Acta Neurol Scand 2014: 130: 380–386 DOI: 10.1111/ane.12279
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Regional cerebral blood flow following single-dose and continuous-dose tadalafil after stroke Lorberboym M, Makhline E, Lampl Y. Regional cerebral blood flow following single-dose and continuous-dose tadalafil after stroke. Acta Neurol Scand: 2014: 130: 380–386. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Purpose – Tadalafil is a potent and selective phosphodiesterase type 5 inhibitor that provides effective treatment for erectile dysfunction (ED). The purpose of this study was to explore the effect of a single on-demand dose of tadalafil compared to low-dose continuous administration on regional cerebral blood flow (rCBF), in patients after stroke. Methods – Thirty consecutive male patients (mean age 58.3 7.9 years) with ED and a history of stroke were included in the study. The baseline single-photon emission computed tomography (SPECT) study was performed 15 min after iv injection of 740 MBq Tc-99m-HMPAO (Ceretec; GE Healthcare Ltd. Chalfont St. Giles, UK). Fifteen randomized patients received a single dose of 20 mg tadalafil in the morning, and a second SPECT study was performed 6 h later. Fifteen other patients received 5 mg of tadalafil each morning for seven consecutive days, and the second SPECT study was performed 6 h after the last dose. The imaging data were evaluated using SPM software (Wellcome Department of Cognitive Neurology, University College, London). Results – Associations between any of the risk factors/comorbidities and the perfusion changes were not detected. All patients showed areas of reduced relative rCBF in the affected hemisphere after tadalafil administration compared to baseline (P < 0.001). No significant difference was found between patients on 5 mg tadalafil and 20 mg dose. Conclusion – Tadalafil administration after cerebral stroke may be associated with diminished blood flow to areas adjacent to the stroke. The alterations in perfusion suggest a need for caution in prescribing tadalafil to patients with a history of stroke, especially with continuous administration that may impose constant stress on the cerebral circulation.
Introduction
Erectile dysfunction (ED) is a chronic condition that may be associated with underlying cardiovascular, neurological, and psychological disorders (1). The prevalence of ED ranges from 2% to 9% in men between the ages of 40 and 49 years, and it then increases to 20–40% in men aged 60–69 years (2). Oral phosphodiesterase type 5 inhibitor (PDE5i) therapies (including sildenafil, vardenafil, and tadalafil) have been commercially available for over a decade and have provided 380
M. Lorberboym1,2, E. Makhline3, Y. Lampl2,3 1 Department of Nuclear Medicine, Edith Wolfson Medical Center, Holon, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3 Department of Neurology, Edith Wolfson Medical Center, Holon, Israel
Key words: tadalafil; cerebral blood flow; stroke; HMPAO; single-photon emission computed tomography; SPM; Statistical Parametric Mapping M. Lorberboym, Department of Nuclear Medicine, Edith Wolfson Medical Center, Holon 58100, Israel Tel.: +011 972 544 630930 Fax: +011 972 3 6355552 e-mail: [email protected] Accepted for publication June 16, 2014
noninvasive, effective, and well-tolerated treatments for ED. Phosphodiesterase type 5 inhibitor acts as selective inhibitors of cyclic guanosine monophosphate (cGMP)-specific PDE5i enzyme which results in increased levels of cGMP and nitric oxide (NO) (3). Sexual stimulation causes local release of NO, and with the inhibition of PDE5i, there are increased levels of cGMP in the corpus cavernosum. The increased levels of cGMP lead to reduced intracellular calcium levels, thereby producing smooth muscle relaxation in the
Tadalafil after cerebral stroke rebral hemorrhage was reported in a patient after taking two tablets of tadalafil 20 mg (15). Considering the substantial interest in routine dosing of PDE5i as a new and novel approach to the management of ED, the aim of this study was to compare the impact of a single on-demand dose of tadalafil vs continuous administration of a low-dose medication on cerebral blood flow in patients with a history of cerebrovascular stroke.
