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Thread: Patients being sought for clinical trial treating weak respiratory muscles after spinal cord injury

  1. #1

    Patients being sought for clinical trial treating weak respiratory muscles after spinal cord injury

    Clinical trial to assess theophylline treatment in patients with weak respiratory muscles after spinal cord injury, at Wayne State University. Involves visit to VA Hospital in Detroit. Trial headed by Harry Goshgarian. For more details, see posting in clinical trial forum.

  2. #2
    I want to point out that there is a very large literature indicating that theophylline treatment will enhance recovery of respiratory function by stimulating plasticity of the phrenic nucleus. Although the effects of theophylline have been most studied in the phrenic nucleus, it is likely that it also has siimilar effects on other neurons in the spinal cord. Harry Goshgaraian at Wayne State has long been the leading scientist in the field of neurorespiratory physiology and plasticity. He has been working with various clinicians around the world, using theophylline to help wean patients off ventilators. Now he has a clinical trial. It requires some travel but it should be of great interest to people who are currently have respiratory difficulties. By the way, the trial will be studying not only ventilator-dependent people but people who have reduced respiratory activity. Wise.

  3. #3
    Acid, I am sorry that I did not have the time to describe the theophylline effects on the respiratory system in greater detail. I had earlier posted a review of the subject Nantwi & Goshgarian (2001). Alkylxanthine-induced recovery of respiratory function following cervical spinal cord injury in adult rats

    More information about the trial can be found on the ican.com site

    Harry Goshgarian's curriculum vitae can be seen at http://www.med.wayne.edu/anatomy/department/goshgar.htm

    I had written the following about the treatment in http://carecure.rutgers.edu/spinewir...erimentRx.html
    Theophylline** Theophylline is an adenosine receptor antagonist. Long used to treat asthma, theophylline has a well known side-effect profile and safety record. Harry Goshgarian at discovered several years ago that theophylline stimulates plasticity of the phrenic nucleus and axonal growth. The phrenic nucleus innervate the diaphragm. Recently, Nantwi & Goshgarian (2001) compared theophylline with other alkyxanthines and showed that those that did not penetrate the blood brain barrier were ineffective and that theophylline was the most potent of the akylxanthines tried. Goshgarian has been working with physicians giving theophylline to ventilator dependent patients to see if they can be weaned. Although there have not been any formal studies of theophylline in spinal cord injury models, much is known about the effects of theophylline on the central nervous system. This is the kind of therapy that probably should go to clinical trial directly. The risks of therapy would be very low.
    Dr. Goshgarian's work has been funded in part by the Kent Waldrep Paralysis Foundation http://www.rehabpub.com/ltrehab/10112000/2.asp and there is an interesting set of side-observations that might be of interest. Several of the patients who were receiving theophylline for weaning off the respirator have reported that they have seen other types of recover.

    Here are some abstracts of papers that he has published on the subject:

