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11-03-2010, 08:35 PM | #1 | |||
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In Remembrance
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1. Synapse. 2008 Mar;62(3):176-84.
Intranasal dopamine application increases dopaminergic activity in the neostriatum and nucleus accumbens and enhances motor activity in the open field. de Souza Silva MA, Topic B, Huston JP, Mattern C. Institute of Physiological Psychology and Center for Biological and Medical Research, University of Düsseldorf, Universitätsstrasse 1, Düsseldorf, Germany. desouza@uni-duesseldorf.de Dopamine (DA) plays an important role in a number of behavioral processes and neurological disorders. The intranasal administration of DA provides improved brain penetrability in comparison to systemic administration. We investigated the effects of intranasal administration of DA on the activity of dopaminergic neurons of the mesostriatal and mesolimbic systems and on motor activity. Rats previously implanted with guide-cannulae in the neostriatum (NS) and nucleus accumbens (NAc) were submitted to microdialysis procedure under urethane anesthesia. Vehicle or DA (0.03, 0.3, or 3.0 mg/kg) was administered bilaterally into the nostrils. In a separate study, animals received an intraperitoneal (i.p.) injection of vehicle or DA (0.03, 0.3, 3.0, or 30.0 mg/kg). Samples were collected every 10 min and analyzed for the content of DA and metabolites using high-performance liquid chromatography. For the open field study, rats were given intranasal vehicle or DA (0.03, 0.3, or 3.0 mg/kg) and placed into the field for 30 min. Motor activity (locomotion and rearing) and grooming were analyzed in blocks of 10 min using Ethovision. Intranasal DA (3.0 mg/kg) significantly increased DA levels in the NS and NAc immediately after administration. A comparable effect was obtained only after i.p. administration of 30 mg/kg DA. In the open field, the 3.0 mg/kg dose significantly decreased grooming behavior in the second 10 min interval and significantly increased locomotor activity in the third 10 min interval. The data indicate that intranasal administration of DA can influence dopaminergic functions and motor activity, and has a potential application in the therapy of diseases affecting the dopaminergic system. PMID: 18081176 [PubMed - indexed for MEDLINE]
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Born in 1953, 1st symptoms and misdiagnosed as essential tremor in 1992. Dx with PD in 2000. Currently (2011) taking 200/50 Sinemet CR 8 times a day + 10/100 Sinemet 3 times a day. Functional 90% of waking day but fragile. Failure at exercise but still trying. Constantly experimenting. Beta blocker and ACE inhibitor at present. Currently (01/2013) taking ldopa/carbadopa 200/50 CR six times a day + 10/100 form 3 times daily. Functional 90% of day. Update 04/2013: L/C 200/50 8x; Beta Blocker; ACE Inhib; Ginger; Turmeric; Creatine; Magnesium; Potassium. Doing well. |
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11-04-2010, 02:25 AM | #2 | |||
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In Remembrance
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Rick,
Well spotted. As you know, I spent a lot of time studying this route of drug delivery. I corresponded with several companies to try and persuade them to carry out reseach on the method. The advantage is that the nasal passage by-passes the BBB, and goes directly into the brain. This means you can get dopamine itself into the brain, and it is instantly available. It is the reason why smokers get instant satisfaction from inhaling nicotine through the nasal passage in tobacco smoke. Even drug takers are ahead of us, when they snort drugs through the nose, or smoke them. THey get an instant high, not like us taking our drugs orally and waiting patiently for an hour. I am not suggesting we snort our drugs. A simple nasal spray should be OK, and a sqirt every couple of hours. I am not sure but taking dopamine rather than levodopa may not cause dyskinesia. Their last sentence is encouraging. The data indicate that intranasal administration of DA can influence dopaminergic functions and motor activity, and has a potential application in the therapy of diseases affecting the dopaminergic system. Ron
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Diagnosed Nov 1991. Born 1936 |
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11-04-2010, 07:10 AM | #3 | |||
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Quote:
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Smooth seas do not make skillful sailors.... Nature loves courage. “The day science begins to study non-physical phenomena, it will make more progress in one decade than in all the previous centuries of its existence.” ~ Nikola Tesla |
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11-04-2010, 08:44 AM | #4 | |||
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In Remembrance
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Ron-
Like you, I have assumed that this route bypassed the BBB, but how certain are we of that? Think about this a minute. The nasal passages are the place where our innards are most intimate with our environment. Why would evolution leave such a hole in our defenses? Maybe the value is in bypassing the whole GI to bloodstream route? That's where carbidopa does its thing only to be left behind at the BBB. One reason we have been cautious with testing the nasal route is the thought of all those unwanted items going through as well as the ldopa. But, lordy, one whiff of wood smoke probably has more crap in it than we can imagine. Some sort of barrier exists even there, although it is no doubt different. It greatly increases the safety factor if the carbidopa and artificial colors are still blocked in some manner and the ldopa allowed to pass just as at the BBB. And we could still benefit from the hour long delay imposed by the oal route. Kind of the best of both worlds. Any thoughts on that?
