Search

Neurocognitive disorders (e.g. dementia, mild cognitive impairment and delirium) belong to the most frequently occurring problems in older patients. For most types of dementia as well as for mild cognitive impairment no causal pharmacotherapy is currently available. This also applies to delirium, which should be primarily treated through the identification and elimination of predisposing factors while cautiously using symptomatic therapy with psychotropic drugs. Despite intensive ongoing research efforts the search for disease-modifying drugs for the treatment of Alzheimer's dementia has not been successful. In the prevention and treatment of neurocognitive disorders, rational and evidence-based pharmacological interventions can nonetheless play an important role. Besides the limited benefits of symptomatic treatment with currently available anti-dementia drugs, this includes the strict management of medical risk factors as well as the avoidance of drugs with delirogenic and dementing side effects.

The origin of a differentiated approach to neuropsychopharmacotherapy in children and adolescents can be traced back to the 1940s and 50s. Certain clinical disorders in the range of psychiatry and neurology were treated with a multiplicity of substances.We conducted an exclusive screening of 700 medical records of patients under 18 years of age from a psychiatric university hospital in Jena (from 1942–1945) and 89 files of children who attended Trüper’s approved school in Jena between 1946 and 1954.Differentiated therapies were administered for ailments such as acute anxiety states, erethism, hyperkinetic syndrome, enuresis, migraine, sleep disturbance, epilepsy, Sydenham’s chorea, spasticity, neuralgia, neuritis, dizziness, pain syndrome, tetany, and syphilis.Interventions for mental disorders were relatively unspecific before the development of neuroleptic and antidepressant agents. During this time, multitudes of treatments were implemented for neurovegetative disorders, psychoneuroses, and different kinds of psychopathies. Barbiturates were administered in both pure and mixed forms. Additionally, since mental disorders were frequently caused by physical disorders, they could be eliminated or improved by the use of chemotherapeutics. Other somatic therapies like convulsive shock treatment with camphor and cardiazol, malaria treatments, hypoglycemic shock therapy, and electroconvulsive treatment have been applied in patients with schizophrenia.

There are currently different groups of drugs for the pharmacotherapy of vertigo, nystagmus and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications and antidepressants, anticonvulsants, aminopyridines as well as acetyl-DL-leucine. In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but currently there is not sufficient evidence for a general recommendation. There is insufficient evidence to support the view that 16 mg t. i. d. or 48 mg t. i. d. betahistine has an effect in Menière's disease. Therefore, higher dosages are recommended. In animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There has been no RCT on the efficacy of beta-blockers or topiramate but one RCT on flunarizine in vestibular migraine. Based on clinical experience, a treatment analogous to that for migraine without aura can be recommended. Acetyl-DL-leucine improved cerebellar ataxia (two observational studies); it also accelerated central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on treatment of vestibular paroxysmia with carbamazepine (VESPA), acute unilateral vestibulopathy with betahistine (BETAVEST), vestibular migraine with metoprolol (PROVEMIG), benign paroxysmal positional vertigo with vitamin D (VitD@BPPV), EA2 with 4-aminopyridine versus acetazolamide (EAT-2-TREAT), and cerebellar ataxias with acetyl-DL-leucine (ALCAT).Zur Pharmakotherapie von vestibulären Erkrankungen kommen im Wesentlichen folgende Wirkstoffgruppen zum Einsatz: Antivertiginosa, Antikonvulsiva, Antidepressiva, Antiphlogistika, Anti-Menière-wirksame Substanzen, Migräneprophylaktika, Aminopyridine (Kaliumkanalblocker) und Acetyl-DL-Leucin (eine modifizierte essenzielle Aminosäure). Die Behandlung des Symptoms Schwindel und der begleitenden vegetativen Beschwerden wie Übelkeit, Brechreiz oder Erbrechen sollte zeitlich stets begrenzt werden. Bei einem akuten einseitigen Vestibularisausfall verbessern Kortikosteroide die Erholung der peripher vestibulären Funktion, ohne ausreichende Evidenz für eine allgemeine Empfehlung.Für die Wirksamkeit von Betahistin (16 mg dreimal täglich oder 48 mg dreimal täglich) bei Morbus Menière gibt es bislang keine ausreichende Evidenz, ggf. sollten hierbei höhere Dosierungen angestrebt werden – insbesondere, da in tierexperimentellen Studien eine Verbesserung der Durchblutung des Innenohrs nachgewiesen wurde. Bei der Vestibularisparoxysmie sind Carbamazepin/Oxcarbazepin wahrscheinlich wirksam, es fehlen aber noch randomisierte kontrollierte Studien (RCTs) dazu. Bei der vestibulären Migräne gibt es bislang keine RCTs zur Wirksamkeit von Betablockern oder Topiramat, so dass hier aufgrund von klinischen Erfahrungen die Therapie in Analogie zur Migräne ohne Aura empfohlen wird.Aminopyridine werden für die Behandlung von Patienten mit Downbeat-Nystagmus (2 RCTs) und der episodischen Ataxie Typ 2 (EA2, 1 RCT) empfohlen. Die Wirksamkeit von Aminopyridinen wurde in tierexperimentellen und funktionellen Bildgebungsstudien evaluiert. Acetyl-DL-Leucin, eine modifizierte essenzielle Aminosäure, verbessert die klinischen Symptome der zerebellären Ataxie (bisher 3 Beobachtungsstudien). Nach tierexperimentellen Studien beschleunigt es auch die zentrale Kompensation vestibulärer Störungen; randomisierte klinische Studien dazu waren negativ. Derzeit werden die folgenden klinischen RCTs zu verschiedenen Erkrankungen durchgeführt: Vestibularisparoxysmie (Carbamazepin, VesPa), akute einseitige Vestibulopathie/Neuritis vestibularis (Betahistin, BETAVEST), vestibuläre Migräne (Metoprolol, PROVEMIG), BPPV (Vitamin D, VitD@BPPV), EA2 (Aminopyridin vs. Acetazolamid, EAT-2-TREAT) und zerebelläre Ataxien (Acetyl-DL-Leucin, ALCAT).

