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The Food and Drug Administration has that "sponsors should enroll participants who reflect the characteristics of clinically relevant populations". Recent reports have noted that global Alzheimer's Disease trials have enrolled predominantly White subjects. However, a thorough analysis of industry-sponsored, United States-only Alzheimer's trials has yet to be performed. A search of the clinicaltrials.gov database and PubMed identified 101 industry-sponsored Alzheimer's trials, performed solely in the United States, with gender data. The percentage of male (46%) vs. female (54%) subjects was higher than expected compared to real-world data. There were 50 Alzheimer's trials with race data. There was a significant overrepresentation of White subjects (92%) compared to all other race groups. These data suggest that significant modifications of subject recruitment methods are needed to increase the enrollment of underrepresented populations into Alzheimer's trials of potential new therapeutic agents in the United States.

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We have identified a migraine locus on chromosome 19p13.3/2 using linkage and association analysis. We isolated 48 single-nucleotide polymorphisms within the locus, of which we genotyped 24 in a Caucasian population comprising 827 unrelated cases and 765 controls. Five single-nucleotide polymorphisms within the insulin receptor gene showed significant association with migraine. This association was independently replicated in a case-control population collected separately. We used experiments with insulin receptor RNA and protein to investigate functionality for the migraine-associated single-nucleotide polymorphisms. We suggest possible functions for the insulin receptor in migraine pathogenesis.

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Migraine is a common neurological disease with a major genetic component. Recently, it has been proposed that a single locus on chromosome 19p13 contributes to the genetic susceptibility of both rare familial hemiplegic migraine (FHM) and more common types of migraine, migraine with aura and migraine without aura. We analyzed 16 families for co-segregation of migraine with aura and chromosome 19p13 markers. Using multipoint model-free linkage analysis, we obtained a lod score of 4.28 near D19S592. Using an affecteds-only model of linkage, we observed a lod score of 4.79 near D19S592. We were able to provide statistical evidence that this locus on chromosome 19p13 is most likely not the gene CACNA1A, mutations in which cause FHM. These data indicate that chromosome 19p13 contains a locus which contributes to the genetic susceptibility of migraine with aura that is distinct from the FHM locus.

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The Internet is capable of providing an unprecedented amount of information to both physicians and patients interested in headache. To assess the status of headache information on the Internet (as of January 2000), a search for 'headache' was performed using 10 leading Internet search engines. The number of web pages identified ranged from 4419 (WebCrawler) to 506 426 (Northern Light). The 'average' search yielded nearly 150 000 web page listings for 'headache'. The content was then reviewed of the top 10 listed web pages for each search (i.e. a total of 100 page listings). The results demonstrate that, at the present time, Internet-based information on headache is extensive but poorly organized. Editorial review of this potential valuable resource is required in order to maximize its utility in headache education and management.

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The clinical utility of genotyping individuals for apolipoprotein E alleles remains controversial. The present summary reviews clinical and scientific data that suggest that vitamin E supplementation may be beneficial in individuals who carry the apolipoprotein E4 allele. We propose that early anti-oxidant intervention with vitamin E supplementation may have life-long beneficial effects for individuals who carry one or more apolipoprotein E4 alleles.

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Chronic fatigue disorders are characterized by a subjectively defined group of symptoms such as chronic fatigue, mental confusion, exertional malaise, weight changes, and/or diffuse multi-joint pains. Significant clinical overlap exists between chronic fatigue disorders and the syndrome of serum inappropriate anti-diuretic hormone (SIADH). Both chronic fatigue disorders and SIADH are characterized by lethargy and mental confusion. Both disorders can be induced or exacerbated by viral illnesses, physical exertion, emotional stress and/or hypotension. Both can be treated with salt loading and glucocorticoids. Therefore, altered water metabolism resulting from inappropriate release and/or response to arginine vasopressin (AVP) is proposed as a pathophysiological basis of certain chronic fatigue disorders. Moreover, these data suggest that salt loading and/or direct inhibition of AVP may be an effective therapeutic approach in individuals with chronic fatigue disorders.

