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3-21-04 The safety, tolerability, pharmacodynamics and pharmacokinetics of naratriptan in healthy elderly subjects
S168
Headache
product (an index of myocardial oxygen consumption). The coronary angiography study demonstrated a statistically significant increase in mean arterial pressure (12.39 mmHg, 95% Cl: 8.00-18.7 mmHg, p -Z 0.05) and mean pulmonary pressure (3.50 mmHg. 95% Cl: 1.75-5.00 mmHg, p < 0.05). However no significant change in heart rate, cardiac output or coronary artery diameter was seen. Subcutaneous naratriptan 1.5 mg is associated with a reduction in CVR. This decrease was not considered to be clinically significant and is smaller than that previously seen in a similar study with iv ergotamine. The vasopressor response demonstrated with naratriptan is smaller than that seen with subcutaneous sumatrlptan 8 mg. Also, unlike sumatriptan, naratriptan produced no significant change in coronary artery diameter. The findings from these detailed cardiovascular studies are consistent with the incidence of cardiovascular adverse events reported by migraine patients taking oral naratriptan.
13-21-04
1 The safety, tolerability, pharmacodynamics and oharmacokinetics of naratriotan in healthv elderlv ipubjects
R. Kempsford, E. Fuseau, J. Moss, P. Bryson ‘. Glaxo We//come Researc/r and Development Ltd., Greentbtrf, Middlesex, UK, ’ Phase t Clinical Trials, Plymouth, UK Naratriptan (GR85548) is a potent 5HTl B/l D agonist developed as an acute migraine therapy. A randornised, double-blind, ascending dose, placebo controlled, parallel group study was performed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of naratriptan in healthy elderly (85-77~; 8 male, 8 female) and young (24-44~; 8 male, 8 female) subjects. Each subject received placebo + placebo, I+1 mg and 2.5+2.5 mg naratriptan tablets (4 hours apart) on three separate study days. Blood pressure (O-24 h) and IBlead ECG (O-12 h) were recorded and serum and urine naratriptan concentrations (O-32 h) were determined. There was no statistically significant difference in mean peak diastolic blood pressure (difference from placebo) between the young and elderty subjects O-24 h after I+1 or 2.5+2.5 mg naratriptan or in mean peak systolic blood pressure after I+1 mg naratdptan. After 2.5+2.5 mg naratriptan mean peak systolic blood pressure (difference from placebo) was comparable o-4,8-12 and 12-24 h but was IOmmHg greater in the elderly 4-8 h after dosing (95% Cl: 4, 18). Pharmacokinetic differences are summarised below: Parameter AUC, CmaX h/2
Cl/F
Clr
Elderly/youngratio(95%CI) l+img
2.5+2.5 mg
1.36 (1.17,1.64) 1.26(1.07.1.64) 1.18 (1.04.1.35) 0.72 (0.61.0.65) 0.66 io.5J3,0.75i
1.32(1.13,1.55) 1.15(1.01,1.32) 1.14(1.04,1.25) 0.76 (0.65,0.66) 0.70 iO.60,0.62j
Apparent clearance decreased linearly with age and increased linearly with weight. There was a linear correlation between creatinine clearance and the apparent and renal clearance of naratriptan. Naratriptan exposure was lower in male subjects compared to females in both young and elderly groups suggesting that gender differences in naratriptan pharmacokinetics are not lost with age. Adverse events were reported by 2 elderly subjects after I+1 mg and 2.5+2.5 mg naratriptan and by 9 and 8 young subjects respectively. Naratriptan at doses up to 2.5+2.5 mg is well tolerated in elderly subjects with a slightly greater effect on systolic but not diastolic blood pressure compared to that in the young. The greater naratriptan exposure seen in elderly subjects is attributable to decreasing renal function with age.