corpus cavernosum and an increase in blood flow in erectile tissue. Although as-needed PDE5 inhibitors are similarly effective in the management of ED, intermittent dosing may not be an optimal treatment for all men and their partners based on individual patterns of sexual activity (4–6). In 2008, approximately 10 years after the release of the first commercially available PDE5i, a shift in the standard of management of ED occurred with the approval of once-daily dose of tadalafil (Cialis; Lilly-ICOS, Indianapolis, IN, USA) by the US Food and Drug Administration (FDA) for the management of ED. The prolonged half-life of tadalafil is well suited to this dosing regimen and offers the advantage of separating medication from sexual interactions; lower dose therapy also carries the theoretical benefit of lower incidence of side effects. Various side effects associated with the use of these medications have been reported, including headache, facial flushing, hypotension, and dizziness. Minor visual changes and ischemic optic neuropathy with subsequent loss of vision are also described as side effects (7). In the central nervous system, the PDE5 inhibitors tadalafil and sildenafil were demonstrated to enhance neurogenesis and increase the numbers of proliferating neural progenitor cells in the ischemic penumbra (8–10). In addition, using the same rat model of stroke, sildenafil was demonstrated to enhance angiogenesis in the ischemic brain (11). However, neurological side effects were also reported after PDE5i administration. As PDE5i can induce migraine and was associated with transient ischemic attack and stroke, it is believed that it can induce vascular changes in the brain (12, 13). As previously noted by Roach (14), transient global amnesia probably results from altered cerebral vasomotor control. Intrace-
Materials and methods Subjects
Thirty consecutive male patients (mean age 58.3 7.9 years) with ED were included in the study. All patients had a territorial or focal/multifocal stroke and vascular risk factors (Table 1). All patients were sub classified according to the A-S-C-O classification (atherosclerosis, small vessel disease, cardiac source, and other causes) (16, 17). Cerebral small vessel disease is defined as ‘groups of pathological processes, with various etiologies that affect the small vessels, arteries, arterioles, venules and capillaries in the brain (18), and small ( premedication 21,520 >3.4 4.5
y
z
Main anatomical location
14
48
28
32 24
62 28
24 62
32
86
10
3.4 577 >3.4 Lt cortical patients post-medication 18,133 >4.5
x
4.5 4.5 4.5 post-medication 12,276 >4.5 4.5
4.5 >4.5 >4.5
4.5 0.001 24 101 >4.5 0.001 0 Rt cortical patients post-medication > premedication 8862 >5.9 0.001 12
80 36
0 18
72
6
48
64
32
Rt cortical patients premedication > post-medication 15,239 >5.9 0.001 50
64
20
996
>5.9
0.001
936 426 114 394
>5.9 >5.9 >5.9 >5.9
0.001 0.001 0.001 0.001
16 64 20 10
70 32 78 56
16 8 50 46
248 125 205 153 872 136
>5.9 >5.9 >5.9 >5.9 >5.9 >5.9
0.001 0.001 0.001 0.001 0.001 0.001
68 48 30 48 14 20
30 52 72 38 50 58
12 52 42 14 26 50
Left middle frontal gyrus, superior frontal gyrus*, limbic lobe, medial frontal gyrus, inferior frontal gyrus, cingulate gyrus, precentral gyrus, insula superior temporal gyrus, caudate, lentiform nucleus, putamen Right superior frontal gyrus, middle frontal gyrus* Left post-central gyrus, precentral gyrus*, superior frontal gyrus Left occipital lobe, middle occipital gyrus*, inferior occipital gyrus, cerebellum posterior lobe, declive, cerebellum anterior lobe, fusiform gyrus, cuneus, lingual gyrus, middle temporal gyrus, superior temporal gyrus Right superior frontal gyrus*, medial frontal gyrus, middle frontal gyrus Interhemispheric, precuneus*, cuneus, cingulate gyrus, calcarine Right subcallosal gyrus*, anterior cingulate, medial frontal gyrus Right inferior frontal gyrus*, insula, superior temporal gyrus, uncus, parahippocampal gyrus Right superior temporal