The approach to drug treatment of vertigo is almost exclusively symptomatic. There are 3 major goals for drug treatment of vertigo: to eliminate the hallucination of motion, to reduce the accompanying neurovegetative and psychoaffective signs (nausea, vomiting, anxiety), and to enhance the process of "vestibular compensation" to allow the brain to find a new sensory equilibrium in spite of the vestibular lesion. Three different types of vertigo drug treatment must be distinguished: the treatment of acute vertigo attacks, the treatment of chronic vertigo, and the treatment of patients with Menière's disease to avoid vertigo attacks. Furthermore, this paper deals with the treatment of motion sickness and of the postoperative nausea and vomiting.

In a time, in which more than 3 billion people (in a single year) use an airplane for long distance travels, the probability is very high that also patients with chronic neurologic diseases are passengers. In this review the essential aspects are described which a patient with Parkinson's disease, multiple sclerosis, epilepsy or after having suffered from a stroke has to take care for. The regularity of the intake of drugs and the problems in resorption of necessary drugs (cave traveller's diarrhea!) are emphasized.

Neuroleptics, antidepressants, mood stabilizers and anxiolytics are the most frequently prescribed drugs in psychiatric therapy. Their introduction came largely in the past five decades. This review summarizes the history that led to their discovery and introduction to the market in the 20th century.

Sleep Disorders are one of the most common complaints of patients seen by general practitioners. Prevalences vary considerably--depending on the kind of research and the definition of sleep disorders--between 4 and 40%. In 2000 the first grand nationwide survey was carried out in primary care settings [1]. 12.3% of the 17,928 questioned stated sleep disorders as the main reason for their consultation, the prevalence of all kinds of sleep disorders being 29%. Like seen in other studies sleep complaints increased with age and predominated significantly in women. In one-third of the sample the differential diagnosis was primary or non-organic insomnia [1] while treatment was mainly conducted by the general practitioner. In two-thirds of the patients sleep disorders existed for more than 12 months while 41%--by their own account--took sleep agents at least once a week. This article gives an overview of the causes and treatment of sleep disorders, particularly therapy of non-organic insomnia.