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Born in 1953, 1st symptoms and misdiagnosed as essential tremor in 1992. Dx with PD in 2000. Currently (2011) taking 200/50 Sinemet CR 8 times a day + 10/100 Sinemet 3 times a day. Functional 90% of waking day but fragile. Failure at exercise but still trying. Constantly experimenting. Beta blocker and ACE inhibitor at present. Currently (01/2013) taking ldopa/carbadopa 200/50 CR six times a day + 10/100 form 3 times daily. Functional 90% of day. Update 04/2013: L/C 200/50 8x; Beta Blocker; ACE Inhib; Ginger; Turmeric; Creatine; Magnesium; Potassium. Doing well. |
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11-04-2010, 08:50 AM | #5 | |||
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In Remembrance
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1. J Pharm Sci. 2010 Apr;99(4):1654-73.
Intranasal delivery to the central nervous system: mechanisms and experimental considerations. Dhuria SV, Hanson LR, Frey WH 2nd. Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA. shyeilla.dhuria@gmail.com The blood-brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS), posing a significant challenge to drug development efforts to treat neurological and psychiatric diseases and disorders. Intranasal delivery is a noninvasive and convenient method that rapidly targets therapeutics to the CNS, bypassing the BBB and minimizing systemic exposure. This review focuses on the current understanding of the mechanisms underlying intranasal delivery to the CNS, with a discussion of pathways from the nasal cavity to the CNS involving the olfactory and trigeminal nerves, the vasculature, the cerebrospinal fluid, and the lymphatic system. In addition to the properties of the therapeutic, deposition of the drug formulation within the nasal passages and composition of the formulation can influence the pathway a therapeutic follows into the CNS after intranasal administration. Experimental factors, such as head position, volume, and method of administration, and formulation parameters, such as pH, osmolarity, or inclusion of permeation enhancers or mucoadhesives, can influence formulation deposition within the nasal passages and pathways followed into the CNS. Significant research will be required to develop and improve current intranasal treatments and careful consideration should be given to the factors discussed in this review. PMID: 19877171 [PubMed - indexed for MEDLINE]
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Born in 1953, 1st symptoms and misdiagnosed as essential tremor in 1992. Dx with PD in 2000. Currently (2011) taking 200/50 Sinemet CR 8 times a day + 10/100 Sinemet 3 times a day. Functional 90% of waking day but fragile. Failure at exercise but still trying. Constantly experimenting. Beta blocker and ACE inhibitor at present. Currently (01/2013) taking ldopa/carbadopa 200/50 CR six times a day + 10/100 form 3 times daily. Functional 90% of day. Update 04/2013: L/C 200/50 8x; Beta Blocker; ACE Inhib; Ginger; Turmeric; Creatine; Magnesium; Potassium. Doing well. |
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"Thanks for this!" says: | Conductor71 (11-04-2010), moondaughter (11-05-2010) |
11-04-2010, 01:23 PM | #6 | ||
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Not only is intranasal administration of medication difficult to control dosage but aren't PWP more apt to have a "runny nose" making it even more difficult for accuracy/control? The best way of bypassing the BBB is intrathecal administration of drugs - a wee bit riskier than snorting for sure.