gyrus*, middle temporal gyrus, inferior temporal gyrus, transverse temporal gyrus, supramarginal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, post-central gyrus, inferior parietal lobule, insula, cerebellum posterior lobe Right Occipital Lobe, Cuneus*, Lingual Gyrus, Inferior Occipital Gyrus, Fusiform Gyrus, Middle Occipital Gyrus Left post-central gyrus*, precentral gyrus insula, transverse temporal gyrus Right superior frontal gyrus, middle frontal gyrus* Right, precuneus, superior parietal lobule*, angular gyrus, inferior parietal lobule Left cerebellum posterior lobe middle occipital gyrus, cuneus, middle temporal gyrus*, cerebellar tonsil, pyramis, inferior semi-lunar lobule Superior temporal gyrus, limbic lobe Inferior parietal lobule, lingual gyrus Supramarginal gyrus, cerebellum anterior lobe, precuneus, posterior cingulate, angular gyrus Left inferior frontal gyrus*, middle frontal gyrus, medial frontal gyrus, limbic lobe, superior frontal gyrus, anterior cingulate, insula Right precuneus*, limbic lobe, posterior cingulate, extra-nuclear Left superior temporal gyrus, middle temporal gyrus*, inferior temporal gyrus, fusiform gyrus Left sublobar, lentiform nucleus*, putamen, extra-nuclear, anterior cingulate, lateral globus pallidus, caudate Right occipital lobe, middle occipital gyrus, cuneus, lingual gyrus* Brainstem, midbrain* Right occipital lobe, middle occipital gyrus, lingual gyrus, cuneus*, parahippocampal gyrus, extra-nuclear, cerebellum anterior lobe, fusiform gyrus, insula, thalamus, caudate, superior temporal gyrus, middle temporal gyrus, transverse temporal gyrus, precentral gyrus Left cerebellum posterior lobe*, cerebellar tonsil, cerebellum anterior lobe, culmen, tuber, declive, left brainstem, pons, fusiform gyrus Right superior frontal gyrus, middle frontal gyrus, inferior parietal lobule, precuneus, middle temporal gyrus*, inferior temporal gyrus, precentral gyrus, supramarginal gyrus, medial frontal gyrus, superior temporal gyrus, superior parietal lobule, post-central gyrus, inferior frontal gyrus, angular gyrus, cingulate gyrus, paracentral lobule Left occipital lobe, precuneus*, cuneus, middle occipital gyrus Left middle temporal gyrus*, superior temporal gyrus, inferior parietal lobule, post-central gyrus Left cerebellum posterior lobe, inferior semi-lunar lobule* Right cerebellum posterior lobe, cerebellar tonsil*, inferior semi-lunar lobule, cerebellum anterior lobe Right superior temporal gyrus*, post-central gyrus Left inferior parietal lobule* Right cerebellum posterior lobe, pyramis* Left inferior parietal lobule, superior temporal gyrus*, insula, supramarginal gyrus Left superior frontal gyrus*, medial frontal gyrus, middle frontal gyrus, inferior frontal gyrus Left cerebellum posterior lobe, cerebellar tonsil*
383
Tadalafil after cerebral stroke Table 2 Regional cerebral blood flow differences between patients group pre- and post-medication uptake Peak coordinate (Montreal Neurological Institute) Number of voxels
T score
Corrected P-value
All patients post-medication > premedication 21,520 >3.4 4.5
y
z
Main anatomical location
14
48
28
32 24
62 28
24 62
32
86
10
3.4 577 >3.4 Lt cortical patients post-medication 18,133 >4.5
x
4.5 4.5 4.5 post-medication 12,276 >4.5 4.5
4.5 >4.5 >4.5
4.5 0.001 24 101 >4.5 0.001 0 Rt cortical patients post-medication > premedication 8862 >5.9 0.001 12
80 36
0 18
72
6
48
64
32
Rt cortical patients premedication > post-medication 15,239 >5.9 0.001 50
64
20
996
>5.9
0.001
936 426 114 394
>5.9 >5.9 >5.9 >5.9
0.001 0.001 0.001 0.001
16 64 20 10
70 32 78 56
16 8 50 46
248 125 205 153 872 136
>5.9 >5.9 >5.9 >5.9 >5.9 >5.9
0.001 0.001 0.001 0.001 0.001 0.001
68 48 30 48 14 20
30 52 72 38 50 58
12 52 42 14 26 50