Headache is one of the most common reasons for a patient to consult the doctor. Of prime importance are the correct differential diagnosis and effective treatment. A differentiation is made between primary and secondary headache. In the international classification, the primary headache syndromes include migraine with and without an aura, tension type headache, headache associated with misuse of analgesics, cluster headache, and a number of rare forms of headache with no structural lesion. The secondary headache syndromes occur symptomatically as sequelae of underlying disease, the spectrum of causes covering more than 300 different disorders. In patients with headache of unclear genesis, careful history-taking and thorough physical examination should be followed by a further diagnostic work-up.

The extent of drug abuse in mass sport is only poorly documented. Studies about drug abuse investigated only the prohibited substances according to the Olympic movement antidoping code. So for instance about the use of anabolic androgenic steroids (AAS) by school children or young students. But only few investigations point to the drug abuse in mass sport regarding the easily accessible over-the-counter drugs of the class of nonsteroidal anti-inflammatory drugs (NSAID). These drugs permit an athlete to compete at his normal level of performance despite injuries or pain. However, the masking of pain may exacerbate the injury. Precautions should be taken to prevent the unwarranted or unmonitored use of anti-inflammatory agents during treatment of sport injuries. The abuse may be extensive since most people consider over-the-counter drugs, such as aspirin and ibuprofen, harmless. Studies in Switzerland among endurance athletes in mass sport examining the use of medications before an event showed a prevalence between 5 and 10% of NSAID. Even if this seems a small number, further investigations should focus on the use of medications among different age groups and preventive information to abstain from the use of certain medication for competitors in mass sport should be worked out.

In recent years, considerable progress has been made both in the diagnosis and treatment of dementia. Drugs have been developed which enhance cognitive performance in a large percentage of those afflicted, delay impairment of the ability to cope with the tasks of daily life, and avoid premature admission to a nursing home. In the practical medical care setting, however, these advantages are being utilized to only a limited extent, and this despite the fact that numerous therapeutic options are now available for the treatment of AD. New therapeutic approaches are aimed at inhibiting the pathological cleavage and extracellular and intracellular deposition of amyloid, preventing the toxic effects of amyloid accumulation around the neurons, and re-establishing intracellular transport deranged by the aggregation of neurofibrils. A further approach is the use of combinations of available substances with differing, possibly synergic, effects. Over and beyond this, treatment of AD in the "presymptomatic stage", or in the stage of only mild cognitive disturbance, is currently the subject of clinical trials.

All dementias had been suggested to be the result of a vessel-disease, now it is known that the greatest part belongs to the dementias of Alzheimer's type but furtheron there exists no possibility for curing or stopping. Since Ginkgo biloba extract is available it is used in this diagnosis. Experimental and clinical studies have shown a widespread possibility to act in this disease and even a neuroprotective potential can be postulated.

This article reviews new drugs and recent knowledge or indications for old drugs for the treatment of neurological disorders. Drugs for disorders such as migraine, epilepsy, Parkinson's disease, Alzheimer's disease, ischemic stroke, amyotrophic lateral sclerosis and multiple sclerosis are considered.

Handouts in their mother tongue might be helpful in informing patients who do not speak German about medications that are prescribed. A survey among 97 producers of CNS active drugs used in neurology and psychiatry showed that only two patient information leaflets on preparations and nine on specific disorders are available in Germany. The producers who answered were mostly open-minded and mentioned causes like the legal situation and logistic problems.

Demographic changes are dramatically increasing the importance of dementia disorders, and among them Alzheimer's disease (AD), which accounts for over 50% of age-associated dementias. Early diagnosis is important in order to detect reversible disorders and, on the other hand, to exploit newly available treatment options as soon as possible. For detection of dementia and differential diagnosis a two-step approach is advocated. Screening is carried out by the primary care physician, who refers the patient for differential diagnosis and thorough workup to a specialist or specialized institution, such as a memory clinic. Patient management is, as usual in geriatric medicine, a multidisciplinary task. The new therapeutic options make early diagnosis mandatory to ensure optimum benefit for the patient in Alzheimer's disease, which today can be diagnosed with sufficient accuracy. Vascular dementia, which is second to AD in frequency of occurrence, can best be prevented and treated by vigorous management of cardiovascular risk factors. In addition to drug treatment, psychotherapeutic approaches (particularly milieu therapy) help to keep patients in their accustomed setting for much longer and to alleviate the caregivers' burden.