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Evolutionary analysis of neurotransmitter receptor systems has previously focused on interspecies differentiation. Recently, emphasis has shifted to intragenic evolution within a single species and the functional relevance associated with intraspecies variations. For example, multiple polymorphisms have been identified within the human dopamine D2 receptor (DRD2) gene, many of which have been used in clinical association studies. In an attempt to evaluate the intragenic evolution of the DRD2 gene, genotypes from 116 humans were determined using five biallelic markers which reside within a 30 kb span of the DRD2 gene, that are non-polymorphic in other higher order primates. Only seven different haplotypes, out of a theoretical maximum of 32, were present in the study group of 232 chromosomes. Moreover, five of the seven haplotypes accounted for 99% (n = 230/232) of the human haplotypes. A phylogenetic tree was generated from the haplotypic data using a maximum parsimony algorithm. The relationship of the haplotypes within the phylogenetic tree is consistent with a progressive step-wise nucleotide conversion within the human gene. These data indicate that specific haplotypic subtypes of the human DRD2 gene exist within the human population and allow for the possibility that functional differences may exist between the DRD2 subtypes. Therefore, future studies focused on a functional analysis of the entire human DRD2 haplotype, as opposed to individual polymorphisms, may provide important insights into the functional relevance of molecular variations within the human DRD2 gene.

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The presence of mRNAs for dopamine receptor subtypes and dopamine transporter in rat peripheral sensory and sympathetic ganglia was investigated using polymerase chain reaction (PCR) and DNA sequencing. Dopamine D1, D2, D3, D5 receptor subtype mRNAs and dopamine transporter mRNA were detected in both superior cervical sympathetic ganglia (SCG) and dorsal root ganglia (DRG) in the rat; the expression of D4 mRNA was only detected in DRG. While two alternatively spliced isoforms of D2 were detected in both ganglia, the alternative splicing transcripts for D3 and D4 were only found in the DRG. These results are useful in further studying the roles of dopamine and the effects of dopaminergic agents in the peripheral nervous system.

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Rapid technological advances in the field of molecular genetics are being applied successfully to the analysis of migraine. Specific mutations leading to an increased risk of rare forms of migraine have been identified in both mitochondrial DNA and a calcium channel gene. Association studies have demonstrated that polymorphic variations in serotonergic and dopaminergic genes may alter the clinical susceptibility to migraine. Massive amounts of additional genetic data relating to migraine will be generated in the next few years. These data are revolutionizing the diagnosis and management of migraine, a heretofore subjective clinical disorder.

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The past decade has seen significant advances in both the scientific and clinical understanding of migraine. At present, a considerable body of data indicates that migraine is characterized by at least three major pathophysiological features: dopaminergic hypersensitivity, inflammation, and relatively "low" 5-HT levels. Clinically, blocking dopamine receptors, reducing inflammation, and/or stimulating a subpopulation of 5-HT1 receptors are effective monotherapeutic approaches in many migraineurs. However monotherapeutic approaches to migraine do not provide rapid, consistent, and complete relief in all migraineurs. Therefore, if monotherapy is suboptimal, it follows logically that concurrent therapy (ie, polytherapy) aimed at modulating two or three of the biological systems should be more efficacious than modulating only a single system. The rationale for the combination use of dopamine antagonists, anti-inflammatory agents, and 5-HT1 agonists are described in the present report.

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BACKGROUND: Unrelated individuals (n = 242) were interviewed directly for the presence of migraine, anxiety disorders, and major depression. MATERIALS AND METHODS: The data described in this study are derived from a clinical genetic relational database that was developed initially for the genetic analysis of migraine. Genotyping of the DRD2 NcoI C to T polymorphism located in exon 6 (His313His) was performed using previously described primers. RESULTS: A significantly increased incidence of migraine with aura (MWA), major depression, generalized anxiety disorder (GAD), panic attacks, and phobia was observed in individuals with the DRD2 NcoI C/C genotype compared with individuals with an DRD2 NcoI T allele. Specifically, 69% (91/131) of DRD2 NcoI C/C individuals in the present study met criteria for at least one of these neuropsychiatric disorders versus only 22% (4/18) of the DRD2 NcoI T/T individuals (Chi-square = 15.29; p < 0.00005). The DRD2 NcoI C allele frequency is significantly higher (Chi-square = 17.13; p < 0.00002) in individuals with MWA, anxiety disorders, and/or major depression (C allele frequency = 0.80) than in individuals who have none of these disorders (C allele frequency = 0.67). CONCLUSIONS: These data indicate that MWA, anxiety disorders, and major depression can be components of a distinct clinical syndrome associated with allelic variations within the DRD2 gene. Clinical recognition of this genetically based syndrome has significant diagnostic and therapeutic implications.

