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Rakel & bope_section-14Rakel & Bope_Section-14 10/29/03 12:55 PM Page 959 TREATMENT OF TOURETTE’S
5. Use of stimulants. Because stimulants can make tics worse, it is often assumed that stimulants are con- SYNDROME
traindicated in the treatment of TS. In reality, the ticsare often mild and easy to treat, and it is the co-morbid ADHD that causes the greatest disability. Failure to address and treat the ADHD can leave a patient significantly disabled. TS and ADHD are intimately related clinically, genetically, and pharmacologically.
6. Exacerbation of tics by medications. Although it is Tourette’s syndrome (TS) is a complex neurobehav- well known that stimulants can exacerbate tics in ioral disorder. Its diagnosis is based on the occurrence individuals with TS, it is less well appreciated that of motor and vocal tics almost daily for a period of at virtually every medication used in the treatment of least 1 year. Coprolalia is seen in less than 10% of TS and its co-morbid conditions can, in some cases, patients and is not required for the diagnosis. TS is a make the tics worse. Such medications include cloni- strongly genetic disorder. Like other behavioral condi- dine (Catapres), clonazepam (Klonopin), haloperidol tions, TS is a polygenic disorder caused by the additive (Haldol), pimozide (Orap), and risperidone (Risperdal).
and epistatic effect of multiple genes interacting with 7. Polypharmacy. The use of multiple medications the environment, each with a small effect. TS should used to be considered bad medical practice. However, be considered a disorder with a wide spectrum of behavioral disorders are due to the combined effect manifestations. Thus, the feature that makes it so of multiple different gene variants, each affecting intriguing is the wide range of co-morbid disorders different neurotransmitters and other pathways and that occur in over 80% of individuals who seek medical each of which may require a different medication for attention. These disorders include attention deficit hyperactivity disorder (ADHD), learning disorder, 8. Drug of choice. Clonidine,* not haloperidol or obsessive-compulsive disorder (OCD) or behavior, pimozide, is the drug of first choice.
other anxiety disorders including panic attacks and Medications for the treatment of tics can be divided generalized anxiety disorder, mood disorders including into two groups. Group I consists of those that are effec- depression and mania, sleep disorders, oppositional tive 60% to 80% of the time, and group II includes drugs defiant disorder (ODD) and conduct disorder, rages, that are less consistently effective or often ineffective.
self-destructive behavior, and others. Space does notallow a discussion of the treatment of these co-morbiddisorders. The focus here is on the treatment of tics.
GROUP I MEDICATIONS
This article is based on my personal experience In my experience, only three medications or groups over the past 25 years with the treatment of over 4000 of medication are included in group I. In order of children and adults with TS. The following are some of preference, they are clonidine,* clonazepam,* and the what I consider basic truths concerning the treatment typical or atypical neuroleptics (Table 1). In the fol- lowing sections, the generic names are given first and 1. Treatment of the whole person. Anyone who takes the U.S. brand names are given in parentheses. They on the treatment of individuals with TS should be are often different in other countries.
prepared to treat the whole spectrum of co-morbiddisorders because of the intimate interaction between Clonidine (Catapres)
the tics and the co-morbid behavior. Moreover, itusually works best for the patient and the physician Clonidine* is an α -adrenergic agonist. By stimulat- if one person treats both disorders.
ing presynaptic α -adrenergic receptors, in modest 2. Waxing and waning of tics. The spontaneous doses it results in a decrease in norepinephrine (NE) waxing and waning of motor and vocal tics can make release. At higher doses it can stimulate postsynaptic evaluation of the true effectiveness of medications α-adrenergic receptors. Clonidine is effective in the difficult. This difficulty increases the need to use treatment of motor and vocal tics 60% to 70% of the double-blind assessments when evaluating the efficacy time. However, it is a short-acting medication, and when given orally, the effects can wear off after 3 to 3. Tics may be the least of the problems. In most 6 hours. Clonidine is also effective in the treatment cases, the tics are often the easiest part of the spectrum of ADHD, and considerable evidence indicates that to treat and are the least of the problems. Once the tics NE plays a significant role in ADHD. Importantly, are minimized with medication, it is often the ADHD, elevated plasma levels of NE breakdown products OCD, or ODD that is the major issue in treatment.
have been associated with learning disorders in indi- 4. Basic pharmacology. Many times the difference viduals with ADHD, which suggests that reducing NE between success or failure in the treatment of TS levels could benefit children with learning disorders.
lies less in finding exotic new treatments for difficult Finally, clonidine* can be effective in the treatment of cases and more in understanding the best route and ODD, OCD, anxiety, phobias, and panic attacks. Thus, timing of administration of a small number of themost effective and reliable medications.
*Not FDA approved for this indication.