    • Basura GJ, Nantwi KD and Goshgarian HG (2002). Theophylline-induced respiratory recovery following cervical spinal cord hemisection is augmented by serotonin 2 receptor stimulation. Brain Res 956:1-13. Summary: Cervical spinal cord hemisection leads to a disruption of bulbospinal innervation of phrenic motoneurons resulting in paralysis of the ipsilateral hemidiaphragm. We have previously demonstrated separate therapeutic roles for theophylline, and more recently serotonin (5-HT) as modulators to phrenic nerve motor recovery; mechanisms that likely occur via adenosine A1 and 5-HT2 receptors, respectively. The present study was designed to specifically determine if concurrent stimulation of 5-HT2 receptors may enhance motor recovery induced by theophylline alone. Adult female rats (250-350 g; n=7 per group) received a left cervical (C2) hemisection that resulted in paralysis of the ipsilateral hemidiaphragm. Twenty-four hours later rats were given systemic theophylline (15 mg/kg, i.v.), resulting in burst recovery in the ipsilateral phrenic nerve. Theophylline-induced recovery was enhanced with the 5-HT2A/2C receptor agonist, (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI; 1.0 mg/kg). DOI-evoked augmentation of theophylline-induced recovery was attenuated following subsequent injection of the 5-HT2 receptor antagonist, ketanserin (2.0 mg/kg). In a separate group, rats were pretreated with ketanserin, which did not prevent subsequent theophylline-induced respiratory recovery. However, pretreatment with ketanserin did prevent DOI-induced augmentation of the theophylline-evoked phrenic nerve burst recovery. Lastly, using immunocytochemistry and in situ hybridization, we showed for the first time a positive co-localization of adenosine A1 receptor mRNA and immunoreactivity with phrenic motoneurons of the cervical ventral horns. Taken together, the results of the present study suggest that theophylline may induce motor recovery likely at adenosine A1 receptors located at the level of the spinal cord, and the concurrent stimulation of converging 5-HT2 receptors may augment the response. Department of Anatomy and Cell Biology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201, USA.
    • Nantwi KD, El-Bohy A and Goshgarian HG (1996). Actions of systemic theophylline on hemidiaphragmatic recovery in rats following cervical spinal cord hemisection. Exp Neurol 140:53-9. Summary: This study assesses the effects of theophylline on enhancing phrenic nerve discharge and functional hemidiaphragmatic recovery after C2 spinal cord hemisection in adult female rats. There were three separate groups of spinal hemisected rats and one nonhemisected group studied. Twenty-four hours following C2 spinal hemisection, ipsilateral phrenic nerve activity was recorded under standardized, normoxic and then hypoxic conditions. After 30 min, theophylline was administered and the recordings were repeated in group 1 animals. In group 2, activity in both phrenic nerves was recorded simultaneously before and after drug administration. In a third group of rats, both ipsilateral phrenic nerve and hemidiaphragmatic activities were monitored before and after the drug. In control nonhemisected animals under standardized recording conditions, the effects of theophylline were quantitatively assessed by determining the mean area under integrated phrenic nerve discharge waveforms before and after drug administration. Generally, theophylline induced biphasic effects; i.e., at a low dose (15 mg/kg) it evoked excitation, while at a high dose (30 mg/kg) depression of respiratory activity predominated. In group 2 animals, respiratory activity was induced in the nerve ipsilateral to the hemisection and enhanced in the contralateral phrenic nerve for up to 3 h after a single standard dose of theophylline (15 mg/kg). Prior to drug administration, there was an absence of respiratory-related activity in both the phrenic nerve and hemidiaphragm ipsilateral to C2 spinal cord hemisection. A standard dose of theophylline, however, induced recovery of activity in both the phrenic nerve and the left hemidiaphragm ipsilateral to the hemisection in group 3 animals. In control (nonhemisected) animals, theophylline enhanced phrenic nerve activity, but decreased the duration of respiratory bursts. These results show for the first time that theophylline can activate latent respiratory motor pathways and thus restore the respiratory drive to phrenic motoneurons lost by spinal cord injury. Respiratory activity is not only reestablished in the phrenic nerve made quiescent by hemisection, but it is also enhanced in the contralateral phrenic nerve. The drug also restores function to the hemidiaphragm paralyzed by the spinal cord hemisection. The findings may have clinical relevance to human cases of cervical spinal cord injury in which respiratory function is compromised. Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA.