Recent investigations have given new insights into pathogenetical determinants of Alzheimer's disease. Amyloid deposition and neurofibrillary tangles are no longer considered to be primary pathological changes. Neurobiological research tries to work out the etiopathogenital cascade that finally causes Alzheimer's disease. So far, several relevant pathogenetical factors have been detected, e.g. pertubated control of glucose breakdown, impairment of oxidative metabolism, impaired neuroprotection due to increased oxidative stress and non-enzymatic protein glycation as well as immunological disturbances. Thus, new strategies for the development of cognition-enhancing drugs are emerging. The authors review reports on agents, that are under investigation for the treatment of cognitive symptomatology in Alzheimer's disease. Some of these agents have already been used for treatment of other medical conditions, e.g. nimodipine, memantine as well as selegiline. Many of them are still experimental. Promising strategies include antioxidative agents (e.g. vitamin E, vitamin C, beta-carotin), acetylcholinesterase-inhibitors with central selectivity (e.g. ENA 713), M1- and M4-muscarinic receptor agonists (milameline) as well as sabeluzole, a benzothazide derivative that shows neurotrophic activities and anti-inflammatory substances like indomethacin.

Between 1984 and 1994 the legally required task force "Advisory Committee to the German Federal Health Office in Matters of Approval and Review of Existing Medicines B3-Psychiatry, Neurology, Anesthesiology" analyzed and evaluated the CNS-active compounds that until then had only possessed a fictitious registration. The evaluation was related to efficacy and safety within the indications claimed by the producers. Reviews and monographies had to be established for 445 basic compounds. One hundred positive and 30 negative monographies were published. "Negative" indicates that none of the claimed indications could be accepted by the committee. It is regrettable that the Federal Health Agency did not notice a considerable part of these negative evaluations until the present date. The process of the "Aufbereitung" was stopped abruptly by the 5th amendment of the German Drug Law in August 1994,--a very doubtful political decision with respect to drug safety in this country.

Sensory and motor symptoms of the limbs, motor restlessness and an urge to move only at rest are the characteristics of the restless legs syndrome (RLS), which often leads to severe sleep disturbances. The clinical diagnosis can be made on the basis of the typical history, normal neurological findings and, in some cases, a positive family history, and can be confirmed by polysomnography. The indication for treatment depends on the patient's discomfort and the severity of the sleep disturbances. L-DOPA is the treatment of first choice both in idiopathic and uremic RLS. A bedtime dose of 100-200 mg L-DOPA standard plus decarboxylase inhibitor is effective against mild and moderate sleep disturbances in RLS. Titration of the dosage and additional treatment with sustained-release preparations of L-DOPA should be applied individually. Opioids and dopamine agonists are effective alternative treatments in idiopathic RLS. Benzodiazepines are indicated only in individual cases. Besides L-DOPA, uremic RLS patients can be treated with opioids and benzodiazepines. Various approaches in the treatment of idiopathic and uremic RLS are reviewed and the practical management of therapy is outlined.

The amin- and phenyl substituted 6,8-dioxabicyclooctanes 10 and 11 show distinct CNS-activities. Intensity and profile depend on the type of amine and the stereochemistry of the products. Therefore, we have synthesized 6,8-dioxabicyclooctanes with different amine-phenyl distances and examined their CNS-activities on mice as well as by receptor binding studies with the PCP-binding site which is part of the NMDA-receptor-complex.

This paper deals with the synthesis and psychopharmacological effects of variations of the sedative and analgesic tricyclic amines 3a and 3b: Starting with the homochiral ketone 4 the amines 5 (primary amino group in equatorial position), 7 (axially oriented dimethylamino group), 9 (additional phenyl residue in position 7), 13b, and 14b (equatorially and axially arranged dimethylaminomethyl group) and 23 and 24 (axial amino group shifted to position 9) are prepared. BBr3 cleaves the phenolic ethers of the secondary amine (+/-)-3a to yield the aminodiphenol (+/-)-10. -Keeping mice under observation for behavioral anomalies (Irwin screen) and analgesic activity (writhing test) shows, that the amines 5, 7, 9, (+/-)-10, 13b, 14b, and 23 do not reach the sedative and analgesic effects of the amines 3a and 3b, described by us.