Left middle frontal gyrus, superior frontal gyrus*, limbic lobe, medial frontal gyrus, inferior frontal gyrus, cingulate gyrus, precentral gyrus, insula superior temporal gyrus, caudate, lentiform nucleus, putamen Right superior frontal gyrus, middle frontal gyrus* Left post-central gyrus, precentral gyrus*, superior frontal gyrus Left occipital lobe, middle occipital gyrus*, inferior occipital gyrus, cerebellum posterior lobe, declive, cerebellum anterior lobe, fusiform gyrus, cuneus, lingual gyrus, middle temporal gyrus, superior temporal gyrus Right superior frontal gyrus*, medial frontal gyrus, middle frontal gyrus Interhemispheric, precuneus*, cuneus, cingulate gyrus, calcarine Right subcallosal gyrus*, anterior cingulate, medial frontal gyrus Right inferior frontal gyrus*, insula, superior temporal gyrus, uncus, parahippocampal gyrus Right superior temporal gyrus*, middle temporal gyrus, inferior temporal gyrus, transverse temporal gyrus, supramarginal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, post-central gyrus, inferior parietal lobule, insula, cerebellum posterior lobe Right Occipital Lobe, Cuneus*, Lingual Gyrus, Inferior Occipital Gyrus, Fusiform Gyrus, Middle Occipital Gyrus Left post-central gyrus*, precentral gyrus insula, transverse temporal gyrus Right superior frontal gyrus, middle frontal gyrus* Right, precuneus, superior parietal lobule*, angular gyrus, inferior parietal lobule Left cerebellum posterior lobe middle occipital gyrus, cuneus, middle temporal gyrus*, cerebellar tonsil, pyramis, inferior semi-lunar lobule Superior temporal gyrus, limbic lobe Inferior parietal lobule, lingual gyrus Supramarginal gyrus, cerebellum anterior lobe, precuneus, posterior cingulate, angular gyrus Left inferior frontal gyrus*, middle frontal gyrus, medial frontal gyrus, limbic lobe, superior frontal gyrus, anterior cingulate, insula Right precuneus*, limbic lobe, posterior cingulate, extra-nuclear Left superior temporal gyrus, middle temporal gyrus*, inferior temporal gyrus, fusiform gyrus Left sublobar, lentiform nucleus*, putamen, extra-nuclear, anterior cingulate, lateral globus pallidus, caudate Right occipital lobe, middle occipital gyrus, cuneus, lingual gyrus* Brainstem, midbrain* Right occipital lobe, middle occipital gyrus, lingual gyrus, cuneus*, parahippocampal gyrus, extra-nuclear, cerebellum anterior lobe, fusiform gyrus, insula, thalamus, caudate, superior temporal gyrus, middle temporal gyrus, transverse temporal gyrus, precentral gyrus Left cerebellum posterior lobe*, cerebellar tonsil, cerebellum anterior lobe, culmen, tuber, declive, left brainstem, pons, fusiform gyrus Right superior frontal gyrus, middle frontal gyrus, inferior parietal lobule, precuneus, middle temporal gyrus*, inferior temporal gyrus, precentral gyrus, supramarginal gyrus, medial frontal gyrus, superior temporal gyrus, superior parietal lobule, post-central gyrus, inferior frontal gyrus, angular gyrus, cingulate gyrus, paracentral lobule Left occipital lobe, precuneus*, cuneus, middle occipital gyrus Left middle temporal gyrus*, superior temporal gyrus, inferior parietal lobule, post-central gyrus Left cerebellum posterior lobe, inferior semi-lunar lobule* Right cerebellum posterior lobe, cerebellar tonsil*, inferior semi-lunar lobule, cerebellum anterior lobe Right superior temporal gyrus*, post-central gyrus Left inferior parietal lobule* Right cerebellum posterior lobe, pyramis* Left inferior parietal lobule, superior temporal gyrus*, insula, supramarginal gyrus Left superior frontal gyrus*, medial frontal gyrus, middle frontal gyrus, inferior frontal gyrus Left cerebellum posterior lobe, cerebellar tonsil*
383
Lorberboym et al. Table 2 (continued) Peak coordinate (Montreal Neurological Institute) Number of voxels
T score
Corrected P-value
x
Multi-focal patients post-medication > premedication 18,323 >3.8 3.8 3.8 3.8 3.8 0.001 Multifocal Patients premedication > post-medication 31,100 >3.8 3.8 >3.8 >3.8
