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Biomedical subjects

C J Mathias

Publications and source records attributed to C J Mathias.

At least 91 records · Page 5Linked to original sources
PubMed1998

Cardiovascular autonomic dysfunction in parkinsonian patients.

Cardiovascular dysfunction may occur in parkinsonian patients for a variety of reasons. Patients usually are more than 50 years old and on various drugs (both antiparkinsonian and for associated medical disorders), some of which may have cardiovascular effects. Autonomic failure increases with age and also is recognized in parkinsonian patients who have the disorder multiple system atrophy, in which there is substantial cardiovascular dysfunction. Thus, recognition of cardiovascular dysfunction and its causes in parkinsonian patients is of importance in diagnosis (in separating the various parkinsonian diseases), in determining prognosis, and finally in management. This article outlines the major areas of cardiovascular dysfunction, including disorders of blood pressure control, heart rate, and regional circulation, especially to vital organs. Clinical features and evaluation are described, together with abnormalities in different parkinsonian disorders and the principles of management.

Autonomic Nervous System↗
PubMed1998

Indium-111-DTPA-folate as a potential folate-receptor-targeted radiopharmaceutical.

UNLABELLED: Indium-111-labeled diethylenetriamine pentaacetic acid (DTPA)-folate was evaluated as a radiopharmaceutical for targeting tumor-associated folate receptors. METHODS: Athymic mice were subcutaneously inoculated with approximately 1.8 x 10(6) folate receptor-positive KB (human nasopharyngeal carcinoma) cells, yielding 0.2- to 0.6-g tumors in 15 days, at which time (111)In-DTPA-folate, (111)In-DTPA or (111)In-citrate was administered by intravenous injection. RESULTS: The (111)In-DTPA-folate conjugate afforded marked tumor-specific (111)In deposition in vivo using this mouse model. The involvement of the folate receptor in mediating tumor uptake of (111)In-DTPA-folate was demonstrated by the blocking of tumor uptake by coadministration of free folic acid (intravenous). The (111)In-DTPA-folate also shows folate receptor-mediated uptake and retention in the kidneys, presumably reflecting radiotracer binding to folate receptors of the proximal tubules. In control experiments, the (111)In-citrate radiopharmaceutical precursor was also shown to afford significant tumor uptake of (111)In, but with much poorer tumor-to-background tissue contrast than that obtained with (111)In-DTPA-folate. Unconjugated (111)In-DTPA showed no tumor affinity. CONCLUSION: Indium-111-DTPA-folate appears suitable as a radiopharmaceutical for targeting tumor-associated folate receptors.

Animals↗
PubMed1997

Abnormal regional blood flow responses during and after exercise in human sympathetic denervation.

1. Blood pressure, superior mesenteric artery (SMA) and skeletal muscle blood flow, cardiac index (CI) and systemic vascular resistance responses to supine leg exercise were measured in six age-matched normal subjects (controls) and in eleven subjects with sympathetic denervation due to primary autonomic failure (AF). 2. During exercise, blood pressure rose in controls but fell markedly in AF. After exercise, blood pressure rapidly returned to baseline in controls but remained low in AF. During exercise, systemic vascular resistance fell in controls and AF but tended to fall further in AF and remained low post exercise. CI increased similarly in controls and AF. 3. During exercise, SMA blood flow fell similarly in controls and AF, but the fall initially was slower in AF; recovery was more rapid post exercise in controls. SMA vascular resistance tended to rise less and more slowly in AF and remained elevated post exercise. 4. Forearm muscle (FM) blood flow and FM vascular resistance did not change from resting values in controls or AF post exercise. After exercise, leg muscle (LM) blood flow rose and LM vascular resistance fell equally in both groups although LM blood flow remained elevated, 10 min post exercise in AF. 5. In sympathetically denervated humans, increased blood flow (due to excessive vasodilatation, lack of sympathetic restraint, or both) in leg muscle during and after exercise in combination with impaired splanchnic vasoconstriction in the early stages of exercise may have contributed to exercise-induced hypotension.