    • Nantwi KD and Goshgarian HG (1998). Effects of chronic systemic theophylline injections on recovery of hemidiaphragmatic function after cervical spinal cord injury in adult rats. Brain Res 789:126-9. Summary: Based on a previous demonstration that acutely administered theophylline induces respiratory-related recovery in an animal model of spinal cord injury, the influence of chronically administered theophylline on maintaining recovery was assessed. The absence of respiratory-related activity in the left phrenic nerve and hemidiaphragm of rats subjected to an ipsilateral C2 spinal cord hemisection was confirmed electrophysiologically 24 h after injury. Theophylline was then injected i.p. for 3-30 consecutive days. Recovery of respiratory-related activity was observed in the majority (29 out of 32) of the experimental animals. We conclude that theophylline not only induces, but also maintains recovery for prolonged periods after cervical spinal cord injury. Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI 48201, USA. knantwi@med.wayne.edu
    • Nantwi KD and Goshgarian HG (1998). Theophylline-induced recovery in a hemidiaphragm paralyzed by hemisection in rats: contribution of adenosine receptors. Neuropharmacology 37:113-21. Summary: Previously, we demonstrated that a single intravenous injection of theophylline can induce recovery in a hemidiaphragm paralyzed by cervical (C2) spinal cord hemisection for up to 3 h. The present study contrasts the actions of enprofylline and theophylline on inducing hemidiaphragmatic recovery after cervical spinal cord hemisection. Both drugs are methylxanthines; however, theophylline is an adenosine receptor antagonist while enprofylline is not. To further test the involvement of adenosine receptors, N6 (L-2-phenylisopropyl) adenosine (L-PIA), an analogue of adenosine was used in conjunction with theophylline. Following a left C2 spinal cord hemisection, animals were injected with either enprofylline (2.5-20 mg/kg) or theophylline (15 mg/kg) alone or in combination. Theophylline-injected animals demonstrated robust respiratory-related activity in the previously quiescent left phrenic nerve and hemidiaphragm. No recovery was observed in any of the enprofylline-injected rats. When enprofylline injection was followed later with theophylline, recovery occurred. Prior L-PIA administration blocked theophylline-induced recovery. When given after theophylline, L-PIA attenuated and then blocked the induced activity in both the nerve and hemidiaphragm ipsilateral to spinal cord hemisection. We conclude that adenosine receptor antagonism is implicated in hemidiaphragmatic recovery after hemisection and theophylline may be useful in the treatment of spinal cord injured patients with respiratory deficits. Wayne State University, School of Medicine, Department of Anatomy and Cell Biology, Detroit, MI 48201, USA.
    • Nantwi KD and Goshgarian HG (2001). Alkylxanthine-induced recovery of respiratory function following cervical spinal cord injury in adult rats. Exp Neurol 168:123-34. Summary: Previous investigations from our laboratory have demonstrated qualitatively that a latent respiratory pathway can be activated by systemic theophylline administration to restore function to a hemidiaphragm paralyzed by an upper (C2) cervical spinal cord hemisection in adult rats. The present study seeks to extend the previous investigations by contrasting and quantitating the actions of theophylline, 8-phenyltheophylline, enprofylline, and 8(p-Sulfophenyl)theophylline in restoring function 24 h after hemidiaphragm paralysis. The alkylxanthines were selected based on their diverse pharmacologic profiles to elucidate the mechanisms that underlie functional recovery after spinal cord injury. To quantitatively assess the magnitude of recovery, electrophysiological experiments were conducted on pancuronium-paralyzed, hemisected animals under standardized recording conditions. The total absence of respiratory-related activity in the phrenic nerve ipsilateral to the hemisection and paralyzed hemidiaphragm was used as the index of a functionally complete hemisection. Thereafter, drug-induced recovered activity in the phrenic nerve ipsilateral to hemisection was quantified and expressed either as a percentage of contralateral phrenic nerve activity in the same animal prior to drug administration or as a percentage of predrug activity in the homolateral nerve in noninjured animals. With either approach, theophylline (5-15 mg/kg) and 8-phenyltheophylline (5-10 mg/kg) dose-dependently induced respiratory-related recovered activity. Enprofylline, a potent bronchodilator, and 8(p-Sulfophenyl)theophylline, an adenosine receptor antagonist with limited access to the central nervous system, were ineffective. Maximal recovery was attained with theophylline (15 mg/kg) and 8-phenyltheophylline (10 mg/kg). At these doses, theophylline and 8-phenyltheophylline induced recovery that was 70.0 +/- 2.5 and 69.3 +/- 4.1% of predrug contralateral nerve activity respectively. When expressed as a percentage of activity in the homolateral nerve in noninjured animals, the magnitude changed to 32.9 +/- 4.9 and 35.7 +/- 6.9%, respectively. Involvement of adenosine receptors in the alkylxanthine-induced actions was confirmed in experiments with the adenosine analog, N6 (l-2-phenylisopropyl) adenosine (L-PIA). It is concluded that central adenosine receptor-mediated mechanisms are implicated in the recovery of respiratory-related activity after spinal cord injury. Furthermore, our results suggest a potential for a new therapeutic approach in the rehabilitation of spinal cord patients with respiratory deficits. Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, 540 East Canfield Avenue, Detroit, Michigan 48201, USA.