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Regional cerebral blood flow following single-dose and continuous-dose tadalafil after stroke Lorberboym M, Makhline E, Lampl Y. Regional cerebral blood flow following single-dose and continuous-dose tadalafil after stroke. Acta Neurol Scand: 2014: 130: 380–386. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Purpose – Tadalafil is a potent and selective phosphodiesterase type 5 inhibitor that provides effective treatment for erectile dysfunction (ED). The purpose of this study was to explore the effect of a single on-demand dose of tadalafil compared to low-dose continuous administration on regional cerebral blood flow (rCBF), in patients after stroke. Methods – Thirty consecutive male patients (mean age 58.3 7.9 years) with ED and a history of stroke were included in the study. The baseline single-photon emission computed tomography (SPECT) study was performed 15 min after iv injection of 740 MBq Tc-99m-HMPAO (Ceretec; GE Healthcare Ltd. Chalfont St. Giles, UK). Fifteen randomized patients received a single dose of 20 mg tadalafil in the morning, and a second SPECT study was performed 6 h later. Fifteen other patients received 5 mg of tadalafil each morning for seven consecutive days, and the second SPECT study was performed 6 h after the last dose. The imaging data were evaluated using SPM software (Wellcome Department of Cognitive Neurology, University College, London). Results – Associations between any of the risk factors/comorbidities and the perfusion changes were not detected. All patients showed areas of reduced relative rCBF in the affected hemisphere after tadalafil administration compared to baseline (P < 0.001). No significant difference was found between patients on 5 mg tadalafil and 20 mg dose. Conclusion – Tadalafil administration after cerebral stroke may be associated with diminished blood flow to areas adjacent to the stroke. The alterations in perfusion suggest a need for caution in prescribing tadalafil to patients with a history of stroke, especially with continuous administration that may impose constant stress on the cerebral circulation.
Introduction
Erectile dysfunction (ED) is a chronic condition that may be associated with underlying cardiovascular, neurological, and psychological disorders (1). The prevalence of ED ranges from 2% to 9% in men between the ages of 40 and 49 years, and it then increases to 20–40% in men aged 60–69 years (2). Oral phosphodiesterase type 5 inhibitor (PDE5i) therapies (including sildenafil, vardenafil, and tadalafil) have been commercially available for over a decade and have provided 380
M. Lorberboym1,2, E. Makhline3, Y. Lampl2,3 1 Department of Nuclear Medicine, Edith Wolfson Medical Center, Holon, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3 Department of Neurology, Edith Wolfson Medical Center, Holon, Israel
Key words: tadalafil; cerebral blood flow; stroke; HMPAO; single-photon emission computed tomography; SPM; Statistical Parametric Mapping M. Lorberboym, Department of Nuclear Medicine, Edith Wolfson Medical Center, Holon 58100, Israel Tel.: +011 972 544 630930 Fax: +011 972 3 6355552 e-mail: [email protected] Accepted for publication June 16, 2014
noninvasive, effective, and well-tolerated treatments for ED. Phosphodiesterase type 5 inhibitor acts as selective inhibitors of cyclic guanosine monophosphate (cGMP)-specific PDE5i enzyme which results in increased levels of cGMP and nitric oxide (NO) (3). Sexual stimulation causes local release of NO, and with the inhibition of PDE5i, there are increased levels of cGMP in the corpus cavernosum. The increased levels of cGMP lead to reduced intracellular calcium levels, thereby producing smooth muscle relaxation in the
Tadalafil after cerebral stroke rebral hemorrhage was reported in a patient after taking two tablets of tadalafil 20 mg (15). Considering the substantial interest in routine dosing of PDE5i as a new and novel approach to the management of ED, the aim of this study was to compare the impact of a single on-demand dose of tadalafil vs continuous administration of a low-dose medication on cerebral blood flow in patients with a history of cerebrovascular stroke.
