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Dr. Bob is Robert Hsiung, MD,
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Posted by tessellated on February 25, 2006, at 12:33:28
In reply to correction, posted by mike99 on February 24, 2006, at 17:41:37
My Pdoc who was a hardcore biochemical guy.
i.e. based his info on research papers, and did often water things down, but was clear.He said provigil blocked presynaptic norephinephrine (NE) autoreceptors.
Autorecptors are molecules located in the presynaptic neuron's axon terminal. It is thought to play a role in providing feedback to the presynaptic neuron and play a role in modulating synaptic activity.
Therefore making the neuron produce more NE, by inhibiting its ability to sense these raised levels of NE.
or
The presynaptic source of norephi (NE) release would be increased due to the autoreceptor not inhibiting the production of more norephinephrine.
Pretty cool no?kinda like tweaking your cars thermostat so it might run hotter.
or altering your computers micro fuse so it would run faster (fun to do on both mac/pc but you can destroy your chip).I think therefore the cardio issues are of concern due to increased levels of NE and the diverse range of effects it has on vasoconstriction and cardio output, respiration, and all sorts of stuff.
I've not personally noticed any BloodPressure and/or cardio effects that are much different than caffeine. Though its got moderate poop out.
But again, the conclusions are not there yet.
Though enough is know to raise concern-untill this concern is proved wrong-which takes research monies.
It's still-relatively a new chemical.Isn't it generic yet? Geesh. Its suppose to be, but is held up in litigation by Cephalon who's gonna market the r-isomer as nuvigil-what b.s.
Modafinil had $289 million, of sales in 2004!Still I would say it is probably the best stim/cognitive enhancing agent to come out for a Loooong time!
Posted by mike99 on February 25, 2006, at 13:13:45
In reply to provigil discussion, posted by tessellated on February 25, 2006, at 12:31:34
That's interesting. Thanks for the info Tessellated.Remeron, Tenex and Clonidine work on presynaptic autoreceptors (by central alpha-2 antagonism and agonism).
I wonder how significant the increase in peripheral NE is, as I think this would/should be clearly stated in the drug monograph.
I can't take stims due to extremely excessive cardiovascular activation and so I wonder if I'd have the same problem w/ Provigil if it in effect increases NE.
Any thoughts on this would be appreciated.
Thanks again for the feedback.
And yeah, I agree the patenting of the active isomer strategy has gotten a little out of control, though I imagine it's sometimes beneficial.
Posted by mike99 on February 25, 2006, at 13:21:12
In reply to Re: provigil discussion, posted by mike99 on February 25, 2006, at 13:13:45
If provigil does antagonize presynaptic noradrenergic autoreceptors resulting in increased NE, wouldn't this classify it as a sympathomimetic?Or perhaps not since I don't think Strattera is considered a sympathomimetic. I wonder then what is the technical definition of a sympathomimetic.
Posted by SLS on February 25, 2006, at 13:38:51
In reply to provigil discussion, posted by tessellated on February 25, 2006, at 12:33:28
> He said provigil blocked presynaptic norephinephrine (NE) autoreceptors.
I respectfully submit that your doctor's information is at least 5 years out of date. The other possibility, of course, is that mine is no longer current.
http://www.rxlist.com/cgi/generic2/modafinil_cp.htm
Modafinil does not appear to be a ligand for any NE receptor. The original work suggesting NE receptor binding by modafinil was spurious.
- Scott
Posted by mike99 on February 25, 2006, at 13:51:04
In reply to Re: provigil discussion » tessellated, posted by SLS on February 25, 2006, at 13:38:51
Scott,It does seem the most recent theory is that provigil is not a ligand for any NE receptor as you state.
Do you have any thoughts then on how provigil stimulates the cardiovascular system, (though this is supposed to be minimal)? And if a beta blocker would safely and effectively counter these effects (my guess is it would)?
Mike
Posted by tessellated on February 25, 2006, at 14:42:49
In reply to Re: provigil discussion » SLS, posted by mike99 on February 25, 2006, at 13:51:04
Guys,
RE: health issues and cardio, i can only say there is the potential for problems. augmenting it w/propanol or a beta blocker etc to compensate sounds logical, but heck man talk to specialist before you start something like that. I'm big on self help, but heart/cardio issues aren't things to take lightly like "moods". 8)Hard to say, who's out of date, and we're getting rather deep symantically here.
