved. Three prospectively identified multiple endpoint analyses indicated improvements in the nerve growth factor treatment groups over the placebo group in all three analyses (p = 0.032; p = 0.008; p = 0.005). Recombinant human nerve growth factor was well tolerated, with injection site discomfort reported as the most frequent adverse event. CONCLUSIONS: Recombinant human nerve growth factor appears to be safe and shows preliminary evidence of efficacy in patients with symptomatic diabetic polyneuropathy.
Adolescent↗
Insulin-like growth factor-I prevents development of a vincristine neuropathy in mice.
Vincristine is a commonly used antitumor agent whose major dose-limiting side-effect is a mixed sensorimotor neuropathy. To assess whether insulin-like growth factor-I (IGF-I), a neurotrophic agent that supports the survival of motoneurons and enhances regeneration of motor and sensory neurons, could prevent the peripheral neuropathy produced by vincristine, mice were treated with both vincristine (1.7 mg/kg, i.p., 2 x /week) and/or IGF-I (0.3 or 1 mg/kg, s.c. daily) for 10 weeks. In mice treated with vincristine alone, there was evidence of a mixed sensorimotor neuropathy as indicated by changes in behavior, nerve conduction and histology. Caudal nerve conduction velocity was significantly slower in mice treated with vincristine alone as compared with vehicle-treated mice. Vincristine treatment alone also significantly increased hot-plate latencies and reduced gait support and stride length, but not toe spread distances. The effects of vincristine were accompanied by degeneration of sciatic nerve fibers and demyelination, indicating a peripheral neuropathy. IGF-I (1 mg/kg, s.c.) administered to vincristine-treated mice prevented the neurotoxic effects of vincristine as measured by nerve conduction, gait, response to noxious stimuli and nerve histology. At a lower dose of 0.3 mg/kg administered s.c., IGF-I partially ameliorated the neuropathy induced by vincristine as this dose only prevented the change in nerve conduction and hot-plate latencies. IGF-I administered alone had no effect on any of these parameters. These results suggest that IGF-I prevents both motor and sensory components of vincristine neuropathy and may be useful clinically in preventing the neuropathy induced by vincristine treatment.
Animals↗
Neurotrophic factors in the treatment of peripheral neuropathy.
Peripheral neuropathies are common and frequently debilitating disorders which may include various subpopulations of motor, sensory or autonomic neurons depending on the underlying aetiology. They are likely to be the first group of neurological disorders to be successfully treated with growth factors since peripheral nerves are accessible to proteins given systemically. Preclinical and ongoing clinical trials of nerve growth factor (NGF) suggest that it will be useful for the treatment of diabetic, toxic and compressive sensory neuropathies. At appropriate doses NGF has no significant side effects in humans. Since NGF administration to mature animals stimulates synthesis of brain-derived neurotrophic factor and perhaps other neurotrophins in peripheral nerves, the spectrum of neuropathies treatable with NGF is wider than might be predicted. Preclinical studies suggest that insulin-like growth factor 1 (IGF-1) will be useful for the treatment of mixed motor and sensory neuropathies. For example, IGF-1 treatment can prevent the experimental motor and sensory neuropathies caused by the antitumour drugs, vincristine and cisplatin. Other neurotrophic factors have also shown promise in preclinical trials. The successful use of growth factors in the treatment of peripheral neuropathies may provide the first true therapy for this previously untreatable and devastating group of neurological disorders.
Animals↗
Nerve growth factor regulates the expression of brain-derived neurotrophic factor mRNA in the peripheral nervous system.
Neurotrophins are profound regulators of neuronal survival in the developing peripheral nervous system and are synthesized by peripheral neurons themselves both during development and in maturity. Neuronal neurotrophin expression may be importantly related to survival of mature neurons, both in normal and pathological states. We show here that brain-derived neurotrophic factor (BDNF) gene expression in dorsal root ganglia is strongly stimulated in vivo by another neurotrophin, nerve growth factor (NGF). Furthermore, colocalization studies show that many BDNF-expressing sensory neurons also express trk A, the high-affinity NGF receptor. These results demonstrate a novel regulatory mechanism for neurotrophin gene expression and suggest a paracrine function for neurotrophins in mature animals.