3-21-05
Risk factors for a poor outcome aura. A casecontrol study-11
of migraine
without
G. Sandrini, F. Granella’, G. Sances, A. Cavallini, A. Costa, A.P. Verri, G. Nappi. ’ lnterunive&y Center for Adaptive Disorders and Headache, Unit of Parma (Institute of Neurology), Italy. lnterunivets#y Center for Adaptive Disorders and Headache, Unit of Pavia 1 (Neurological Institute “C Mondino”) la/y Over the last few years, several epidemiological studies have been carried out in order to define further the clinical characteristics of migraine. However, no convincing data are yet available about the factors affecting the outcome of this disorder. The aim of the present study was the identification of the factors associated with a negative evolution of migraine without aura. The first part of the study, concerning clinical factors, has been presented elsewhere. Psychological, neurophysiological and neuroendocrfne factors are reported here. A case-control study was performed. One hundred and twelve patients (32 males and 80 females; mean age 38.5 f 8.3 years) consecutively referred to the Headache Center of Pavia, suffering from migraine without aura, with a disease duration
of over than 10 years and a negative outcome (CA), were considered. An equal number of consecutfve patients, matched for gender, age and time of migraine onset, with a positive outcome, were the controls (CO). The outcome was considered negative if the attack frequency during the previous year was higher than that observed in the 3 years following the onset of disease, and positive if the attack frequency in the previous year was equal or lower than that of the first 3 years. The patients were submitted to: 1) a semistructured interview (SCID) for the diagnosis of mental disorders according to DSM-IIIR; 2) a neurophysiological evaluation for the study of pain pressure threshold, measured by an electronic pressure algorneter (temporalis, frontalis, trapezius and deltoid muscles, and the third hand finger were studied on both sides); the activity of both frontalis and trapezius muscles, during either rest or a mental task, measured by an EMG device; 3) a naloxone test (10 mg Lv.) with measurement of cortisol and LH plasma levels. Statistiil analysis was performed by chi-square test and MANOVA. Mood disorders were significantly associated with a poor outcome (observed ratio, OR: 1.92; confidence interval, Cl: 1.09-3.04) - major depression in particular (OR: 3.88, Cl: 2.03-8.81) -while somatoform disorders were more frequent in CO than in CA (OR: 0.44, Cl: 0.19-8.98). The pain pressure threshold was more frequently reduced in CO than in CA, while no differences were detected between groups in EMG levels. Corttsol and LH peaks after naloxone administration were significantly lower in CA than in CO, suggesting an impairment of hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes in patients with a poor outcome of migraine.
I3 21
06
Comparison between new daily persistent headaches treated for extra cranial infection spontaneously occurring cases
Carlos Santoni-Williams, Univetsidad Autonoma
and
Juan R. Santoni. Rehabilitation Center and de Santa Domingo, Dominican Republic
In 218 cases of non-migrainous New Daily Persistent Headaches (NDPH), after a negative neurological examination, and Neuroimaging (in 72 cases) excluding organic or S.O. lesions, laboratory search for an extra cranial infection was performed according to section 9 of I.H.S. classtfication. All patients had urine culture, antibody levels for Salmonella, Proteus, Streptococcus, Toxoplasma and EBV. Thirty one had EEG, five; LP. Headache persistence before diagnosis and up to remission were computed In days, as well as antibiotic Rx duration. Comparison of persistence to remission was made between cases treated for infection, and “spontaneous” cases without infection or treatment. Occurrence of symptoms i.e. fever, etc., and cervical adenopathy were noted. Extra cranial infection was found in 172. Data expressed in means were: age 30.4 yrs., 15.9 days before diagnosis, remittance after 8.9 days of antibiotics indicated for 10 days. i.e. 0.8.9:lO ratio. For 44 uninfected cases, age was 32.8 years, 18 days before diagnosis, and “spontaneous” remittance after 15 days. Subdivision by pathologies showed the following remittance: antibiotic duration ratios: in 47 Salmonella 5.8:8.4,44 Cystitis 7.5:10, in 41 Proteus 5.3:9, 23 Streptococcus 5.1:8.7, in 12 Toxoplasma 18.522.7, in 5 EBV 4:21. Cervical adenopathy was the outstanding sign: 127/218 (59%). We conclude that identification of NDPH’s infectious nature leads to antibiotic use and prompt remission, compared to a prolonged course to remission in “spontaneous” cases.
3-21-07
New look at face pain
V.B. Ulzibat, S.V. Shishon, I.V. Nazaroy, A.A. Sozontov. Rehabilitolog~ 21 Oboronnaya, Tula, Russia
institute
of Clinical
We want to share our opinion about the origin and formation mechanism of head and face pain. Being agree with the compression theory of trifacial neuralgia, we think, that the reason of its squeezing is cicatdcial changing of muscular tissue. The cicatrfcial process can lead to squeezing of vessels which are feeding the nerve, that leads to decease too. For effective treatment we have to know in what level the irritation of trifacial nerve branches happened, and also the affection of sens’kive fibers of facial nerve is possible. In our theory favour there is a fact telling that the count of neuralgia increases in proportion of the age of patients. We think that the presence of trigger’s zones near the wing of nasolabial fold, above the upper lip, on the chin confirms our conclusion about the presence of cicatricial process in muscles of facial expression and the compression of nerve branches is conditioned by the cicatricial process in different facial muscles, but not by the nerve compression in narrow Meal canals. The analysis of results. which were recetved basing on operations directed to removal of pathologic formations, lets us suggest this theory as a basic factor in development of trfgeminal neuralgia.