The RX list's info is the same as it was years back, and it isn't even the PDR, and probably about a nurses level of science. As far as the specifics, "direct or indirect alpha-adrenergic agonist" does not necessarily include "auto-adrenergic receptor (modulation)", as these structures are presynaptic and located in the axon not at the synaptic cleft where most neurotransmission occurs.Notice they don't even mention beta adrenergic activity.
An additional point is that there are probably more than just the alpha/beta receptor adrenergic subtypes that have yet to be isolated and/or understood. Look at serotonin (5HT). Its got 5HT1A, 5HT1B, 5HT2A, I think 8 and still counting....
Regardless: modafinil is probably an atypical sympathomimetic as it has effects upon NE-but not dopamine(DA). These are both subtypes of a larger chemical family the catecholamines which create excitation similar to (mimetic/mimicry) and directly upon the sympathetic nervous system. here's a cool diagram
http://en.wikipedia.org/wiki/Sympathetic_nervous_systemI do know that if I take 400mg I definitely notice increased heart rate, respiration, and the impulse to ramble and do things. At that quantity it feels very close to other stims-and a tad unpleasant.
Phwew!
8ed> Scott,
>
> It does seem the most recent theory is that provigil is not a ligand for any NE receptor as you state.
>
> Do you have any thoughts then on how provigil stimulates the cardiovascular system, (though this is supposed to be minimal)? And if a beta blocker would safely and effectively counter these effects (my guess is it would)?
>
> Mike>
> Scott,
>
> It does seem the most recent theory is that provigil is not a ligand for any NE receptor as you state.
>
> Do you have any thoughts then on how provigil stimulates the cardiovascular system, (though this is supposed to be minimal)? And if a beta blocker would safely and effectively counter these effects (my guess is it would)?
>
> Mike
Posted by mike99 on February 25, 2006, at 15:30:19
In reply to Re: provigil discussion, posted by tessellated on February 25, 2006, at 14:42:49
Hmmm...confusing, confusing.
I'll definitely talk w/ my Dr. about cardio issues related to provigil, but in all likelihood he probably knows less about it than everyone who's posted to this thread (and he's a sharp guy--board-certified in sleep medicine and pulmonology, so he should be quite knowledgeable about provigil).
I'm generally healthy but extremely senstive to/intolerant of stimulants.
I wonder about the sympathomimetic activity of provigil because this might have negative consequences when combined with a beta blocker (as beta blockers "increase pressor affects of sympathomimetics" due to beta receptors being blocked but alpha adrenergic receptors not).
Posted by tessellated on February 25, 2006, at 17:12:33
In reply to Re: provigil discussion, posted by mike99 on February 25, 2006, at 15:30:19
Yeah,
I just cant wait untill its ALL figured out.
Everything would be sooo much easier.
Posted by mike99 on February 25, 2006, at 17:29:01
In reply to Re: provigil discussion, posted by tessellated on February 25, 2006, at 14:42:49
>> As far as the specifics, "direct or indirect alpha-adrenergic agonist" does not necessarily include "auto-adrenergic receptor (modulation)", as these structures are presynaptic and located in the axon not at the synaptic cleft where most neurotransmission occurs.
Good point--the monograph states "At pharmacologic concentrations, modafanil does not bind to MOST POTENTIALLY RELEVANT receptors for norepinephrine, serotonein, dopamine..."
Whatever "most potentially relevant" means. Not very informative IMHO.
> Notice they don't even mention beta adrenergic activity.
They sure don't.
Ditto's on wishing there was more to go on.
Posted by zeugma on February 25, 2006, at 17:42:12
In reply to Re: provigil discussion, posted by mike99 on February 25, 2006, at 15:30:19
I have to agree with SLS, Provigil is not an alpha-2 antagonist (antagonist of pre-synaptic NE autoreceptors). If that were the case then depleting an animal of norepinephrine would result in a loss of its effect (similar to the way depleting an individual whose depression has remitted on desipramine results in a relapse), but this seems not to be the case.