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TABLE 1. Primary Groups of Drugs for the Treatment of Chronic Tics in Tourette’s Syndrome
*Not FDA approved for this indication†Not available in the United States.
clonidine can be effective in the treatment of many of The most common errors leading to treatment fail- the important co-morbid conditions. It is especially ure in treating TS subjects with the clonidine patch* relevant that clonidine is one of the very few medica- are starting with a whole patch then abandoning tions that can consistently and reliably treat both tics treatment because of too much sedation or because it and ADHD. This property makes it a particularly was ineffective. The problem with sedation can be valuable alternative to the use of stimulants in the avoided by cutting the patch and starting with less treatment of TS subjects with co-morbid ADHD.
than a whole patch. The medication does not leak out Because it is effective for such a broad range of the TS of a cut patch. I have seen many cases in which a spectrum, I start treatment of most TS patients and whole patch was too much, 1/2 patch was too little, but many mild to moderately severe ADHD patients with 3/4 or 7/8 of a patch was just right. The problem with a clonidine. It covers a range of symptoms, so successful whole patch being ineffective can often be avoided initiation of treatment with clonidine can often obvi- by further increasing the dose. The maximal dose is ate the need to use any other medication. A number two TTS-3 patches. The average dose is one to two of strategies can be used to maximize the advantages patches. It is common for the patch to be effective for of clonidine and minimize the disadvantages. With several weeks and then lose its effectiveness. This the use of these strategies, a sizable number of TS change in effectiveness can usually be eliminated by a patients can be effectively treated with clonidine further increase in the dose. Only one to two such alone. If additional medications are needed, the dose upward adjustments are typically required. Parents required is often less than if a foundation of clonidine and patients seem to understand these changes best when told that “the dose is adjusted with a pair of Transdermal Clonidine (Catapres-TTS). The
scissors.” It is also important to let them know that single major disadvantage of clonidine* is that it can they do not need to call the doctor with every change be very sedating, especially when given orally.
in dose. They can be given a range to operate within, However, this side effect and the need to give frequent doses because of its short duration of action can be One of the most common problems with use of the ameliorated by the use of transdermal clonidine, clonidine patch* is the development of a rash immedi- known as the Catapres Transdermal Treatment ately under the patch as a result of contact dermatitis.
System.* It is available as TTS-1, TTS-2, and TTS-3.
This rash is due to an allergy to the patch material The latter two are equivalent to a patch two and three itself, not the clonidine.* It can often lead to the child times the size of TTS-1. The use of a TTS-1 patch once complaining that the patch itches, and the patch will a week is equivalent to the use of 0.1 mg of oral cloni- then be pulled off. A first line of defense against such dine* per day. For children, 1/4 to 1/2 patch per week is removal is to use only the clonidine patch itself and the usual starting dose. When the dose is right, the not the large covering patch that comes in the box.
tics may subside within a few days. If the parents are In some cases, the allergy is to the covering patch in a hurry to get the tics under control, the dose can rather than the clonidine patch itself. A second be increased every 1 to 2 days. If they are not so des- approach is to change the patch every 3 to 4 days perate, the dose is usually increased by 1/2 patch every instead of weekly. Because the rash sometimes occurs week until satisfactory control of the tics or too much predominantly on days 5 to 7, earlier changing can sedation is noted. In most cases, 1/2 patch has no effect, avoid the problem. Another approach is to have and it is thus necessary to increase to a whole patch.
the patient or parents purchase some water-based, *Not FDA approved for this indication.
*Not FDA approved for this indication.
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over-the-counter hydrocortisone ointment and rub it every 3 to 6 hours. Parents often report that they can into the area where the patch is to be placed, let it dry, see the medication wearing off after this time interval.
and then apply the patch. If all these measures fail, They can repeat the dose as often as necessary by and they do about 20% to 30% of the time, a final very using a dose just under that causing tiredness. Many effective approach is to switch to clonidine cream.* patients report that their physicians have previously The patch also becomes very difficult to use in the treated their TS with oral clonidine but suggested summer when children sweat a lot or swim. Although they take it at bedtime to avoid problems with seda- the patch is waterproof and can resist brief showers, tion. Although such administration can be effective tub baths, and brief dips in the pool, it is not compat- because of the short duration of action of clonidine, it ible with daily swims of an hour or more. These situa- often results in less than optional control of the tics in tions also call for the use of clonidine cream** or an oral form of clonidine or guanfacine (Tenex).† Clonidine as a Sleeping Medication. In many
Clonidine Cream.∗∗ I have had hundreds of TS
cases, what is usually considered an undesirable side patients who responded to only clonidine patches† effect can become an effective therapeutic effect.