Love the term MUCOADHESIVES - much more dignified than calling it snot) TG |
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11-05-2010, 02:33 AM | #7 | |||
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In Remembrance
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Rick,
There is no doubt that the nasal passage by-passes the BBB. i have corresponded with researchers and companies who are working on the topic. See http://www.biomedcentral.com/1471-2202/9/S3/S5 "Abstract Intranasal delivery provides a practical, non-invasive method of bypassing the blood-brain barrier (BBB) to deliver therapeutic agents to the brain and spinal cord. This technology allows drugs that do not cross the BBB to be delivered to the central nervous system within minutes. It also directly delivers drugs that do cross the BBB to the brain, eliminating the need for systemic administration and its potential side effects. This is possible because of the unique connections that the olfactory and trigeminal nerves provide between the brain and external environment. I had extensive correspondance with Dr W. Frey years ago. If you do a search you will find extensive evidence that confirms the nasal passage is an almost instantaeous route into the brain, by passi9ng the BBB. Ron
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11-05-2010, 02:46 AM | #8 | |||
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In Remembrance
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Hi Moondaughter,
I was not suggesting that we deliver glutathione by this route, although it could be interesting. I have been keen to see a trial on delivery of dopamine itself by a nasal route. The effect would be instasntaneous. Far better than injecting apomorphine, as a rescue therapy. Another question is would dopamine delivered this way avoid dyskinesia, which levodopa causes. Ron
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Diagnosed Nov 1991. Born 1936 |
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11-05-2010, 08:14 AM | #9 | |||
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Thanks for responding Ron, Good question. I think the whole issue of dosing itself needs reevaluationttaking into consideration cycles, seasons, sx response, when to increase/decrease the dose giving rise to respect and awareness for individual biochemistry. I raised the example of intranasal glutathione to suggest there may be an issue of sterilization - peerhaps this issue is the reason why this delivery method is not more commonly used becausse in fact it is such a a close and effective delivery method. Cheers! md
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Smooth seas do not make skillful sailors.... Nature loves courage. “The day science begins to study non-physical phenomena, it will make more progress in one decade than in all the previous centuries of its existence.” ~ Nikola Tesla |
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11-05-2010, 08:16 AM | #10 | ||
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http://pubs.acs.org/subscribe/journa...06filmore.html
"Others think they may have found a completely different therapeutic tunnel to the brain that bypasses the BBB and is noninvasive—through the nose. For some time, it has been known that viruses can make their way to the CNS through the nasal passage. Various work also has shown that cocaine, a drug of abuse that is snorted, exhibits its rapid effects by taking a direct path to the brain. Animal studies in recent years have demonstrated that dropping both small and large therapeutic drugs through the nasal cavity delivers them to the brain, often in only a few minutes (3). If this method could be developed further, it would offer a framework in which to target various neurological conditions without the complexities (and expense) of carrier molecules and their potential to cause side effects while traveling through the bloodstream.[/B][/B]" Interesting thoughts but I would be concerned about long term effects on nasal mucosa. There is already Apokin and Parcopa for alternate routes. Regular or fast disolving L-Dopa can be taken sublingual or buccal routes. Is the goal to deliver dopamine as a quick rescue (and shorter durational effect) or is the goal to be able to cut dosage of dopamine through efficiency and thus decrease the side effect of dyskinesia. Then there is the question of a "direct hit" of dopamine crossing the BBB triggering dyskinesia even with reduced dose. Am I following this discussion correctly? Just trying to keep up with the "big boys". TG |
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