Headache
product (an index of myocardial oxygen consumption). The coronary angiography study demonstrated a statistically significant increase in mean arterial pressure (12.39 mmHg, 95% Cl: 8.00-18.7 mmHg, p -Z 0.05) and mean pulmonary pressure (3.50 mmHg. 95% Cl: 1.75-5.00 mmHg, p < 0.05). However no significant change in heart rate, cardiac output or coronary artery diameter was seen. Subcutaneous naratriptan 1.5 mg is associated with a reduction in CVR. This decrease was not considered to be clinically significant and is smaller than that previously seen in a similar study with iv ergotamine. The vasopressor response demonstrated with naratriptan is smaller than that seen with subcutaneous sumatrlptan 8 mg. Also, unlike sumatriptan, naratriptan produced no significant change in coronary artery diameter. The findings from these detailed cardiovascular studies are consistent with the incidence of cardiovascular adverse events reported by migraine patients taking oral naratriptan.
13-21-04
1 The safety, tolerability, pharmacodynamics and oharmacokinetics of naratriotan in healthv elderlv ipubjects
R. Kempsford, E. Fuseau, J. Moss, P. Bryson ‘. Glaxo We//come Researc/r and Development Ltd., Greentbtrf, Middlesex, UK, ’ Phase t Clinical Trials, Plymouth, UK Naratriptan (GR85548) is a potent 5HTl B/l D agonist developed as an acute migraine therapy. A randornised, double-blind, ascending dose, placebo controlled, parallel group study was performed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of naratriptan in healthy elderly (85-77~; 8 male, 8 female) and young (24-44~; 8 male, 8 female) subjects. Each subject received placebo + placebo, I+1 mg and 2.5+2.5 mg naratriptan tablets (4 hours apart) on three separate study days. Blood pressure (O-24 h) and IBlead ECG (O-12 h) were recorded and serum and urine naratriptan concentrations (O-32 h) were determined. There was no statistically significant difference in mean peak diastolic blood pressure (difference from placebo) between the young and elderty subjects O-24 h after I+1 or 2.5+2.5 mg naratriptan or in mean peak systolic blood pressure after I+1 mg naratdptan. After 2.5+2.5 mg naratriptan mean peak systolic blood pressure (difference from placebo) was comparable o-4,8-12 and 12-24 h but was IOmmHg greater in the elderly 4-8 h after dosing (95% Cl: 4, 18). Pharmacokinetic differences are summarised below: Parameter AUC, CmaX h/2
Cl/F
Clr
Elderly/youngratio(95%CI) l+img
2.5+2.5 mg
1.36 (1.17,1.64) 1.26(1.07.1.64) 1.18 (1.04.1.35) 0.72 (0.61.0.65) 0.66 io.5J3,0.75i
1.32(1.13,1.55) 1.15(1.01,1.32) 1.14(1.04,1.25) 0.76 (0.65,0.66) 0.70 iO.60,0.62j
Apparent clearance decreased linearly with age and increased linearly with weight. There was a linear correlation between creatinine clearance and the apparent and renal clearance of naratriptan. Naratriptan exposure was lower in male subjects compared to females in both young and elderly groups suggesting that gender differences in naratriptan pharmacokinetics are not lost with age. Adverse events were reported by 2 elderly subjects after I+1 mg and 2.5+2.5 mg naratriptan and by 9 and 8 young subjects respectively. Naratriptan at doses up to 2.5+2.5 mg is well tolerated in elderly subjects with a slightly greater effect on systolic but not diastolic blood pressure compared to that in the young. The greater naratriptan exposure seen in elderly subjects is attributable to decreasing renal function with age.