Autonomic Nervous System Diseases↗
PubMed1997

Distinction of idiopathic Parkinson's disease from multiple-system atrophy by stimulation of growth-hormone release with clonidine.

BACKGROUND: Idiopathic Parkinson's disease is a common neurodegenerative disease that is difficult to distinguish from other parkinsonian syndromes such as multiple-system atrophy (MSA). In MSA, autonomic dysfunction is common and is associated with either parkinsonian or cerebellar features, or both. Differentiation of idiopathic Parkinson's disease from MSA is important because prognosis, complications, and response to therapy vary according to disorder. Our aim was to find out whether clonidine/growth hormone (GH) testing distinguishes idiopathic Parkinson's disease from MSA. METHODS: Clonidine is a centrally active alpha 2-adrenoceptor agonist that raises concentrations of GH in serum in healthy people and those with pure autonomic failure (with peripheral lesions), but not in those with MSA (with a central autonomic deficit). We investigated the effects of clonidine on 14 people with idiopathic Parkinson's disease (without autonomic deficits). 31 people with MSA of the three different clinical forms (parkinsonian, cerebellar, and mixed), 19 people with pure autonomic failure, and 27 healthy participants. In nine people with parkinsonian MSA (MSA-P), the GH response to levodopa was also assessed. FINDINGS: Clonidine raised serum GH concentrations in patients with idiopathic Parkinson's disease (median increase 8.98 [IQR 6.6-16.6] mU/L), normal participants (13.2 [7.0-18.6] mU/L), and patients with pure autonomic failure (12.5 [5.6-18.2] mU/L). In those with MSA who had central autonomic failure, GH concentrations were unchanged (MSA-P; 0.41 [-0.30 to 2.09] mU/L and cerebellar MSA [MSA-C] 1.67 [0-4.49] mU/L). The GH response to clonidine in idiopathic Parkinson's disease was significantly different from that in MSA-P (p < 0.0002). In MSA-P, the dopamine precursor levodopa raised GH concentrations (from mean 2.7 [SE 1.0] mU/L to mean 18.2 [6.0] mU/L, p < 0.05) and GH-releasing hormone (GHRH) concentrations (from mean 20.6 [3.25] ng/L to mean 68.0 [10.6] ng/L, p < 0.05), excluding dysfunction of pituitary somatotrophs or GHRH neurons as a cause for the absent GH response to clonidine in MSA. INTERPRETATION: The GH responses to clonidine clearly differentiated idiopathic Parkinson's disease from MSA-C and MSA-P. Together with the levodopa studies they indicated a specific alpha 2-adrenoceptor-hypothalamic deficit in MSA. The clonidine-GH test may provide further insight into central neurotransmitter and alpha 2-adrenoceptor-hypothalamic abnormalities in MSA.

Adrenergic alpha-Agonists↗
PubMed1997

Mixed bis(thiosemicarbazone) ligands for the preparation of copper radiopharmaceuticals: synthesis and evaluation of tetradentate ligands containing two dissimilar thiosemicarbazone functions.

A series of four "mixed" bis(thiosemicarbazone) keto aldehyde derivatives containing dissimilar thiosemicarbazone functions were synthesized and evaluated as ligands for preparation of radiocopper-labeled radiopharmaceuticals. The pyruvaldehyde-based mixed bis(thiosemicarbazone) ligands CH3C[=NNHC(S)NH2]CH[=NNHC(S)NHMe] (4a), CH3C[=NNHC(S)NHMe]-CH[=NNHC(S)NH2] (4b), CH3C[=NNHC(S)NH2]CH[=NNHC(S)NMe2] (4c), and CH3C[=NNHC-(S)NHMe]CH[=NNHC(S)NMe2] (4d) were obtained by reaction of thiosemicarbazide, N4-methylthiosemicarbazide, or N4,N4-dimethylthiosemicarbazide with pyruvaldehyde 2-thiosemicarbazones that had been generated by oxidative cleavage of the appropriate pyruvic aldehyde dimethyl acetal 2-thiosemicarbazone. The 67Cu-labeled complexes of ligands 4a-d were prepared and screened in a rat model to assess the potential of each chelate as a 62Cu radiopharmaceutical for imaging with positron emission tomography. In the rat model the 67Cu complexes of ligands 4a-d exhibit significant uptake into the brain and heart after intravenous injection, following trends similar to those previously reported for the related bis(thiosemicarbazone) complexes, Cu-PTS, Cu-PTSM, and Cu-PTSM2 (derived from pyruvaldehyde bis(thiosemicarbazone), pyruvaldehyde bis(N4-methylthiosemicarbazone), and pyruvaldehyde bis(N4,N4-dimethylthiosemicarbazone), respectively). Ultrafiltration studies using solutions of dog and human serum albumin reveal that the 67Cu complexes of ligands 4a-d, like the Cu(II) complex of pyruvaldehyde bis(N4-methylthiosemicarbazone), interact more strongly with human albumin than dog albumin.