corpus cavernosum and an increase in blood flow in erectile tissue. Although as-needed PDE5 inhibitors are similarly effective in the management of ED, intermittent dosing may not be an optimal treatment for all men and their partners based on individual patterns of sexual activity (4–6). In 2008, approximately 10 years after the release of the first commercially available PDE5i, a shift in the standard of management of ED occurred with the approval of once-daily dose of tadalafil (Cialis; Lilly-ICOS, Indianapolis, IN, USA) by the US Food and Drug Administration (FDA) for the management of ED. The prolonged half-life of tadalafil is well suited to this dosing regimen and offers the advantage of separating medication from sexual interactions; lower dose therapy also carries the theoretical benefit of lower incidence of side effects. Various side effects associated with the use of these medications have been reported, including headache, facial flushing, hypotension, and dizziness. Minor visual changes and ischemic optic neuropathy with subsequent loss of vision are also described as side effects (7). In the central nervous system, the PDE5 inhibitors tadalafil and sildenafil were demonstrated to enhance neurogenesis and increase the numbers of proliferating neural progenitor cells in the ischemic penumbra (8–10). In addition, using the same rat model of stroke, sildenafil was demonstrated to enhance angiogenesis in the ischemic brain (11). However, neurological side effects were also reported after PDE5i administration. As PDE5i can induce migraine and was associated with transient ischemic attack and stroke, it is believed that it can induce vascular changes in the brain (12, 13). As previously noted by Roach (14), transient global amnesia probably results from altered cerebral vasomotor control. Intrace-
Materials and methods Subjects
Thirty consecutive male patients (mean age 58.3 7.9 years) with ED were included in the study. All patients had a territorial or focal/multifocal stroke and vascular risk factors (Table 1). All patients were sub classified according to the A-S-C-O classification (atherosclerosis, small vessel disease, cardiac source, and other causes) (16, 17). Cerebral small vessel disease is defined as ‘groups of pathological processes, with various etiologies that affect the small vessels, arteries, arterioles, venules and capillaries in the brain (18), and small ( premedication 21,520 >3.4 4.5
y
z
Main anatomical location
14
48
28
32 24
62 28
24 62
32
86
10
3.4 577 >3.4 Lt cortical patients post-medication 18,133 >4.5
x
4.5 4.5 4.5 post-medication 12,276 >4.5 4.5
4.5 >4.5 >4.5
4.5 0.001 24 101 >4.5 0.001 0 Rt cortical patients post-medication > premedication 8862 >5.9 0.001 12
80 36
0 18
72
6
48
64
32
Rt cortical patients premedication > post-medication 15,239 >5.9 0.001 50
64
20
996
>5.9
0.001
936 426 114 394
>5.9 >5.9 >5.9 >5.9
0.001 0.001 0.001 0.001
16 64 20 10
70 32 78 56
16 8 50 46
248 125 205 153 872 136
>5.9 >5.9 >5.9 >5.9 >5.9 >5.9
0.001 0.001 0.001 0.001 0.001 0.001
68 48 30 48 14 20
30 52 72 38 50 58
12 52 42 14 26 50
Left middle frontal gyrus, superior frontal gyrus*, limbic lobe, medial frontal gyrus, inferior frontal gyrus, cingulate gyrus, precentral gyrus, insula superior temporal gyrus, caudate, lentiform nucleus, putamen Right superior frontal gyrus, middle frontal gyrus* Left post-central gyrus, precentral gyrus*, superior frontal gyrus Left occipital lobe, middle occipital gyrus*, inferior occipital gyrus, cerebellum posterior lobe, declive, cerebellum anterior lobe, fusiform gyrus, cuneus, lingual gyrus, middle temporal gyrus, superior temporal gyrus Right superior frontal gyrus*, medial frontal gyrus, middle frontal gyrus Interhemispheric, precuneus*, cuneus, cingulate gyrus, calcarine Right subcallosal gyrus*, anterior cingulate, medial frontal gyrus Right inferior frontal gyrus*, insula, superior