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This review describes a novel genetic approach to the assessment of receptor function that is based on association studies of polymorphisms within human genes. The realization that variations within human genes may significantly affect gene function has led to increased use of this approach in recent years. Analysis of polymorphisms within the human 5-HT2A receptor is used as a specific example of the application of association genetics to elucidate gene function. The interaction of many neuroleptics and antidepressants with 5-HT2A receptors points up the potential importance of this receptor for understanding and treating neuropsychiatric disorders such as schizophrenia and depression.

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Although serotonin has been shown to play an important role in peripheral pain mechanisms, the specific subtypes of serotonin receptors involved in pain and hyperalgesia remain poorly understood. To date, no previous study has attempted to determine the presence of any serotonin receptor subtype in human dorsal root ganglia. In this study, the presence of messenger RNA for eight human serotonin receptor subtypes in lumbar dorsal root ganglia was detected using the method of polymerase chain reaction. Dorsal root ganglia were excised post mortem from four patients. Oligonucleotide primers were chosen based on unique regions of complimentary DNA sequence for eight cloned human serotonin receptor subtypes (i.e. 5-HT1A, 5-HT1D alpha, 5-HT1D beta, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2C and 5-HT7). The presence of 5-HT1D alpha, 5-HT1D beta, 5-HT1E, 5-HT1F, 5-HT2A and 5-HT7 receptor subtype messenger RNA was detected in dorsal root ganglia from three of the four subjects. 5-HT1A receptor subtype messenger RNA was detected in one of the four subjects. No 5-HT2C receptor subtype messenger RNA could be detected. Findings from this study may direct further efforts to determine the role of serotonin receptors in the peripheral nervous system.

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This review summarizes a growing body of biological, pharmacologic, and genetic data that support a role for dopamine in the pathophysiology of certain subtypes of migraine. Most migraine symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Conversely, dopamine receptor antagonists are effective therapeutic agents in migraine. Recent genetic data suggest that molecular variations within dopamine receptor genes play a modifying role in the pathophysiology of migraine with aura. Therefore, modulation of dopaminergic neurotransmission should be considered in the therapeutic management of migraine.

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Migraine has a major genetic component. Although most recent scientific studies have focused on the role of 5-hydroxytryptamine and neuropeptides in migraine, dopaminergic systems are also implicated in the pathogenesis. Therefore, the dopamine D2 receptor (DRD2) was analyzed as a candidate gene since antagonists of this receptor have been reported to be effective in the acute treatment of migraine. Individuals with migraine with aura (n = 52) have an increased frequency (0.84) of the DRD2 NcoI C allele (chi-square = 6.47; p < 0.005) compared with control individuals (n = 121; C allele frequency = 0.71). Individuals with migraine without aura (n = 77) showed the same DRD2 T allele frequency (0.70) as the control group. Migraine with aura was present in 27% of the C/C individuals, 16% of the C/T individuals, and 5.2% of the T/T individuals. These data suggest that activation of the DRD2 receptor plays a modifying role in the pathophysiology of migraine with aura. As a result, these data provide a molecular rationale for the documented efficacy of DRD2 antagonists in the treatment of migraine with aura.

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Migraine is known to have a major genetic component and has been associated with a wide variety of comorbid disorders including arthritis and heart disease. Since migraine and some of its comorbid disorders involve inflammation, complement C3, a protein involved in acute inflammation, was selected for analysis as a candidate gene in an ongoing study of the genetic basis of migraine. Polymorphism frequencies for complement C3F (0.19) and C3S (0.81) in a sample of 137 unrelated migraineurs were found to be consistent with a control group as well as previous population studies, indicating that this common polymorphism has no association with migraine susceptibility. However, C3F positive individuals with migraine were found to have an increased incidence of osteoarthritis (Chi square = 10.06; p < 0.0008) and hypertension (Chi square = 5.18; p < 0.01). Therefore, the data in the present study indicate that certain migraine comorbidities that have been reported in the literature may result from Berkson's bias as opposed to a shared pathophysiological variation in the C3 gene.