Animals↗
PubMed1997

Cerebellar presentation of multiple system atrophy.

Early diagnosis of multiple-system atrophy (MSA) is important in patients presenting with late-onset cerebellar ataxia because it has a less favourable prognosis than other degenerative ataxic disorders. We report cerebellar presentation of MSA in a series of 16 patients, 3 of whom later developed parkinsonism. Two-thirds of them had early evidence of impaired postural reflexes with a history of recurrent falls. Some of these had a narrow-based, unsteady gait, unlike the more classic broad-based gait ataxia of cerebellar disease. On review of the patients' histories, genitourinary dysfunction (particularly impotence) was present at the onset of, or preceding, cerebellar ataxia in 60% of patients, but this had often been attributed to age, or to urological or gynaecological causes. External striated anal or urethral sphincter electromyography (EMG) demonstrated features of chronic denervation and reinnervation in 14 (93%) of 15 patients, consistent with degeneration in Onuf's nucleus as occurs in MSA. Autonomic function tests were abnormal in 9 (64%) of 14 patients. Our data suggest that close enquiry into genitourinary function and analysis of the gait disorder can be useful pointers to a diagnosis of MSA in patients with an unexplained adult-onset progressive cerebellar syndrome, and that sphincter EMG is the most useful investigation in this context.

Adult↗
PubMed1997

Postprandial hypotension and parkinsonian state in Parkinson's disease.

Abnormal postprandial cardiovascular responses such as postprandial hypotension (PPH) occur in primary autonomic failure and contribute significantly to morbidity. The extent and frequency of PPH and its relationship to the parkinsonian state in idiopathic Parkinson's disease (IPD) is unknown. By studying 20 patients with IPD (without autonomic failure) and 16 age-matched controls after both groups ingested a standard isocaloric balanced liquid meal, we have shown that supine PPH complicates IPD and is related to marked worsening of the parkinsonian state as measured by a cumulative score of tremor, rigidity, bradykinesia, posture, and gait. Furthermore, significant postural hypotension is unmasked that results in postural intolerance due to presyncopal symptoms. Our study indicates that, in patients with IPD, ingestion of a meal may lead to abnormal postprandial cardiovascular responses and aggravation of the parkinsonian stage. The underlying mechanisms are unclear, although vasodilatory gut peptides released in response to food ingestion may be contributory.

Adult↗
PubMed1997

Simultaneous arterial and urinary bladder pressure recordings in multiple system atrophy and in spinal disorders with detrusor hyperreflexia.

Simultaneous arterial and urinary bladder pressure measurements were recorded during bladder filling in 21 patients with urinary bladder symptoms; seven patients had autonomic failure due to multiple system atrophy (MSA), seven had spinal cord disease of different aetiology with detrusor hyperreflexia (DH) and seven had no neurological abnormalities. A significant increase in average systolic blood pressure (BP) was recorded on bladder filling in the neurologically intact patients (from 110 to 137 mmHg) and in the patients with spinal cord disease and DH (from 109 to 129 mmHg). In those with MSA, the BP rose in four and fell in three patients. The vesicopressor response during cold receptor-mediated DH was not significantly higher when compared with room-temperature saline and when compared with the BP response during bladder filling in the neurologically intact patients. Finally, intravesical lignocaine retained in the bladder for 15 min did not influence the BP response to cold receptor stimulation in patients with spinal cord disease and DH. These findings and their pathophysiological and clinical implications are discussed.

