Friday, January 07, 2005

Attenace: Upcoming Treatment Option For ADHD

For decades, the options for pharmacological treatment of ADHD have been limited to methylphenidate (Ritalin), various forms of amphetamine, atomoxetine (Strattera), and pemoline (Cylert).  Methylphenidate and amphetamine are Schedule-II drugs, meaning that they are designated as having a high potential for abuse.  Pemoline has been associated with liver damage, so it is not a first-line option.  There have been recent reports of liver damage with Strattera as well.  Although it remains to be seen how widespread the atomoxetine problem is, it is difficult to be enthusiastic about atomoxetine until that question is resolved.  Other options, such as bupropion and tricyclic antidepressants, have limited efficacy.  Therefore, there is a need for a better option.  See CNS Spectrums Apr 2003, 8(4) p253-8 for a review of nonstimulant treatment options for ADHD. 

Recently, there has been some interest in using modafinil to treat ADHD.  Modafinil (Provigil) is a wakefulness-promoting agent that is used for treatment of narcolepsy, sleepiness associated with sleep apnea, and fatigue associated with multiple sclerosis.  It is a controlled substance, but is classified as Schedule-IV.  This means that the FDA thinks it has a low potential for abuse.   Years of experience with modafinil have led to no particular safety concerns.

These factors indicate that there is a need for another option, and that modafinil might be a good one.  Now we see a report that this may come to pass:
Cephalon (CEPH) Files Application For Marketing Approval Of New Modafinil Formulation For The Treatment Of Children And Adolescents With Attention-Deficit/Hyperactivity Disorder

WEST CHESTER, Pa., Dec. 21  /PRNewswire-FirstCall/ -- Cephalon, Inc.  today announced that it has filed a supplemental new drug application (sNDA) with the U.S. Food and Drug Administration (FDA) requesting marketing approval of ATTENACE(TM) (modafinil) Tablets [C-IV], a new proprietary dosage form of modafinil for the treatment of attention- deficit/hyperactivity disorder (ADHD) in children and adolescents between the ages of six and 17.

In August 2004, Cephalon announced results from three multi-center clinical trials that showed that ATTENACE 340 mg and 425 mg tablets significantly improve symptoms of ADHD in children and adolescents. Based upon the strength of the study results, the company accelerated the filing of its application with the FDA from the first quarter of 2005 to the fourth quarter of 2004. The company is targeting a launch of ATTENACE by early 2006.

"Physicians and parents continue to seek treatment for children and adolescents with ADHD that provides a balanced efficacy and tolerability profile. In our phase 3 trials, we were encouraged that ATTENACE improved the symptoms of many children and adolescents with ADHD to levels within the range considered normal for those without ADHD, as measured by the ADHD rating scales used in our studies. There was a low discontinuation rate due to adverse events in these studies as well," said Paul Blake, MB, FRCP, Senior Vice President of Clinical Research and Regulatory Affairs. [...]
It is not clear why Cephalon is marketing modafinil with a different name  Modafinil currently is sold in 100mg and 200mg strengths as Provigil.  It makes sense to make a larger tablets, if those are the doses required to see sufficient effect, but why the different name?.  I suspect the FDA required them to use a name other than Provigil, for reasons that make sense to bureaucrats and nobody else.

I can't comment much on the effectiveness of modafinil for treatment of ADHD.  A cursory Medline (Medscape Medline, free registration required) search turned up a  few reports, but there were small studies.  All I can really say is that the pilot studies look encouraging. 

What about the down side?  The main concerns are the abuse potential, and the risk of adverse effects.  The FDA has indicated that modafinil has a low abuse potential.  As I've mentioned before, here at Corpus Callosum, abuse potential is difficult to assess a priori.  Still, as far as I know, there is no particular black market for the product, despite a fair amount of publicity.  This could change when it is marketed for use in children.  Personally, I think people will try to abuse it, but most serious drug abusers are not going to be impressed.  It does not cause euphoria, and dose escalation does not lead to a proportional increase in effect, beyond a certain point.  That is, there is a limit to what the drug can do for a person; increasing the dose beyond that is pointless.  On the other hand, there are people out there who will abuse anything.  Some people abuse Haldol, for example.  Cripes, some people abuse organic solvents.

Are there dangerous adverse effects?  So far, none is apparent.  The usual cautions apply to this;  it should not be used casually.  In fact, sleep disorders carry a definite risk to health, so even a moderate risk with the drug could be acceptable.  ADHD, on the other hand, is not directly hazardous to health.  Therefore, a higher standard should be set for the safety of modafinil when used for this new indication.

I am not prepared to recommend that modafinil be used for ADHD, because I have not seen the larger studies that the FDA requires for approval for a new indication.  Once they get the approval (and they almost certainly will), I'm sure I'll see the studies, and comment further. 

