Osmophobia in allodynic migraineurs: cause or consequence of central sensitization?

Migraine is a primary headache characterized by recurrent attacks of head pain associated with nausea or vomit, photophobia, phonophobia and osmophobia. The presence of osmophobia during migraine attacks seems to be a very specific complaint. Cutaneous allodynia (CA) is very common in migraineurs, and it is the most evident clinical manifestation of central sensitization, a mechanism involved in migraine chronification. This study was aimed at identifying the possible correlation between osmophobia and CA in migraineurs. 673 migraineurs were studied (492 episodic, 181 chronic). The prevalence of both CA and osmophobia was higher in chronic than in episodic migraineurs. The association between these two symptoms was significant in chronic migraineurs at Chi square test. The highlighted relationship between CA and osmophobia may be interpreted in different ways: central sensitization induced by recurrent pain stimulation may in parallel induce a distortion of both cutaneous sensitivity (CA) and olfaction (osmophobia); alternatively, the recurrent olfactory stimulation in subjects with a hypersensitivity to olfactory stimuli may co-work with repetitive pain stimulation to induce the central sensitization process.

Negative emotions in migraineurs dreams: the increased prevalence of oneiric fear and anguish, unrelated to mood disorders.

BACKGROUND: Migraineurs brain has shown some functional peculiarities that reflect not only in phonophobia, and photophobia, but also in mood and sleep. Dreaming is a universal mental state characterized by hallucinatory features in which imagery, emotion, motor skills, and memory are created de novo. We evaluated dream contents and associated emotions in migraineurs. MATERIALS AND METHODS: 412 subjects: 219 controls; and 148 migraineurs (66 with aura, MA; 82 without aura, MO), and 45 tension type headache patients (TTH). A semistructured retrospective self-reported questionnaire was used to evaluate dreams. The Generalized Anxiety Disorder Questionnaire (GAD-7), and the Patient Health Questionnaire (PHQ-9) were administered to evaluate anxiety and depression. RESULTS: Migraineurs showed increased levels of anxiety (P = 0.0002 for MA versus controls, P = 0.004 for MO versus controls). Fear and anguish during dreaming were more frequently reported by migraine patients compared to controls, independently by anxiety and depression scores. DISCUSSION: The brain of migraineurs seems to dream with some peculiar features, all with a negative connotation, as fear and anguish. It may be due to the recorded negative sensations induced by recurrent migraine pain, but it may just reflect a peculiar attitude of the mesolimbic structures of migraineurs brain, activated in both dreaming and migraine attacks.

Is the brain of migraineurs "different" even in dreams?

Migraineurs brain is hyper-excitable and hypo-metabolic. Dreaming is a mental state characterized by hallucinatory features in which imagery, emotion, motor skills and memory are created de novo. To evaluate dreams in different kinds of headache. We included 219 controls; 148 migraineurs (66 with aura-MA, 82 without aura-MO); 45 tension type headache (TTH) patients. ICHD-II diagnostic criteria were used. Ad hoc questionnaire was used to evaluate oneiric activity. The Generalized Anxiety Disorder Questionnaire, and the Patient Health Questionnaire were administered to evaluate anxiety and mood. The prevalence of dreamers was similar in different groups. Frequency of visual and auditory dreams was not different between groups. Migraineurs, particularly MA, had an increased frequency of taste dreams (present in 19.6 % of controls, 40.9 % of MA, 23.2 % of MO, 11.1 % of TTH, p < 0.01), and of olfactory dreams (present in 20 % of controls, 36 % of MA, 35 % of MO and 20 % of TTH, p < 0.01). Anxiety and mood did not influence these results. The increased frequency of taste and olfactory dreams among migraineurs seems to be specific, possibly reflecting a particular sensitivity of gustative and olfactory brain structures, as suggested by osmofobia and nausea, typical of migraine. This may suggest the role of some cerebral structures, such as amygdala and hypothalamus, which are known to be involved in migraine mechanisms as well in the biology of sleep and dreaming.

Effectiveness of diclofenac eyedrops in reducing inflammation and the incidence of cystoid macular edema after cataract surgery.