    • Nantwi KD and Goshgarian HG (2002). Actions of specific adenosine receptor A1 and A2 agonists and antagonists in recovery of phrenic motor output following upper cervical spinal cord injury in adult rats. Clin Exp Pharmacol Physiol 29:915-23. Summary: 1. Previous studies from our laboratory have established that a latent respiratory motor pathway can be activated to restore function to a hemidiaphragm paralysed by upper cervical (C2) spinal cord hemisection during a reflex known as the 'crossed phrenic phenomenon'. In addition, theophylline, a general adenosine A1 and A2 receptor antagonist, can activate the latent pathway by acting centrally through antagonism at adenosine receptors. 2. The present study was designed to assess the relative contributions of adenosine A1 and A2 receptors in inducing functional recovery in our model of spinal cord injury. Specific adenosine A1 and A2 agonists and antagonists were used in an electrophysiological study. 3. Our results demonstrate that, in hemisected rats, systemic administration of the adenosine A1 receptor-specific antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) restores, in a dose-dependent manner, phrenic nerve respiratory related output that is lost following hemisection. Furthermore, DPCPX augments respiratory activity in non-injured animals. The A2 receptor agonist CGS-21680 mediates its effects by predominantly acting on peripheral rather than central nervous system (CNS) receptors. CGS-21680 modulates respiratory related phrenic nerve activity in non-injured animals by enhancing tonic activity, but does not induce recovery of phrenic nerve activity in hemisected animals in the majority of cases. When CGS-21680 was administered prior to DPCPX in hemisected rats, the magnitude of recovery of respiratory function was significantly greater than that elicited by DPCPX alone. However, when the A2 receptor agonist was administered after DPCPX, the magnitude of recovery was virtually unchanged, whereas activity in the right phrenic nerve was significantly enhanced. The A1 receptor agonist N6-cyclohexyladenosine depressed respiratory activity in non-injured, as well as hemisected, rats. The A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine did not affect respiratory activity. 4. We conclude that while antagonism at central adenosine A1 receptors mediates functional restitution in hemisected animals, activation of A2 receptors located outside of the CNS subserves the A1 receptor-mediated respiratory recovery. Wayne State University, School of Medicine, Department of Anatomy and Cell Biology, Detroit, Michigan 48201, USA. knantwi@med.wayne.edu
    • Phillis JW and Goshgarian HG (2001). Adenosine and neurotrauma: therapeutic perspectives. Neurol Res 23:183-9. Summary: Cerebral ischemia studies demonstrating that stimulation of adenosine A1 receptors by either endogenously released adenosine or the administration of selective receptor agonists causes significant reductions in the morbidity and mortality associated with focal or global brain ischemias have triggered interest in the potential of purinergic therapies for the treatment of traumatic injuries to the brain and spinal cord. Preliminary findings indicate that activation of A1 adenosine receptors can ameliorate trauma-induced death of central neurons. Other avenues of approach include the administration of agents which elevate local concentrations of adenosine at injury sites by inhibiting its metabolism to inosine by adenosine deaminase, rephosphorylation to adenosine triphosphate by adenosine kinase; or re-uptake into adjacent cells. Amplification of the levels of endogenously released adenosine in such a 'site and event specific' fashion has the advantage of largely restricting the effect of such inhibitors to areas of injury-induced adenosine release. Another approach involving purinergic therapy has been applied to the problem of respiratory paralysis following high spinal cord injuries. In this instance, the adenosine antagonist theophylline has been used to enhance residual synaptic drive to spinal respiratory neurons by blocking adenosine A1 receptors. Theophylline induced, and maintained, hemidiaphragmatic recovery for prolonged periods after C2 spinal cord hemisection in rats and may prove to be beneficial in assisting respiration in spinal cord injury patients. Department of Physiology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201-1928, USA. jphillis@med.wayne.edu