On the other hand, animals that lacked dopamine transporters experienced no stimulating effect from either methamphetamine or Provigil, indicating that DA reuptake inhibition is involved. These animals were hypersensitive to caffeine, so it's safe to say that caffeine and Provigil do not share the same mechanisms.
An experiment was also conducted in which Provigil's effect on the ventrolateral proptic nucleus (a major site of sleep regulation) and apparently Provigil blocked the NE transporters in that region:
If Provigil does act as an NE transport blocker it must be extremely localized, because every other NE transport blocker inhibits cataplexy, and Provigil does not do so at all.
The author who comments on the study I cited above theorizes that the combination of weak DA reuptake inhibition, and localized NE reuptake inhibition, may combine to produce its wakefulness effect. Provigil does release orexin, but it has no direct effect on that system (i.e. it is not a ligand for a known orexin receptor). Its effect on GABA inhibition is also well documented:
These effects on GABA and norepinephrine are extremely localized and peculiar, at they seem so to me.
-z
Posted by tessellated on February 25, 2006, at 20:15:32
In reply to Re: provigil discussion, posted by zeugma on February 25, 2006, at 17:42:12
Zuegma,
cool refs, like this serious kinda info.
now are alpha-2 sites presynaptic autoreceptors?
i did not believe this to be the case.
but....
lemme spend time on the refs many thanks,
8edps: antagonizing a presynaptic autoreceptor can result in an increase of NE release. as they modulate NE production; and can infact inhibit NE release/production if agonists/excess NE are present. An antagonist can have post synaptic agonistic affect. Get it? Stimulation can cause inhibition and vice versa.. It's freaking complex....
> I have to agree with SLS, Provigil is not an alpha-2 antagonist (antagonist of pre-synaptic NE autoreceptors). If that were the case then depleting an animal of norepinephrine would result in a loss of its effect (similar to the way depleting an individual whose depression has remitted on desipramine results in a relapse), but this seems not to be the case.
>
> On the other hand, animals that lacked dopamine transporters experienced no stimulating effect from either methamphetamine or Provigil, indicating that DA reuptake inhibition is involved. These animals were hypersensitive to caffeine, so it's safe to say that caffeine and Provigil do not share the same mechanisms.
>
> An experiment was also conducted in which Provigil's effect on the ventrolateral proptic nucleus (a major site of sleep regulation) and apparently Provigil blocked the NE transporters in that region:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14998233&query_hl=3&itool=pubmed_docsum
>
> If Provigil does act as an NE transport blocker it must be extremely localized, because every other NE transport blocker inhibits cataplexy, and Provigil does not do so at all.
>
> The author who comments on the study I cited above theorizes that the combination of weak DA reuptake inhibition, and localized NE reuptake inhibition, may combine to produce its wakefulness effect. Provigil does release orexin, but it has no direct effect on that system (i.e. it is not a ligand for a known orexin receptor). Its effect on GABA inhibition is also well documented:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8813612&query_hl=6&itool=pubmed_docsum
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9774168&query_hl=10&itool=pubmed_docsum
>
> These effects on GABA and norepinephrine are extremely localized and peculiar, at they seem so to me.
>
> -z
>
>
Posted by mike99 on February 25, 2006, at 20:55:34
In reply to Re: provigil discussion, posted by tessellated on February 25, 2006, at 20:15:32
..rs
This may likely be to what your doc was referring.
In the CNS alpha-2 receptors are presynaptic autoreceptors.
Stimulating this receptor by NE or drugs such as clonidine or tenex inhibits NE release (presynaptically), which theoretically should result in decreased activation of the corresponding post-synaptic noradrenergic receptors.
Antagonizing the same receptor by a drug like remeron/mirtazapine conversely results in increased NE release.
To the best I could gather, the 2006 PDR still states provigil is not an agonist or antagonist at any "potentially relevant receptors for NE, etc...". I think this would, or at least should include the alpha-2 autoreceptor.
Posted by mike99 on February 25, 2006, at 21:13:55
In reply to Re: provigil mechanism of action?, posted by Racer on February 25, 2006, at 3:22:53
By what mechanism would provigil stimulate the heart/sympathetic nervous system? And how does this compare to the sympathomimetics?