PURPOSE: To evaluate the effectiveness of diclofenac eyedrops in reducing inflammation and the incidence of angiographic cystoid macular edema (CME) after cataract surgery and intraocular lens (IOL) implantation. SETTING: Eye Clinic, Institute of Biomedical Sciences, San Paolo Hospital, Milan, Italy. METHODS: Eighty-eight patients having cataract extraction were enrolled in a randomized clinical trial: 42 were given diclofenac eyedrops and 46, placebo. Postoperative inflammation in both groups was graded for 6 months using a dedicated system. RESULTS: Eight patients (9%) had evidence of angiographic CME approximately 1 month after surgery: seven of these were in the placebo group (P = .039). This difference was not significant 3 and 6 months postoperatively. The signs of ocular inflammation were greater in the eyes receiving placebo; the difference was particularly evident up to 1 week after surgery. There was no significant difference in visual acuity between the two groups at any follow-up point, but the contrast sensitivity of the eyes that received diclofenac improved significantly at 10.5 cycles per degree 1 month postoperatively. CONCLUSION: Diclofenac eyedrops effectively reduced ocular inflammation and the occurrence of angiographic CME after cataract surgery.

Stereoselective pharmacokinetics of moguisteine metabolites in healthy subjects.

We studied the pharmacokinetics of moguisteine, a racemic non-narcotic peripheral antitussive drug, in 12 healthy male subjects after a single oral administration of 200 mg. The unchanged drug was absent in plasma and urine of all subjects. Moguisteine was immediately and completely hydrolyzed to its main active metabolite, the free carboxylic acid M1. Therefore, we evaluated the kinetic profiles of M1, of its enantiomers R(+)-M1 and S(-)-M1, and of M1 sulfoxide optical isomers M2/I and M2/II by conventional and stereospecific HPLC. Maximum plasma concentrations for M1 (2.83 mg/l), M2/I (0.26 mg/l) and M2/II (0.40 mg/l), were respectively reached at 1.3, 1.6 and 1.5 h after moguisteine administration. Plasma concentrations declined after the peak with mean apparent terminal half-lives of 0.65 h (M1), 0.88 h (M2/I) and 0.84 h (M2/II). Most of the administered dose was recovered in urine within 6 h from moguisteine treatment. The systemic and renal clearance values indicated high renal extraction ratio for all moguisteine metabolites, and particularly for M1 sulfoxide optical isomers. Plasma concentration-time profiles and urinary excretion patterns for M1 enantiomers R(+)-M1 and S(-)-M1 were quite similar. Thus, for later moguisteine pharmacokinetic evaluations the investigation of the plasma concentration-time curve and the urinary excretion of the sole racemic M1 through non-stereospecific analytical methods may suffice in most cases.

Assay of moguisteine metabolites in human plasma and urine: conventional and chiral high-performance liquid chromatographic methods.

Moguisteine is a novel peripheral non-narcotic antitussive agent. Pharmacokinetic studies in animal and in man showed that no unchanged drug is present in plasma, urine and faeces after oral administration. The main active metabolite, M1, is the free carboxylic acid of moguisteine, which maintains a stereogenic centre and consists of R(+)-M1 and S(-)-M1 enantiomers. M1 is partly metabolized to M2, its sulfoxidation derivative. A conventional HPLC method is described for the simultaneous determination of M1 and M2 in human plasma and urine after administration of therapeutic moguisteine doses. Plasma samples, previously acidified with phosphoric acid, are extracted with dichloromethane; urine samples are analyzed after appropriate dilution with methanol. Chromatography is performed using a Lichrosorb RP2 column and a linear gradient. M1 enantiomers can be determined in plasma extracts and urine samples by a chiral HPLC method using a beta-cyclodextrin column. The analytical characteristics of both HPLC procedures proved to be adequate to analyze samples of subjects treated with therapeutic doses of moguisteine during clinical pharmacokinetic studies.

Direct HPLC separation of enantiomers of main moguisteine metabolite: comparison of different stationary phases.