temporal gyrus, uncus, parahippocampal gyrus Right superior temporal gyrus*, middle temporal gyrus, inferior temporal gyrus, transverse temporal gyrus, supramarginal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, post-central gyrus, inferior parietal lobule, insula, cerebellum posterior lobe Right Occipital Lobe, Cuneus*, Lingual Gyrus, Inferior Occipital Gyrus, Fusiform Gyrus, Middle Occipital Gyrus Left post-central gyrus*, precentral gyrus insula, transverse temporal gyrus Right superior frontal gyrus, middle frontal gyrus* Right, precuneus, superior parietal lobule*, angular gyrus, inferior parietal lobule Left cerebellum posterior lobe middle occipital gyrus, cuneus, middle temporal gyrus*, cerebellar tonsil, pyramis, inferior semi-lunar lobule Superior temporal gyrus, limbic lobe Inferior parietal lobule, lingual gyrus Supramarginal gyrus, cerebellum anterior lobe, precuneus, posterior cingulate, angular gyrus Left inferior frontal gyrus*, middle frontal gyrus, medial frontal gyrus, limbic lobe, superior frontal gyrus, anterior cingulate, insula Right precuneus*, limbic lobe, posterior cingulate, extra-nuclear Left superior temporal gyrus, middle temporal gyrus*, inferior temporal gyrus, fusiform gyrus Left sublobar, lentiform nucleus*, putamen, extra-nuclear, anterior cingulate, lateral globus pallidus, caudate Right occipital lobe, middle occipital gyrus, cuneus, lingual gyrus* Brainstem, midbrain* Right occipital lobe, middle occipital gyrus, lingual gyrus, cuneus*, parahippocampal gyrus, extra-nuclear, cerebellum anterior lobe, fusiform gyrus, insula, thalamus, caudate, superior temporal gyrus, middle temporal gyrus, transverse temporal gyrus, precentral gyrus Left cerebellum posterior lobe*, cerebellar tonsil, cerebellum anterior lobe, culmen, tuber, declive, left brainstem, pons, fusiform gyrus Right superior frontal gyrus, middle frontal gyrus, inferior parietal lobule, precuneus, middle temporal gyrus*, inferior temporal gyrus, precentral gyrus, supramarginal gyrus, medial frontal gyrus, superior temporal gyrus, superior parietal lobule, post-central gyrus, inferior frontal gyrus, angular gyrus, cingulate gyrus, paracentral lobule Left occipital lobe, precuneus*, cuneus, middle occipital gyrus Left middle temporal gyrus*, superior temporal gyrus, inferior parietal lobule, post-central gyrus Left cerebellum posterior lobe, inferior semi-lunar lobule* Right cerebellum posterior lobe, cerebellar tonsil*, inferior semi-lunar lobule, cerebellum anterior lobe Right superior temporal gyrus*, post-central gyrus Left inferior parietal lobule* Right cerebellum posterior lobe, pyramis* Left inferior parietal lobule, superior temporal gyrus*, insula, supramarginal gyrus Left superior frontal gyrus*, medial frontal gyrus, middle frontal gyrus, inferior frontal gyrus Left cerebellum posterior lobe, cerebellar tonsil*
383
Tadalafil after cerebral stroke Table 2 Regional cerebral blood flow differences between patients group pre- and post-medication uptake Peak coordinate (Montreal Neurological Institute) Number of voxels
T score
Corrected P-value
All patients post-medication > premedication 21,520 >3.4 4.5
y
z
Main anatomical location
14
48
28
32 24
62 28
24 62
32
86
10
3.4 577 >3.4 Lt cortical patients post-medication 18,133 >4.5
x
4.5 4.5 4.5 post-medication 12,276 >4.5 4.5
4.5 >4.5 >4.5
4.5 0.001 24 101 >4.5 0.001 0 Rt cortical patients post-medication > premedication 8862 >5.9 0.001 12
80 36
0 18
72
6
48
64
32
Rt cortical patients premedication > post-medication 15,239 >5.9 0.001 50
64
20
996
>5.9
0.001
936 426 114 394
>5.9 >5.9 >5.9 >5.9
0.001 0.001 0.001 0.001
16 64 20 10
70 32 78 56
16 8 50 46
248 125 205 153 872 136
>5.9 >5.9 >5.9 >5.9 >5.9 >5.9
0.001 0.001 0.001 0.001 0.001 0.001
68 48 30 48 14 20
30 52 72 38 50 58
12 52 42 14 26 50