I realize the peripheral stimulation of provigil is supposed to be minimal (one of its advantages), but it does seem to activate the sympathetic system.
Could provigil possibly cause release of epinephrine and epinephrine from the adrenals?
Thanks Zeugma for the excellent references.
Posted by mike99 on February 25, 2006, at 21:16:34
In reply to so how does provigil stimulate the heart?, posted by mike99 on February 25, 2006, at 21:13:55
if provigil could result in the release of epinephrine and norepinephrine from the adrenals.
Posted by zeugma on February 26, 2006, at 8:48:11
In reply to Typo...I meant to ask.., posted by mike99 on February 25, 2006, at 21:16:34
>
> if provigil could result in the release of epinephrine and norepinephrine from the adrenals. >>yes, modafinil does.
I experienced a syncopal episode when I switched from 30 mg Ritalin to Provigil 200 mg. I experienced this in the evening (I took Provigil early in the am). I experienced much more profound effects on heart rate on Ritalin (I experience none on Provigil). Neither drug affected my BP.
-z
Posted by SLS on February 26, 2006, at 9:11:37
In reply to Re: provigil discussion » SLS, posted by mike99 on February 25, 2006, at 13:51:04
> Do you have any thoughts then on how provigil stimulates the cardiovascular system,
Not really. Again, I would refer you to structures in the hypothalamus and reticular formation that contain orexinergic (hypocretin) and glutamatergic neurons. The hypothalamus most certainly serves to regulate vital bodily functions.
Regarding modafinil and dopamine, at least one mechanism by which limbic areas rich in DA neurons are stimulated is via the glutamate-releasing properties of modafinil in the thalamus. The GABA-glutamate balance is shifted towards glutamate, thus stimulating (disinhibiting) the nucleus accumbens, a reward center located in the limbic system. I don't believe modafinil affects directly any DA receptor or transporter.
My first guess is that beta blockers would help to mitigate any tachycardia or perhaps even anxiety. The beta blocker probably would not act to antagonize the pharmacology of modafinil, but, rather, to simply compensate for it downstream. Losartan might be an ideal drug as it would also help mitigate the increase in blood pressure seen with modafinil. It would help reduce the effects of the excess plasma NE that modafinil is capable of producing. It should accomplish this by preventing the stimulation of peripheral NE alpha-1 receptors by endogenous NE.
The problem with some of the older studies of modafinil is that they focused almost exclusively on the effects it had on aminergic neurotransmission, particularly NE and DA. Unfortunately, some of the investigators jumped to conclusions prematurely regarding the mechanisms of involvement of these neurotransmitters. Just because a particular pathway must be intact for a drug to produce changes downstream doesn't mean that this pathway is directly affected by the test drug. However, this was the basis by which the original research inferred a direct effect for modafinil on NE receptors.
Modafinil was originally pronounced to be a central alpha-1 adrenergic agonist. No more.
The package label and PDR entries for modafil were written after the NE receptor theories were debunked. The mechanisms by which modafinil produces wakefulness are not well understood, but probably do involve hypocretin. By contrast, the mechanisms by which modafinil improves depression (usually implemented as an augmenting agent) might involve the shifting of thalamic glutamate/GABA balance towards glutamate and the subsequent activation of DA neurons in the nucleus accumbens.Sorry for the redundancies.
- Scott
Posted by zeugma on February 26, 2006, at 12:50:20
In reply to Re: provigil discussion, posted by SLS on February 26, 2006, at 9:11:37
the mechanisms by which modafinil improves depression (usually implemented as an augmenting agent) might involve the shifting of thalamic glutamate/GABA balance towards glutamate and the subsequent activation of DA neurons in the nucleus accumbens.>>
Modafinil also elevates serotonin levels in cortex and dorsal raphe, which is surely relevant to depression.
-z
Posted by SLS on February 26, 2006, at 14:38:46
In reply to Re: provigil discussion » SLS, posted by zeugma on February 26, 2006, at 12:50:20
> the mechanisms by which modafinil improves depression (usually implemented as an augmenting agent) might involve the shifting of thalamic glutamate/GABA balance towards glutamate and the subsequent activation of DA neurons in the nucleus accumbens.>>
>
> Modafinil also elevates serotonin levels in cortex and dorsal raphe, which is surely relevant to depression.