Under acidic conditions the secondary amines 10a and 10b, the primary amine 15, the amide 17a, and the urethane 17b were cyclized to yield the 2,6-epoxy-3-benzazocines 11a, 11b, 16, 18a and 18b, respectively. Ring closure of the inverse amide 5a, however, failed to give the tricyclic N/O-acetal 6. With LiAlH4 the epoxy bridge of the urethane 18b was opened to afford the bicyclic 3-benzazocine 20. While the N-(2-methoxyethyl) derivative 11b did not influence the behaviour of mice, the N-methyl derivative 11a showed strong central effects.

The butadiene derivatives 10a-c react with the oxa-bicyclooctanone 9 to give the cyclohexene annulated oxatropanes 11a-c. The acetoxyderivatives 11b and 11c can be transformed into the cyclohexadiene or benzene derivatives 13 and 12, respectively. 11a reacts with HN3 to afford the tricyclic oxazepanone 14 which can be reduced to give 15a; the oxime-tosylate 16b reacts with Al(CH3)3/DIBALH to yield the oxazepane 15c. Treatment of the oxabicyclooctanes 9 and 19 with benzonitrile oxide or diazomethane affords the isoxazoline or pyrazoline annulated oxatropanes 21, 22, and 20, respectively. 21 was reduced to the amino alcohol 23. 15c and 23 show CNS-activity in the mouse.

Reaction of the 8-oxabicyclooctenone and -octanone derivatives 3 and 4 with aniline and metal hydrides yields the 3 alpha-isomers of the aniline derivatives 7 and 8, preferably. The configuration can be determined by NMR-spectroscopy and by cyclization to the scopoline analogue 9b. Depending on the N-substitution the pyran rings of the alpha-isomers are flattened (7,8) or deformed to give a boat conformation (10,11,13). The conformationally restricted aniline derivative 18 can be obtained from 4 with 2-aminobenzaldehyde and diborane, trans-configuration is preferred in 18. Some substrates reveal CNS-effects in mice.

The tricyclic hemiacetal 1 is transformed with amines to the N/O-acetals 3 and 10, with nitromethane to the 4-nitromethyl derivative 13, and with the Wittig reagents 15a and 15b to the 2-benzopyrans 16 and 19. Reduction and methylation of 13 yield the tertiary amine 4; through three steps the secondary amine 18 and the tertiary amine 5 are prepared from 16 and 19, respectively. The 1,3-dioxane ring of all these 2,6-epoxy-3-benzoxocine derivatives exists in the chair conformation with an equatorial C-4 substituent. After application of the amines 5, 11c, and 18 mice do not show any symptoms of central activity; weak CNS-effects are observed with the alcohols 1 and 2. For the tertiary amine 4, which causes considerable central effects (Straubtail-phenomenon, convulsions, etc.), an ED50 of 78 mg/kg is determined in the mouse "writhing"-test.

The 2-(2-Bromophenyl)-acetaldehyde acetals 8 are treated with n-BuLi and the aldehydes 7 and 11 to form the hydroxyacetales 9 and 12, respectively. 9 is cyclized under acidic conditions to the epoxybenzoxocine 2; analogously 12 yields the epoxydibenzoxocine 14.

The synthesis of 9,10-epithio-9,10-dihydroanthracenes is presented. Since the direct synthesis from benzo[c]thiophene and dehydrobenzene was not possible, benzo[c]thiophene and 1,4-benzoquinone were reacted by means of Diels-Alder cyclization to 9,10-epithio-1,4,9,10-tetrahydro-1,4-dioxoanthracene, which we intended to convert into 9,10-epithio-9,10-dihydroanthracene after intermediate transfer to suitable derivatives. The configurations at the connection points 4a and 9a of the partly or completely hydrogenated derivatives in one ring were ascertained, as were those in positions 1 and 4, Sp2-hybridisation of both the C-atoms 4a and 9a resulted in the elimination of the sulphur atom.