Adult↗
PubMed1997

Cardiovascular and hormonal responses to food ingestion in humans with spinal cord transection.

In sympathetic denervation due to primary autonomic failure, ingestion of food causes a fall in blood pressure (BP) and exacerbates postural hypotension. It is not known whether these responses occur in tetraplegics with physiologically complete cervical spinal cord transection, who also have sympathetic dysfunction because of disruption of descending spinal sympathetic pathways. We, therefore, studied the effect of a liquid meal on BP, heart rate (HR) and neurohormonal levels in tetraplegics. Paraplegics with low lesions and without sympathetic dysfunction served as controls. After food ingestion, there was no fall in BP in tetraplegics or in controls. HR did not change in either group. After fund, plasma noradrenaline was unchanged in tetraplegics, but rose in controls, while plasma renin activity (PRA) rose in tetraplegics but not in controls. The fall in BP and rise in HR on head-up tilt after the meal in tetraplegics was similar to that before the meal. There was no change in PRA following pre-prandial tilt in either group; post-prandial tilt raised levels in the tetraplegics, unlike in controls. Thus there is considerable variance in the responses to food between tetraplegics and paraplegic controls, and even greater differences when compared with published data in other autonomic disorders with sympathetic dysfunction; this may relate to the site and the nature of the sympathetic lesion and the ability to activate compensatory mechanisms.

Adult↗
PubMed1997

Systemic and regional (including superior mesenteric) haemodynamic responses during supine exercise while fasted and fed in normal man.

The systemic and regional (including superior mesenteric artery, SMA) responses to exercise in the fasting and fed state were studied in ten normal subjects before, during and after 9 min of graded supine bicycle exercise on two separate occasions, when fasted and after a liquid meal. During exercise, blood pressure (BP) and cardiac index rose similarly in both states. Resting SMA blood flow was higher when fed (519 (282-619) versus 240 (133-255) ml/min, p < 0.01). SMA blood flow fell during exercise in both states, to 98 (63-154) ml/min, p < 0.01 when fasted and to 55 (42-149) ml/min, p < 0.01 when fed. SMA vascular resistance rose during exercise in both states, but rose less when fasted by 36 (6-57)% versus 143 (36-240)% (NS). Resting forearm and leg blood flow (FBF and LBF) and vascular resistance (FVR and LVR) were similar fasted and fed. FBF and FVR did not change after exercise in either state. LBF rose and LVR fell similarly in both states. We conclude that in normal subjects, although splanchnic oxygen demand is likely to be greater after food, during light to moderate exercise splanchnic vasoconstriction contributes to maintenance of BP.

Aged↗
PubMed1997

Haemodynamic and hormonal effects of two different oral glucose loads in normal human subjects.

Systemic and regional haemodynamics and hormonal responses to two isovolaemic, iso-osmotic solutions of 0.5 and 1.0 g/kg of glucose were compared in ten normal young subjects (mean age 24 +/- 3 years). Measurements were made while subjects were supine before glucose and every 15 min for 60 min after ingestion of each solution. Superior mesenteric artery (SMA) blood flow rose similarly after each dose. There were corresponding reductions in SMA vascular resistance after each dose but no difference between doses. Pulsatility index of the SMA was lower after 1.0 g/kg. There was no change in blood pressure, heart rate, cardiac index or forearm muscle blood flow after either dose. Plasma glucose levels rose after each dose and were higher after 1.0 g/kg. There was no difference in the plasma insulin rise between doses. Plasma levels of noradrenaline and adrenaline did not change after either dose. These results suggest that with glucose loads within the ranges we used, changes in SMA blood flow are not dose-related and larger increases in SMA blood flow or in plasma insulin than we observed are needed to reflexly activate cardiac output and raise plasma noradrenaline levels in young normal subjects.