>
> -z
I did not know this. Do you think this is an effect secondary to another mechanism of action of modafinil, or does the molecule affect 5-HT neurons directly? In other words, are the outflows of 5-HT in these areas secondary to increases in the releases of hypocretin or glutamate produced elsewhere by modafinil?Again, we see hypocretin:
I found this interesting:
Here, modafinil seems to act as an amplifier. By itself, though, it does not elicit 5-HT increase. I noticed some other work by these same authors suggesting otherwise, but at concentrations too high to be relevant to those in clinical use.
- Scott
Posted by tessellated on February 26, 2006, at 14:48:22
In reply to Re: provigil discussion » zeugma, posted by SLS on February 26, 2006, at 14:38:46
OK, now I've gotta question.
What are your guys' thoughts on combining MAOI's with modafinil?
The fears are also of potentiating hypertension.
???
Posted by mike99 on February 26, 2006, at 15:28:14
In reply to Re: provigil discussion, posted by SLS on February 26, 2006, at 9:11:37
>>Losartan might be an ideal drug as it would also help mitigate the increase in blood pressure seen with modafinil. It would help reduce the effects of the excess plasma NE that modafinil is capable of producing. It should accomplish this by preventing the stimulation of peripheral NE alpha-1 receptors by endogenous NE.
Hey Scott,
Thanks for the info. Please correct me if I'm mistaken, but I believe losartin is an angiotensin II receptor antagonist.
And while this would lower blood pressure by preventing vasoconstriction and inhibiting aldosterone sectretion from the adrenals, it would not block peripheral NE alpha-1 receptors from endogenous NE (or epinephrine).
I think only an alpha-1 antagonist such as prazosin or a mixed alpha/beta blocker such as labetalol or carvedilol could do this.
Posted by mike99 on February 26, 2006, at 15:31:33
In reply to Re: Typo...I meant to ask.. » mike99, posted by zeugma on February 26, 2006, at 8:48:11
> >
> > if provigil could result in the release of epinephrine and norepinephrine from the adrenals. >>
>
> yes, modafinil does.
>
> I experienced a syncopal episode when I switched from 30 mg Ritalin to Provigil 200 mg. I experienced this in the evening (I took Provigil early in the am). I experienced much more profound effects on heart rate on Ritalin (I experience none on Provigil). Neither drug affected my BP.So you experienced a single episode of syncope and haven't had any problems with it since?
Posted by mike99 on February 26, 2006, at 15:44:04
In reply to Re: provigil discussion, posted by mike99 on February 26, 2006, at 15:28:14
Since it increases plasma epinephrine and norephinephrine, and I'm guessing also direct NE release from sympathetics to the heart.Don't know if anyone really cares about this, so if not please ignore this, but I am very sensitive to sympathomimetics.
I'm hoping provigil may be an alternative since it has less effects on the cardiovascular system. Yet it does seem to have definite sympathomimetic activity.
I've heard of people often combining sympathomimetics with beta blockers to counter the cardiovascular effects. My understanding is this has the potential for "unopposed beta blockade"--where beta receptors are blocked out of proportion with alpha receptors and that this can be very dangerous.
For example, in the ER someone with a cocaine or amphetamine OD should never be treated with a beta blocker solely, but rather a mixed alpha/beta antagonist such as labetalol or carvedilol. This is my understanding.
I don't think many docs are even aware of this.
Anyhow, I am digressing but would be interested in anyone who's switched to provigil due to stimulant intolerance or combined it with an alpha or beta blocker.
Cheers.
Posted by zeugma on February 26, 2006, at 16:10:34
In reply to Re: provigil discussion » zeugma, posted by SLS on February 26, 2006, at 14:38:46
Here, modafinil seems to act as an amplifier. By itself, though, it does not elicit 5-HT increase. I noticed some other work by these same authors suggesting otherwise, but at concentrations too high to be relevant to those in clinical use.>>
I believe you're referring to this:
Doses of modafinil administered to rats are much higher than those administered to other species, including mice:
So possibly the effect on 5-HT observed by Fuxe et al. is therapeutically relevant to humans, in isolation.