Hemispheric and regional cerebral blood flow were measured in 448 patients before and after application of various drugs. Of the tested substances, only a few affected hCBF: ephedrine-xanthines decreased hCBF, and midodrine, proxazole, vincamine, hexobendine, extract of ginkgo biloba, dextran, dextran-sorbitol, carboanhydrase inhibitor, and ouabain incresaed hCBF. In the rCBF maps different reaction patterns of regional flow were observed which were statistically tested by regression analysis. Homogeneous responses were seen as diffuse increases or decreases of rCBF. Heterogeneous responses occurred when perfusion of pathologic and normal areas reacted differently. An increase in rCBF in well-perfused areas with a shunt of blood from poorly supplied areas (intracerebral steal) was observed only with central vasodilators during the first days after an attack. Inverse cerebral steal phenomena with improvement of perfusion in the focus and decrease of flow in the surrounding brain may be elicited by different mechanisms. The effectiveness of drugs on cerebral circulation can be tested by measuring rCBF, but their therapeutic value for the treatment of patients with cerebrovascular disease must be shown in controlled clinical trials.

Most sleep disturbances (burring those occurring in the scope of acute psychoses) can be treated ambulatory. In chronic and syndromatic sleep disturbances it is recommended to carry out an intensive (cure type) therapy with i.v. infusions. After 10-20 infusions (antidepressants, neuroleptics, tranquilizers), slowly a transfer is made to peroral treatment where the preparations are incrementally lowered and withdrawn (to prevent rebound phenomena). An acceptable hypnoticum finalizers treatment. Numerous alternative therapy plans are explained.

With respect to the enhancing effect of nootropics on learning and memory, the influence of some of these drugs on the high affinity choline uptake has been investigated. Meclofenoxate competes with choline uptake in vitro because of its similar side chain; other nootropics are without in vitro effects. A single dose of pramiracetam enhances the choline uptake in cortex and hippocampus. Application of meclofenoxate decreases the uptake of choline. Other nootropics lack acute effects. Possible increases of uptake after repeated dosage disappear within 24 h.

The synthesis of tinofedrine (I), (+)-(R)-alpha-((S)-1-[3,3-di-3-thienylallyl)amino]benzylalcohol, a new cerebrally active drug, and the verification of its structure by spectrometric methods are reported.

N-substituted analogs of 3,4-methylenedioxyphenylisopropylamine (MDA) were tested ror analgesic potency and influence on motor activity in mice following potency and influence on motor activity in mice following oral administration. These compounds also were tested for thei psychotomimetic potency in man. Unsubstituted MDA and its monoalkyl-homologs with a low number of C-atoms (N-methyl-, N-methyl-, N-ethyl-MDA) showed both enhancement of motor-activity in mice and psychotomimetic effects in man. MDA and N-methyl-MDA also showed an analgesic effec wthich was enhanced by the inclusion of a weakly labis group (N-mallyl, N-hydroxyethyl). These latter two compounds, however, did not influence motor-activity, which makes them more recommendable as possible analgesic compounds. Structural parallels between these compounds, morphine, endorphins and enkephalins, may explain their similar spectrum of pharmacological effects.

As a continuation of our efforts on the synthesis of 9,10-epoxy-9,10-dihydroanthracene compounds with basic side chain several substituted 9-amino-methyl derivatives have been prepared by Diels-Alder cyclization of substituted benzo[c]furanes with benzyne. The benzo[c]furanes were obtained by vacuum flash thermolysis of 1,4-epoxy-1,2,3,4-tetrahydronaphthalene-1-carbonamides which were produced by Diels-Alder reaction of 2-furan-carbonamides with benzyne and by subsequent hydrogenation.

It is reported on the most important disease as a sequel of the intake of central-effective pharmaca (sedatives, hypnotics antiepileptics, analgesics and psychopharmaca). Psychopathological and neurological syndromes are described in detail.

The authors deal with the synthesis of 3-substituted 6,7-dimethoxy-1-thiaisochroman-1,1-dioxide and 3,4-dihydro-6,7-dimethoxy-2H-1,2-benzothiazine-1,1-dioxide derivatives. The compounds in the first-named group were found to exert effects on the central nervous system, those produced by the basic amides being particularly marked, which differ from those of currently used psychopharmacological agents.