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The long anticipated 'genetic revolution' in neuropsychiatry has yet to have an impact on the practice of clinical medicine. Excitement in the 1980s over major genetic breakthroughs in schizophrenia and manic depression, for example, has been replaced in the late 1990s by the sobering realization that most common neuropsychiatric disorders are multifactorial. Despite considerable effort and resources, no 'causative' genetic variation has been identified that plays a definitive major role in any common neuropsychiatric disorder.

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2-[5-[[(trifluoromethyl)sulfonyl]oxy]-1H-indol-3-yl]ethylamine (18), its N,N-di-n-propyl (12), N,N-diethyl (13), and N,N-dimethyl (14) derivatives, and 4-[3-[2-(N,N-dimethylamino)ethyl]-1H-indol-3-yl]-N-(p-methoxybenzyl) acrylamide (GR46611, 19) were synthesized and tested for binding affinities to cloned 5-HT1A, 5-HT1D alpha, 5-HT1D beta, and D2 receptors. In addition, the intrinsic efficacy was measured as the reduction of forskolin-stimulated cAMP in cells transfected with 5-HT1D alpha and 5-HT1D beta receptors in vitro. The 5-substituted indolyethylamines investigated displayed agonist activity at the 5-HT1D receptors with varying degrees of preference for the 5-HT1D alpha vs the 5-HT1D beta receptors. The primary amine and N,N-dimethyl substitution seemed to be optimal for 5-HT1D alpha affinity. Furthermore, the N,N-diethyl (13) and N,N-dimethyl (14) derivatives showed a 10-25 times preference for the 5-HT1D alpha vs the 5-HT1D beta receptor. In addition, all of the novel compounds showed affinity for the 5-HT1A receptor in vitro (Ki values ranging from 18 to 40 nM). The most promising derivative 14 was virtually devoid of central 5-HT1A agonist activity in rats, as determined by in vivo biochemical assays. Paradoxically, 14, like 19, induced a hypothermic response and a decrease in 5-HIAA levels in the prefrontal cortex and hypothalamus in guinea pigs after systemic administration. Sumatriptan failed to produce either of these effects due to a poor brain penetration.

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BACKGROUND AND OBJECTIVES: Sumatriptan is a novel drug for migraine headache pain, which, on the basis of its mechanism of action, may have therapeutic potential in other pain states. Sumatriptan inhibits neurogenic inflammation in dural vessels by activating the 5-HTIB and 5-HTID inhibitory serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes on terminals of trigeminal neurons. This study was designed to determine the role of sumatriptan in peripheral pain mechanisms by detecting whether 5-HTIB and 5-HTID receptors and the recently cloned excitatory 5-HT7 receptor, for which sumatriptan displays moderate binding affinity, are present in peripheral sensory neurons, and by determining the effect of sumatriptan on peripheral neurogenic inflammation. METHODS: A polymerase chain reaction (PCR) technique was used to detect mRNA for 5-HT receptors in rat lumbar dorsal root ganglia. Rat knee joint plasma extravasation was used to determine the effect of sumatriptan on peripheral neurogenic inflammation. RESULTS: The mRNA for the sumatriptan-activated receptors 5-HTIB, 5-HTID, and 5-HT7, was detected in lumbar dorsal root ganglia. In rat knee joint, capsaicin-activated C-fibers stimulated plasma extravasation to 273 +/- 62% of baseline. Low-concentration sumatriptan (50 nM) significantly inhibited capsaicin-induced plasma extravasation to 106 +/- 6% of baseline. High-concentration sumatriptan (1 microM) significantly enhanced capsaicin-induced plasma extravasation to 572 +/- 55% of baseline. CONCLUSIONS: Sumatriptan inhibits peripheral neurogenic inflammation, probably via 5-HT1B/1D receptors, and may be a novel therapy for inflammatory pain states. However, high concentrations (> 200 nM) may enhance neurogenic inflammation, possibly by activation of 5-HT7 receptors, which may explain lack of migraine relief and excessive injection site pain in 20-30% of patients treated with sumatriptan.

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