What really puzzles me is that modafinil has absolutely no REM-suppressant or anticataleptic effect. This in itself is surprising, since most drugs that work through the alpha-1 adrenoceptor (directly or not) are REM-suppressant and anticataleptic, and I am recovering from my usual Sunday series of REM-distorted sleep episodes that were not a problem when I was on methylphenidate (meaning I could nap on methylphenidate and not experience a sleep-onset REM period that causes immediate, unpleasant waking). Buspirone, too, through stimulation of post-synaptic 5-HT1A receptors or alpha-2 adrenoceptors, blocks REM, making it useful as a quick REM suppressant (but I am trying to stay awake today, so fell asleep involuntarily- but last week I was able to nap during the afternoon after taking buspirone). So I was especially interested in the following passage of the reference you cited:
<<
It has been hypothesized that activation of 5-HT neurons contributes to the function of ascending arousal systems projecting to the forebrain (O'Hearn and Molliver, 1984; McQuade and Sharp, 1995, 1997; Portas et al., 1998). Within the brainstem, serotonergic inputs to REM-sleep active areas in the pedunculopontine tegmental and laterodorsal tegmental nucleus (Honda and Semba, 1994; Vertes and Kocsis, 1994) would tend to suppress REM sleep (Thakkar et al., 1998; Monti and Monti, 2000; Portas et al., 2000). Consistent with this model, in vitro data have shown that 5-HT and 5-HT1A agonists inhibit neurons in those regions (Luebke et al., 1992; Leonard and Llinas, 1994). Furthermore, microinjections of 5-HT into the laterodorsal tegmental nucleus in behaving (unanesthetized) cats and rats have been shown to produce a dose-dependent suppression of REM sleep (Sanford et al., 1994; Horner et al., 1997). In addition, there is direct evidence that suppression of 5-HT neuronal activity in the DRN increases REM sleep (Portas et al., 1996). Thus, direct activation of 5-HT neurons by hcrts could promote wakefulness or suppress sleep states through these and other brainstem and forebrain projections. >>The statement elsewhere in the article that the hypocretin ACTIVATED GABAA signalling in the dorsal raphe is consistent with the fact that both modafinil and clonazepam induce sleep onset REM for me:
<<In the present study, we have found that high concentrations of hcrts can have an indirect inhibitory effect on 5-HT cells by exciting GABAergic interneurons in the DRN area. It remains to be determined how hcrts interact with other transmitters in regulating the GABAergic inputs to the 5-HT cells. Nevertheless, the present results show that the influence of hcrts in the DRN is more complex than simply the direct excitation of 5-HT neurons.>>
Most narcoleptics lack hypocretin in their CSF, but nonetheless they still experience the hypocretinergic effects (increased waking, and aggravation of cataplexy/REM). In fact one physician even speculated (under the sway of earlier thorists who maintained that modafinil worked directly on alpha-1 receptors) that modafinil must be a mixed agonist/antagonist at alpha-1 receptors, since it induced cataplexy and sleep onset REM in his patient.
I would guess that it is hypocretin that is responsible for much of modafinil's effects, from reading the article you cited.
I suppose hypocretin's activation of GABAergic interneurons in the DRN might also be responsible for why modafinil is not especially epileptigenic.
By the way, Karel Fuxe is one of the most illustrious names in neuropharmacology.
-z
Posted by zeugma on February 26, 2006, at 16:15:47
In reply to Re: Typo...I meant to ask.. » zeugma, posted by mike99 on February 26, 2006, at 15:31:33
Posted by zeugma on February 26, 2006, at 16:27:47
In reply to i guess provigil IS an atypical sympathomimetic, posted by mike99 on February 26, 2006, at 15:44:04
Sorry, I can't answer the questions about MAOI's or how to deal with Provigil's sympathomimetic activity, Scott is much more knowledgeable than I am about these matters.
I am probably somewhat tolerant to symapathomimetic activity through years of heavy caffeine use in an attempt to treat my ADHD and sleep disorder.
I do know that an individual has combined MAOI's with Provigil to control narcolepsy and atypical depression, but all I've read is that case study. I don't know about Nardil or other MAOI's.
-z
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Dr. Bob is Robert Hsiung, MD,
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