3-21-05
Risk factors for a poor outcome aura. A casecontrol study-11
of migraine
without
G. Sandrini, F. Granella’, G. Sances, A. Cavallini, A. Costa, A.P. Verri, G. Nappi. ’ lnterunive&y Center for Adaptive Disorders and Headache, Unit of Parma (Institute of Neurology), Italy. lnterunivets#y Center for Adaptive Disorders and Headache, Unit of Pavia 1 (Neurological Institute “C Mondino”) la/y Over the last few years, several epidemiological studies have been carried out in order to define further the clinical characteristics of migraine. However, no convincing data are yet available about the factors affecting the outcome of this disorder. The aim of the present study was the identification of the factors associated with a negative evolution of migraine without aura. The first part of the study, concerning clinical factors, has been presented elsewhere. Psychological, neurophysiological and neuroendocrfne factors are reported here. A case-control study was performed. One hundred and twelve patients (32 males and 80 females; mean age 38.5 f 8.3 years) consecutively referred to the Headache Center of Pavia, suffering from migraine without aura, with a disease duration
of over than 10 years and a negative outcome (CA), were considered. An equal number of consecutfve patients, matched for gender, age and time of migraine onset, with a positive outcome, were the controls (CO). The outcome was considered negative if the attack frequency during the previous year was higher than that observed in the 3 years following the onset of disease, and positive if the attack frequency in the previous year was equal or lower than that of the first 3 years. The patients were submitted to: 1) a semistructured interview (SCID) for the diagnosis of mental disorders according to DSM-IIIR; 2) a neurophysiological evaluation for the study of pain pressure threshold, measured by an electronic pressure algorneter (temporalis, frontalis, trapezius and deltoid muscles, and the third hand finger were studied on both sides); the activity of both frontalis and trapezius muscles, during either rest or a mental task, measured by an EMG device; 3) a naloxone test (10 mg Lv.) with measurement of cortisol and LH plasma levels. Statistiil analysis was performed by chi-square test and MANOVA. Mood disorders were significantly associated with a poor outcome (observed ratio, OR: 1.92; confidence interval, Cl: 1.09-3.04) - major depression in particular (OR: 3.88, Cl: 2.03-8.81) -while somatoform disorders were more frequent in CO than in CA (OR: 0.44, Cl: 0.19-8.98). The pain pressure threshold was more frequently reduced in CO than in CA, while no differences were detected between groups in EMG levels. Corttsol and LH peaks after naloxone administration were significantly lower in CA than in CO, suggesting an impairment of hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes in patients with a poor outcome of migraine.
I3 21
06
Comparison between new daily persistent headaches treated for extra cranial infection spontaneously occurring cases
Carlos Santoni-Williams, Univetsidad Autonoma
and
Juan R. Santoni. Rehabilitation Center and de Santa Domingo, Dominican Republic
In 218 cases of non-migrainous New Daily Persistent Headaches (NDPH), after a negative neurological examination, and Neuroimaging (in 72 cases) excluding organic or S.O. lesions, laboratory search for an extra cranial infection was performed according to section 9 of I.H.S. classtfication. All patients had urine culture, antibody levels for Salmonella, Proteus, Streptococcus, Toxoplasma and EBV. Thirty one had EEG, five; LP. Headache persistence before diagnosis and up to remission were computed In days, as well as antibiotic Rx duration. Comparison of persistence to remission was made between cases treated for infection, and “spontaneous” cases without infection or treatment. Occurrence of symptoms i.e. fever, etc., and cervical adenopathy were noted. Extra cranial infection was found in 172. Data expressed in means were: age 30.4 yrs., 15.9 days before diagnosis, remittance after 8.9 days of antibiotics indicated for 10 days. i.e. 0.8.9:lO ratio. For 44 uninfected cases, age was 32.8 years, 18 days before diagnosis, and “spontaneous” remittance after 15 days. Subdivision by pathologies showed the following remittance: antibiotic duration ratios: in 47 Salmonella 5.8:8.4,44 Cystitis 7.5:10, in 41 Proteus 5.3:9, 23 Streptococcus 5.1:8.7, in 12 Toxoplasma 18.522.7, in 5 EBV 4:21. Cervical adenopathy was the outstanding sign: 127/218 (59%). We conclude that identification of NDPH’s infectious nature leads to antibiotic use and prompt remission, compared to a prolonged course to remission in “spontaneous” cases.
3-21-07
New look at face pain
V.B. Ulzibat, S.V. Shishon, I.V. Nazaroy, A.A. Sozontov. Rehabilitolog~ 21 Oboronnaya, Tula, Russia
institute
of Clinical
We want to share our opinion about the origin and formation mechanism of head and face pain. Being agree with the compression theory of trifacial neuralgia, we think, that the reason of its squeezing is cicatdcial changing of muscular tissue. The cicatrfcial process can lead to squeezing of vessels which are feeding the nerve, that leads to decease too. For effective treatment we have to know in what level the irritation of trifacial nerve branches happened, and also the affection of sens’kive fibers of facial nerve is possible. In our theory favour there is a fact telling that the count of neuralgia increases in proportion of the age of patients. We think that the presence of trigger’s zones near the wing of nasolabial fold, above the upper lip, on the chin confirms our conclusion about the presence of cicatricial process in muscles of facial expression and the compression of nerve branches is conditioned by the cicatricial process in different facial muscles, but not by the nerve compression in narrow Meal canals. The analysis of results. which were recetved basing on operations directed to removal of pathologic formations, lets us suggest this theory as a basic factor in development of trfgeminal neuralgia.