and in whom no other medications were effective, Because NE is the arousal neurotransmitter, individ- including oral clonidine,† haloperidol, and pimozide.
uals with elevated central nervous system NE are When only patches are effective and then a severe often overaroused, especially children with TS and allergic reaction develops to the patch such that it can ADHD. Clonidine* can be a very effective, non–habit- no longer be used, patients or parents are devastated.
forming, nonaddictive sleeping aid for such individ- In the past 5 years I have found that an excellent uals. The bedtime dose usually ranges from 0.1 to solution to this problem is to switch to clonidine 0.3 mg. Occasionally, parents complain that their cream. It is not available at most pharmacies, but TS/ADHD children wake up and roam the house in the fortunately, usually at least one pharmacy in each middle of the night. Because of its short duration of reasonably large city does compounding and can action, clonidine is excellent for inducing sleep but is make clonidine in cream form. If the patient had been less effective in maintaining sleep throughout the using a TTS-1 patch, the prescription would read night. A clonidine patch* can be helpful in this regard.
0.1 mg/0.1 mL, use 0.05 to 0.15 mL on the forearm The combination of a clonidine patch* supplemented one to two times daily, with the amount being with bedtime oral clonidine* can treat both problems “1 month’s supply.” The cream is supplied in tuberculin of getting to sleep and staying asleep.
syringes with a plastic cap. The markings allow easy Although both clonidine* and guanfacine* are blood dispensing of 0.1 mL. The patient, not the parent, pressure medications, hypotension is rarely a trouble- should rub it into the forearm and make sure that no some side effect. Even fairly substantial doses are clothing comes in contact with it for 30 minutes. By not associated with significant decreases in blood this time the medication has been adsorbed into the pressure, thus suggesting that in the absence of skin and will not rub off. It will also not sweat off and hypertension, only a modest decrease in blood will not come off in the pool. In those who swim a lot, pressure occurs. In addition, these medications have an alternative is to use the cream after swimming no significant effect on the QT interval.
each day. In some cases, morning and afternoon Much time was devoted to the use of clonidine* application of the cream is necessary to keep symp- because it can be so effective in the treatment of TS toms in check. If a compounding pharmacy is not and its co-morbid conditions. In some children with located in your area, one might be found on the significant motor and vocal tics, ADHD, learning prob- Internet. Many compounding pharmacies will fill pre- lems, OCD, and ODD who are failing all their classes scriptions from any state or country.
and are a constant visitor to the principal’s office Oral Clonidine. Oral clonidine** is the last prefer-
because of disruptive behavior, all these symptoms ence for a route of administration of clonidine.** In have disappeared after the use of a clonidine patch.* my experience, oral clonidine is much more likely to Equally impressive, after several months their grades cause an unacceptable degree of sedation than trans- may have risen to A’s and B’s. Some children have dermal clonidine** is, probably because of the fact returned to the clinic proudly displaying plaques for that blood levels rise quickly after oral administration “most improved student.” Not all children responded and result in a higher blood level than what is obtained with transdermal clonidine.** Blood levelsthen drop and the tics return. Thus, as the parents Guanfacine (Tenex)
or patients recall the day, they are either “tired orticcing.” The even blood levels obtained with trans- Guanfacine* is also an α -adrenergic agonist. It has dermal clonidine** avoid this up-and-down course.
a slightly longer duration of action than oral cloni- Nonetheless, some patients still prefer oral clonidine.
dine* does and a modestly lower incidence of sedation The side effects can be minimized by giving the med- as a side effect. As such, it is widely used in place ication in small, frequent doses such as 0.025 or 0.05 mg of oral clonidine. The usual starting dose is 0.25 to0.5 mg three times daily (tid). Maintenance dosesare usually 0.5 to 1 mg tid. Guanfacine has all the *May be compounded by pharmacists.
**Not commercially available in the United States.
†Not FDA approved for this indication.
*Not FDA approved for this indication.