Moguisteine is a new non-narcotic antitussive agent. The molecule contains a chiral centre, which is maintained in the metabolite structure. The unchanged drug is not found in the plasma of treated animals or humans. The main moguisteine metabolite, M1, is the free racemic acid generated by hydrolysis of the ethyl-ester group of moguisteine. HPLC separation of M1 enantiomers was attempted using various chiral stationary phases. Separation of the enantiomers was achieved with alpha-1-AGP and beta-cyclodextrin columns, which showed similar enantioselectivity and good resolution. However, the routine application of alpha-1-AGP columns turned out to be difficult, due to the limiting low flow rate which displayed baseline problems and progressive loss of resolution. beta-Cyclodextrin columns showed greater efficiency than alpha-1-AGP columns, as the former allows reproducible separation and can easily be applied to biological sample analysis in pharmacokinetic studies.

Influence of glutathione administration on the disposition of free and total platinum in patients after administration of cisplatin.

The kinetics of platinum (Pt) was studied in 12 patients suffering from non-small-cell lung cancer or pleural mesothelioma. Each subject received an infusion of cisplatin (CDDP, 80 mg/m2), and six patients were pretreated with glutathione (GSH, 2.5 g given i.v.) at 15 min prior to the cisplatin infusion. After a 3- to 4-week interval, all patients were given a second course of treatment on the same schedule. A biexponential model was fitted to plasma concentrations of total and ultrafilterable Pt. The excretion of Pt in urine was evaluated during the first 48 h after the CDDP infusion. Following the administration of CDDP alone or with GSH pretreatment, the pharmacokinetic parameters of Pt did not significantly differ between the treatments. Also, the unbound fraction determined at each sampling time did not vary significantly between the treatments. However, it is noteworthy that the mean values obtained for the terminal half-life, the volume of distribution, the renal clearance, the percentage of the dose excreted in the urine, and the mean residence time of total Pt were higher in patients who had been pretreated with GSH, suggesting that GSH might increase both the rate of Pt elimination and the extent of Pt distribution and, as a consequence of the latter, might prolong the residence time of Pt in the body. In addition, the unbound fraction of Pt from the 4th to the 48th was higher following the first dose of CDDP+GSH than after treatment with CDDP alone. Because of the rather high variability in the values of the parameters obtained, further work is planned using a larger number of patients.

First dose and steady state pharmacokinetics of nimesulide and its 4-hydroxy metabolite in healthy volunteers.

The pharmacokinetics of nimesulide (4-nitro-2-phenoxymethane-sulfonanilide, NMS), a non-steroidal antiinflammatory drug, and of its 4-hydroxy metabolite (4-nitro-2-(4'-hydroxy-phenoxy)-methane sulfonanilide, OH-NMS) was studied after a single oral dose (200 mg) and after repeated treatments (100 mg every 12 hours for 7 days) of NMS to two groups of 12 healthy volunteers. Plasma concentrations of NMS and OH-NMS were followed for 48 hours after the single dose and up to the 12th hour on the 1st day and on the 7th day during repeated treatment. After the single dose of 200 mg peak plasma concentrations of the drug (9.85 micrograms/ml) were reached at 3.17 hours and the half-life during the elimination phase was 4.95 hours. The metabolite reached highest plasma levels (3.03 micrograms/ml) at 5.33 hours and its apparent half-life was similar to that of the parent drug (4.78 hours). NMS plasma levels on the 7th day, predicted from the results of the 1st day, were similar to the measured values. The pharmacokinetics of NMS or OH-NMS after single or repeated dose was not time or dose dependent.

Dose-response decrease in plasma tryptophan and in brain tryptophan and serotonin after tryptophan-free amino acid mixtures in rats.

Rats fasted 15 hours were treated p.o. with increasing amounts (660 and 1320 mg/kg body weight) of a mixture containing a fixed proportion of seven essential amino acids (L-phenylalanine 13.6%, L-leucine 6.0%, L-isoleucine 12.1%, L-methionine 12.1%, L-lysine 30.3%, L-threonine 10.6%, L-valine 15.2%) and lacking tryptophan. The mixtures produced a dose-response decrease of free (by 34% after the lower dose and by 58% after the higher dose of the mixture) and total (by 10 and 31%) plasma tryptophan and of brain tryptophan (by 38 and 65%), serotonin (by 17 and 41%) and 5-hydroxyindole acetic acid (by 21 and 49%). The mechanisms of these changes are discussed.