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    I just posted a literature summary concerning theophylline therapy of spinal cord injury http://carecure.rutgers.edu/spinewir...ne_Phrenic.htm

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    Dr. Young,

    When setting up a clinical trial do you have forms you use for disclosure to patients, screening requirements, recruitment materials, etc.? If not, could you point me in the direction of someone who might?

    Thanks

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    Here is a checklist for consent forms that is sometimes used as a guideline. Wise.

    http://ohrp.osophs.dhhs.gov/humansub...onsentckls.htm

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    Sorry, I don't know why the server is no longer delivering the article. I will try to fix the link. Wise.

  8. #8
    Acid, good questions. The standard model to assess the plasticity of the phrenic system is a hemisection at C2. This denervates the phrenic nucleus on one side. The diaphragm on the cut side stops working but recovers remarkably rapidly when theophylline is given. But, the recovery is sustained after the theophylline is stopped, suggesting that it is doing something to cause permanent restructuring of the connection to the denervated phrenic nucleus at C3.

    The current theory is that theophylline increases excitability of "latent" (i.e. present but inactive) connections to the denervated phrenic nucleus on one side and at the same time also promotes growth of axons to reconnect to that phrenic nucleus. The former is believed to be a result of theophylline blockade of a1 adenosine receptors on presynaptic terminals. The latter may be due to theophylline's blockade of phospodiesterase which breaks down cAMP. So, theophylline increases cAMP levels in axons and several groups have reported that axons with elevated cAMP levels will ignore Nogo and other axon growth inhibitors in the spinal cord.

    Since theophylline is being used in millions of people to treat asthma, has a good safety record, and appears to increase respiratory drive and plasticity, it would be a great drug to test in clinical trials for people with spinal cord injury. A few people who have received theophylline have anecdotally reported improved function in the arms, as well as improved respiration. This needs to be tested and confirmed in a well-run clinical trial.

    That is why I think that this is a good idea and will be following the results of this trial closely.

    Wise.

  9. #9
    I have been taking theophylin for over one year now. I am not part of any formal study, but I persuaded my doctor to prescribe off label using Dr Goshogarians papers as the basis. My vital capacity has increased from an average 1600- 1800, to around 2400-2600(high of 3300) at present. My secretions are much easier to remove now, but I still have a trach and we use assisted cough to remove secretions.

    I also believe that Theophylin has increased my sensation in different places. I still cannot feel anything as far as touch, but I do have the ability to sense pain and feel more pain. My theory so far is that I have had the pain all along, but because the drug heightens the sensitivity, it unmasks the pain. And for whatever reason, I am much more sensitive in my abdomen and lower back. The sensations seem very deep even in my legs and feet. I have also gained some limited control over my rectal muscles and can push during bowel programs with some success which I also believe is a result of the drug.

  10. #10
    Originally posted by Wise Young:

    Here is a checklist for consent forms that is sometimes used as a guideline. Wise.

    http://ohrp.osophs.dhhs.gov/humansubjects/assurance/consentckls.htm


    Great stuff. Thanks doc.

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