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advantages of clonidine. However, as with oral cloni- Atypical Neuroleptics
dine, it can still be unacceptably sedating, and I preferthe clonidine patch* to both oral clonidine and oral Atypical neuroleptics have the advantage that they are much less likely to cause tardive dyskinesia, One of the side effects of both clonidine (in any predominantly because of the fact that they cause form) and guanfacine is that instead of decreasing less inhibition of dopamine D receptors. However, symptoms of overarousal and hyperactivity, it can inhibition of these receptors is the reason that neu- increase these symptoms. Thus, in about 5% to 10% of roleptics are so effective in the treatment of tics. Of cases, parents report that their children are more the atypical neuroleptics (risperidone [Risperdal],* active and more irritable and have more trouble sleep- olanzapine [Zyprexa],* molindone [Moban],* ziprasi- ing. It has been suggested that ADHD is primarily a done [Geodon], quetiapine [Seroquel],* clozapine disorder of NE regulation and that both too little and [Clozaril]), risperidone* has the greatest affinity for too much NE can cause problems of inattention. Thus, dopamine D receptors. This affinity conforms with if a child had a low-NE form of ADHD, clonidine* my clinical experience that it is also the most effective could make it worse. Alternatively, as mentioned ear- atypical neuroleptic for the treatment of tics. Starting lier, at higher doses clonidine can have direct action doses are usually 0.25 to 0.5 mg tid, with maintenance on postsynaptic α-adrenergic receptors. This effect doses of 0.5 to 1 mg tid. Risperidone is relatively short could also result in activation rather than suppression acting. A common reason for failure of risperidone is administration of the medication only one or twotimes per day. If these times are in the morning andevening, recurrence of tics in the afternoon or evening Clonazepam (Klonopin)
may seem to be a failure of the drug. This “failure” Clonazepam* is one of the most frequently over- can often be eliminated by giving a third dose at looked medications for the treatment of tics. When clonidine* is less than optimally effective, clonazepammay be the second drug of choice. The starting dose is 0.125 to 0.25 mg one to three times per day, dependingon the age of the child. A common maintenance dose is Group II medications are those that in my experi- 0.25 to 0.5 mg tid. As with clonidine, the major side ence are effective in less than 50% of cases, are not effect is sedation. Other benzodiazepines may also be generally available in the United States, or require effective. Although the dependency potential of clon- special expertise. Careful attention to the use of type I azepam is often a concern, it is very rare for TS individ- medications results in control of tics in over 90% of uals to request progressively higher and higher doses.
TS cases. Group II medications and treatments, inalphabetical order, include antiandrogens, antibiotictreatment of PANDAS (pediatric autoimmune neu- Neuroleptics
ropsychiatric disorder associated with streptococcal Neuroleptics such as haloperidol (Haldol), pimozide infections), anticonvulsants, baclofen (Lioresal), (Orap), and fluphenazine (Prolixin)* used to be the behavioral management, β-blockers, botulinum toxin, drugs of choice for treating TS. They are effective in calcium channel blockers, clomiphene citrate 80% of cases. However, with the advent of the Web, (Clomid), cyproterone (Androcur),† deprenyl (Eldepryl),* parents often check out medications before using dronabinol (Marinol), electroencephalographic biofeed- them, and the statement that permanent neurologic back, herbal remedies, 5-hydroxytryptophan,† lecithin, changes such as tardive dyskinesia can occur often marijuana, mecamylamine (Inversine),* metoclo- frightens parents and patients so much that these pramide (Reglan),* naltrexone (ReVia),* nicotine patch neuroleptics have de facto become drugs of third (Habitrol),* ondansetron (Zofran),* pergolide (Permax), choice. If clonidine* and clonazepam* have been inef- reserpine, selective serotonin reuptake inhibitors, fective, before neuroleptics can be used, it is often nec- tetrabenazine,‡ tramadol (Ultram), tricyclic antide- essary to calm parents’ fears of them. I have treated pressants, and L-tryptophan. Interested readers can over 2000 TS patients with a major neuroleptic and obtain further details from the National Library of have seen only 2 cases of mild tardive dyskinesia, both in individuals who received over 15 mg/d of haloperi- In the vast majority of cases, the motor and vocal dol for many years. The usual doses of these medica- tics of TS or the chronic motor tic disorders can be tions are 0.25 to 2 mg of haloperidol, 0.5 to 4 mg of effectively treated with the use of one or more of the pimozide, and 0.5 to 5 mg of fluphenazine per day.
type I medications listed earlier. The difference Although at these low doses occasional patients may between success and failure often lies less in turning have akathisia, or extrapyramidal symptoms, I have to type II medications and more in paying careful never seen a case of tardive dyskinesia. Patients attention to the pharmacologic aspects of the three should have the QT interval monitored when taking *Not FDA approved for this indication.
†Investigational drug in the United States.
‡Not available in the United States.
*Not FDA approved for this indication.
Rakel and Bope: Conn’s Current Therapy 2004. Copyright 2004 by Elsevier Inc.
DELIBERAZIONE DELLA GIUNTA COMUNALE N. 1 DEL 24 GENNAIO 2008 “VERTENZA COMUNE DI MONTEGROTTO TERME C/ TALARICO SABRINA – GIUDIZIO CIVILE PENDENTE AVANTI AL TRIBUNALE DI PADOVA RUBRICATO AL N. 13569/04 R.G. – NOMIVA CONSULENTE TECNICO DI PARTE. =================================================================== LA GIUNTA COMUNALE PREMESSO che: - in data 24/12/2004 è stato no