Decrease in plasma tryptophan after tryptophan-free amino acid mixtures in man.

Male healthy subjects, fasting 12 hours, ingested increasing amounts of a mixture containing a fixed proportion of seven essential amino acids (L-isoleucine 11.5%, L-leucine 18.0%, L-lysine 13.1%, L-methionine 18.0%, L-phenylalanine 18.0%, L-threonine 8.2%, L-valine 13.1%) and lacking tryptophan. The diets produced a rapid fall in plasma tryptophan which was proportional to the total amount of the amino acids ingested. Following the highest dose administered (36.6 g) plasma tryptophan fell to a minimum of about 35% the initial level and remained markedly reduced at 6 hours after treatment. The mechanism of this decrease and its potential clinical relevance are discussed.

Pharmacokinetics of isosorbide mononitrate in a new sustained release oral form in comparison with a conventional formulation.

40 mg of isosorbide mononitrate (isosorbide-5-mononitrate, IS5MN) in conventional (Ismo 20) and sustained release formulations (Ismo Diffutab) were administered to 5 male healthy volunteers. The administration of the sustained release formulation was repeated for seven days in order to evaluate the possible occurrence of accumulation. Pharmacokinetic data showed that the sustained release formulation reached significantly lower and delayed mean peak plasma levels compared with the conventional formulation, respectively 452.8 +/- 67.8 ng/ml and 706.7 +/- 57.3 (mean +/- SE) (p less than 0.05). Peak times were 4.6 +/- 0.2 and 2.4 +/- 0.2 (p less than 0.005) h, respectively. A longer plasma half-life together with larger AUC for the sustained release formulation was also observed. The pharmacokinetic parameters of the sustained release formulation are consistent with a therapeutic usefulness and suggest further clinical evaluation.

Normal and slow-release formulations of bezafibrate: a comparative pharmacokinetic study in man.

In this study the pharmacokinetics of a new slow-release formulation of bezafibrate (a hypolipaemic drug) were evaluated in a group of six healthy volunteers. In the first part of the study the bioavailability of this formulation was compared to the normal preparation of bezafibrate. In the second part of the experiment the possible accumulation was studied. The subjects were administered the slow-release preparation at 08h00 for seven consecutive days. The resulting data indicate that the slow-release formulation shows a lower dispersion of Tmax values. There was an increase of the plasma half-life from 1.9 to 5.5 h, but a possibility of accumulation could be excluded.

Analysis of tiadenol in human plasma by capillary gas chromatography with electron capture detection.

A sensitive and specific method for the quantitative determination of tiadenol in human plasma is described. After addition of the internal standard, both compounds were quantitatively extracted into chloroform and then derivatized with heptafluorobutyric anhydride (the structures of both derivatives were confirmed by electron impact mass spectrometry). Quantitation was achieved by capillary gas chromatography, using a (63) Ni-electron capture detector. Linearity was observed in the concentration range 5-100 ng ml(-1) and the minimum concentration of tiadenol detectable in plasma was 2.0 ng ml(-1). The method was successfully applied to plasma specimens collected from healthy human volunteers following a single oral administration of 800 mg of tiadenol.

Determination of bezafibrate in human plasma and urine by high-performance liquid chromatography.

A selective and time-saving high-performance liquid chromatographic method to assess bezafibrate plasma and urine levels is described. Bezafibrate is extracted from plasma matrix using diethyl ether, after acidification with hydrochloric acid. The urine samples are directly analysed, after dilution with the mobile phase. The method is used to assess bezafibrate plasma and urine levels in man, after administration of therapeutic doses of bezafibrate. The results obtained are in agreement with previously published data.

Gas chromatographic determination of glibenclamide in plasma.

A gas-chromatographic method for glibenclamide determination in plasma is described. It involves derivatization of the drug with dinitrofluorobenzene and the use of an electron-capture detector. The quantitative evaluation is performed using tolbutamide as internal standard. Characteristics and specificity of the method for the principal metabolite of glibenclamide are examined.