Left middle frontal gyrus, superior frontal gyrus*, limbic lobe, medial frontal gyrus, inferior frontal gyrus, cingulate gyrus, precentral gyrus, insula superior temporal gyrus, caudate, lentiform nucleus, putamen Right superior frontal gyrus, middle frontal gyrus* Left post-central gyrus, precentral gyrus*, superior frontal gyrus Left occipital lobe, middle occipital gyrus*, inferior occipital gyrus, cerebellum posterior lobe, declive, cerebellum anterior lobe, fusiform gyrus, cuneus, lingual gyrus, middle temporal gyrus, superior temporal gyrus Right superior frontal gyrus*, medial frontal gyrus, middle frontal gyrus Interhemispheric, precuneus*, cuneus, cingulate gyrus, calcarine Right subcallosal gyrus*, anterior cingulate, medial frontal gyrus Right inferior frontal gyrus*, insula, superior temporal gyrus, uncus, parahippocampal gyrus Right superior temporal gyrus*, middle temporal gyrus, inferior temporal gyrus, transverse temporal gyrus, supramarginal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, post-central gyrus, inferior parietal lobule, insula, cerebellum posterior lobe Right Occipital Lobe, Cuneus*, Lingual Gyrus, Inferior Occipital Gyrus, Fusiform Gyrus, Middle Occipital Gyrus Left post-central gyrus*, precentral gyrus insula, transverse temporal gyrus Right superior frontal gyrus, middle frontal gyrus* Right, precuneus, superior parietal lobule*, angular gyrus, inferior parietal lobule Left cerebellum posterior lobe middle occipital gyrus, cuneus, middle temporal gyrus*, cerebellar tonsil, pyramis, inferior semi-lunar lobule Superior temporal gyrus, limbic lobe Inferior parietal lobule, lingual gyrus Supramarginal gyrus, cerebellum anterior lobe, precuneus, posterior cingulate, angular gyrus Left inferior frontal gyrus*, middle frontal gyrus, medial frontal gyrus, limbic lobe, superior frontal gyrus, anterior cingulate, insula Right precuneus*, limbic lobe, posterior cingulate, extra-nuclear Left superior temporal gyrus, middle temporal gyrus*, inferior temporal gyrus, fusiform gyrus Left sublobar, lentiform nucleus*, putamen, extra-nuclear, anterior cingulate, lateral globus pallidus, caudate Right occipital lobe, middle occipital gyrus, cuneus, lingual gyrus* Brainstem, midbrain* Right occipital lobe, middle occipital gyrus, lingual gyrus, cuneus*, parahippocampal gyrus, extra-nuclear, cerebellum anterior lobe, fusiform gyrus, insula, thalamus, caudate, superior temporal gyrus, middle temporal gyrus, transverse temporal gyrus, precentral gyrus Left cerebellum posterior lobe*, cerebellar tonsil, cerebellum anterior lobe, culmen, tuber, declive, left brainstem, pons, fusiform gyrus Right superior frontal gyrus, middle frontal gyrus, inferior parietal lobule, precuneus, middle temporal gyrus*, inferior temporal gyrus, precentral gyrus, supramarginal gyrus, medial frontal gyrus, superior temporal gyrus, superior parietal lobule, post-central gyrus, inferior frontal gyrus, angular gyrus, cingulate gyrus, paracentral lobule Left occipital lobe, precuneus*, cuneus, middle occipital gyrus Left middle temporal gyrus*, superior temporal gyrus, inferior parietal lobule, post-central gyrus Left cerebellum posterior lobe, inferior semi-lunar lobule* Right cerebellum posterior lobe, cerebellar tonsil*, inferior semi-lunar lobule, cerebellum anterior lobe Right superior temporal gyrus*, post-central gyrus Left inferior parietal lobule* Right cerebellum posterior lobe, pyramis* Left inferior parietal lobule, superior temporal gyrus*, insula, supramarginal gyrus Left superior frontal gyrus*, medial frontal gyrus, middle frontal gyrus, inferior frontal gyrus Left cerebellum posterior lobe, cerebellar tonsil*
383
Lorberboym et al. Table 2 (continued) Peak coordinate (Montreal Neurological Institute) Number of voxels
T score
Corrected P-value
x
Multi-focal patients post-medication > premedication 18,323 >3.8 3.8 3.8 3.8 3.8 0.001 Multifocal Patients premedication > post-medication 31,100 >3.8 3.8 >3.8 >3.8