Animals↗
Docetaxel neuropathy.
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Antineoplastic Agents, Phytogenic↗
Kappa opioid receptors participate in nerve growth factor-induced hyperalgesia.
It has recently been observed that nerve growth factors induces the rapid onset of thermal hyperalgesia, and the more delayed onset of mechanical hyperalgesia when administered to mature rats. Though several mechanisms have been proposed to explain this phenomenon, it is still not well understood. Previous studies have shown that nerve growth factor can directly excite nociceptive sensory ganglion neurons in culture via activation of kappa excitatory opioid receptors. The possible involvement of these excitatory opioid receptors in mediating the hyperalgesia was investigated. Nerve growth factor-induced thermal hyperalgesia in rodents was prevented by co-administration of the non-selective opiate antagonist naloxone, as well as by the kappa-selective antagonist nor-binaltorphimine. Addition of the long-acting opioid antagonist, naltrexone, partially prevented mechanical hyperalgesia. Administration of low dose dynorphin to mice (a selective kappa-receptor agonist) mimicked the hyperalgesia effects of nerve growth factor. Opiate antagonists and anti-nerve growth factor antibody both interfered with Freund's adjuvant-induced inflammatory hyperalgesia. Altogether, these observations suggest that activation of excitatory opioid receptors plays a role in mediating nerve growth factor-induced hyperalgesia and that, in turn, nerve growth factor contributes to the hyperalgesia associated with inflammatory states. Since opioid receptor antagonists are well tolerated clinically, they may be useful for patients receiving nerve growth factor as part of ongoing trials of the factor in peripheral neuropathy.
Animals↗
Neurotrophic factors in the therapy of peripheral neuropathy.
Neurotrophic factors are proteins that promote the survival and differentiation of specific populations of neurones. With the successful cloning and large-scale production of many different neurotrophic factors, it has become practical to consider their application in the treatment of neurological disease. Several groups of neurotrophic factors hold particular promise for the therapy of peripheral nervous system disease in the near future. These include the neurotrophin gene family, cytokines such as CNTF and the IGF family. Evidence is accumulating that an abnormal availability of some of these factors may contribute towards the pathophysiology of some types of neuropathy, most notably diabetic neuropathy. Pre-clinical studies in animal models have demonstrated the likely efficacy of factors such as NGF for small-fibre sensory neuropathy, BDNF, CNTF and IGF-I for motor neurone disease, and NT-3 for large-fibre neuropathy. Clinical trials of several growth factors are currently underway for the treatment of peripheral nerve disease, and other clinical trials are currently being planned.
Diabetic Neuropathies↗
Nerve growth factor administration protects against experimental diabetic sensory neuropathy.
Small fiber sensory neuropathy is one of the most common complications of diabetes mellitus. Currently there is no adequate therapy to prevent this often debilitating problem. Nerve growth factor (NGF) is a protein that promotes the survival and integrity of a large percentage of sensory neurons including the small fiber pain transmitting neurons which are often prominently affected in diabetic neuropathy. We report here that exogenously administered NGF is capable of preventing the behavioral and biochemical manifestations of diabetic sensory neuropathy in a streptozocin induced rat model. NGF administration prevented the elevation of tailflick threshold (a measure of the rat's response to a thermal noxious stimulus) which occurred in streptozocin-induced diabetic rats. Further, it prevented the induced reduction in levels of the neuropeptides substance P and calcitonin gene related peptide measured from cervical dorsal root ganglia. Finally, NGF did not ameliorate the prolonged latency of the compound action potentials measured from the caudal nerve of the tail. In view of these results, a clinical trial of NGF in diabetic neuropathy has now commenced.
Action Potentials↗