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Monday, January 03, 2005

Another Update on Cloning

The latest issue of the New England Journal of Medicine has an article that clarifies some of the science, as well as the ethical issues, regarding human cloning. 
Human Cloning — The Science and Ethics of Nuclear Transplantation
Rudolf Jaenisch, M.D.
Volume 351:2787-2791         December 30, 2004         Number 27

In addition to the moral argument against the use of somatic-cell nuclear transfer for the creation of a child ("reproductive cloning"), there are overwhelming scientific reasons to oppose this practice. In contrast, many believe that the practice of somatic-cell nuclear transfer with the goal of generating an embryonic stem-cell line (sometimes referred to as "therapeutic cloning") is justified, because it holds the promise of yielding new ways of studying and treating a number of diseases. Once isolated from a patient, an embryonic stem cell thus derived would be "customized" to the needs of the patient who had served as the nuclear donor and thus would obviate the need for immunosuppressive treatment as part of a therapeutic application. In addition, because embryonic stem cells can generate most, if not all, types of cells in vitro, a stem cell isolated from a patient with a complex genetic disease could be used to study the pathogenesis of the disease in culture. [...]
Unfortunately, this article was not published on an open-access basis.  I'm not sure why not; often, they provide open access to editorials of public interest.  On the other hand, it is such a technical article, that it might not be very informative to nonscientists.

Dr. Jaenisch discusses, in detail, the reasons that reproductive cloning is not feasible for the reproduction of humans.  He then discussed the distinction between reproductive cloning and therapeutic cloning.  The latter technique, therapeutic cloning, is more accurately called somatic-cell nuclear transfer (SCNT). 

Figure 1. Comparison of Normal Development with "Reproductive Cloning" and the Derivation of Embryonic Stem Cells through Nuclear Transfer ("Therapeutic Cloning").

During normal development (left), a haploid (1n) sperm cell fertilizes a haploid oocyte to form a diploid (2n) zygote that undergoes cleavage to become a blastocyst embryo. The blastocyst is implanted in the uterus and ultimately develops into a newborn animal. During "reproductive cloning" (center), the diploid nucleus of an adult donor cell is introduced into an enucleated oocyte recipient, which, after artificial activation, divides into a cloned (nuclear-transfer) blastocyst. On transfer into surrogate mothers, a few of these blastocysts will develop into newborn clones, and most will be abnormal. In contrast, the derivation of embryonic stem cells through nuclear transfer (right) requires the explantation of cloned blastocysts in culture in order to derive an embryonic stem-cell line that can be differentiated in vitro, potentially into any type of cell that occurs in the body, to be used in research or for therapeutic purposes.

Without going into too much detail, I'll outline the most important point of the article.  SCNT results in a "cell mass" that does not have the potential to develop into a viable organism.  Cells are removed from this mass to generate the embryonic stem cell lines.

If one accepts that the "cell mass" is not an embryo, then it follows that it is possible to generate embryonic stem cells without destroying an embryo. 

I know, the semantics get kind of confusing.  If there is no embryo, how can the cells be called "embryonic" cells?  The point, though, is that the "cell mass" produced by SCNT at no point has the potential to go on to develop into a viable organism.  Dr. McHugh (link), of the President's Council on Bioethics (PCBE), proposed calling the cell mass a "clonote."  I suppose that would make the resulting stem cells "clonic stem cells" instead of embryonic stem cells.  But for scientific purposes, they would be just as good as embryonic stem cells. 

Since most, if not all, of the objections to the use of embryonic stem cells come from the destruction of an embryo, the use of SCNT would eliminate those objections.

However, one must accept that the "cell mass," or clonote, really is different than an embryo, in some ethically meaningful way.  Dr. Jaenisch explains:
[...] after nuclear transfer, the epigenetic differences established during gametogenesis are subject to erasure, because both parental genomes of the somatic donor cell — not just the sperm genome, as in fertilization — are introduced into the oocyte from the outside and are thus equally exposed to the reprogramming activity of the oocyte cytoplasm. Therefore, in cloned animals, imprinted genes should be particularly vulnerable to inappropriate methylation, which causes abnormal expression — a prediction that has, as noted above, been verified experimentally. For cloning to be made safe, the two parental genomes of a somatic donor cell would need to be physically separated and individually treated in "oocyte-appropriate" and "sperm-appropriate" ways. At present, it seems that this is the only rational approach to guaranteeing the creation of the epigenetic differences that are normally established during gametogenesis. Such an approach is beyond our present abilities, implying that serious biologic barriers (rather than mere technical problems) hinder faithful reprogramming after nuclear transfer and thus preclude the use of nuclear cloning as a safe reproductive procedure.

[...] Indeed, the blastocyst produced by somatic-cell nuclear transfer harbors fundamental biologic deficiencies that preclude its ever becoming a healthy human with any acceptable efficiency. Therefore, we may be justified in distinguishing the embryo produced by in vitro fertilization from the product of somatic-cell nuclear transfer.
The validity of this distinction is discussed further by Dr. Jaenisch on the PCBE site, here

What this shows is that is it important to understand the technical details of the process in order for one to make an informed decision about the moral permissibility of this particular kind of cloning, and the use of this particular kind of embryonic stem cell.  Specifically, it is not valid simply to look at the terms "embryonic stem cell," or "cloning," and render a judgment.  I do not mean to argue that such judgments cannot be made, or that one must accept Dr. Jaenisch's distinction between clonotes and zygotes.  However, one must understand the distinction, even if one does not accept it, in order to make an informed judgment.

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