Adult↗
PubMed1997

Pharmacological manipulation of human gastrointestinal blood flow.

The splanchnic circulation is one of the largest vascular regions in man. In the past, this has been difficult to study because of methodological problems. The adapting of noninvasive Doppler techniques has made it possible to develop reproducible measurements of coeliac and superior mesenteric artery blood flow, which are the main contributors to the gastrointestinal vasculature. This has resulted in the further understanding of neurogenic and humoral control of this region in a number of physiological and pathophysiological states, and has contributed towards the knowledge of its pharmacological control. These studies are of relevance to cardiovascular homeostasis and, in particular, systemic blood pressure control which depends upon various factors including responses in different vascular regions. In this review the key physiological factors which influence pharmacological studies on this circulation will be discussed. Examples will be provided, in subjects with cardiovascular and neurological disorders, of how administration of endogenous and exogenous substances, including drugs with specific pharmacological effects, alter human gastrointestinal blood flow. These will include insulin, alcohol, the somatostatin analogue octreotide, the central acting sympatholytic clonidine and the angiotensin II-converting inhibitor captopril. The relevance of these studies to subjects with postural hypotension due to sympathetic denervation and to primary hypertension, in particular, will be discussed.

Adrenergic alpha-Agonists↗
PubMed1997

Autonomic effects of selegiline: possible cardiovascular toxicity in Parkinson's disease.

OBJECTIVES: The United Kingdom Parkinson's Disease Research Group (UKPDRG) trial found an increased mortality in patients with Parkinson's disease randomised to receive selegiline (10 mg/day) and levodopa compared with those taking levodopa alone. Unwanted effects of selegiline on cardiovascular regulation have been investigated as a potential cause for the unexpected mortality finding of the UKPDRG trial. METHODS: The cardiovascular responses to a range of physiological stimuli, including standing and head up tilt, were studied in patients with Parkinson's disease receiving levodopa alone and a matched group on levodopa and selegiline. RESULTS: Head up tilt caused selective and often severe orthostatic hypotension in nine of 16 patients taking selegiline and levodopa, but was without effect on nine patients receiving levodopa alone. Two patients taking selegiline lost consciousness with unrecordable blood pressures and a further four had severe symptomatic hypotension. The normal protective rises in heart rate and plasma noradrenaline were impaired. The abnormal response to head up tilt was reversed by discontinuation of selegiline. Drug withdrawal caused a pronounced deterioration in motor function in 13 of the 16 patients taking selegiline. CONCLUSION: Therapy with selegiline and levodopa in combination may be associated with severe orthostatic hypotension not attributable to levodopa alone. Selegiline also has pronounced symptomatic motor effects in advanced Parkinson's disease. The possibilities that these cardiovascular and motor findings might be due either to non-selective inhibition of monoamine oxidase or to amphetamine and met-amphetamine are discussed.

Aged↗
PubMed1997

Separation of peripheral and central cardiovascular actions of angiotensin II.

The pressor and vasoconstrictor action of angiotensin II (ANG II) is considered to be caused by a combination of its direct and indirect vascular effects, the latter mediated by the sympathetic nervous system. The purpose of this study was to determine the extent to which the direct and indirect actions of ANG II contribute to its pressor and vascular effects. Blood pressure, cutaneous vascular, and plasma norepinephrine responses to intravenous ANG II were measured in conscious rabbits before and after inhibition of central sympathetic outflow with intravenous and intracisternal clonidine and after ganglionic blockade with intravenous pentolinium. Intravenous ANG II caused a similar dose-related rise in blood pressure before and after sympathetic blockade with intravenous clonidine, intracisternal clonidine, and intravenous pentolinium. In contrast, the dose-related fall in cutaneous ear blood flow and cutaneous ear temperature and rise in cutaneous ear vascular resistance induced by intravenous ANG II were abolished after intravenous clonidine, intracisternal clonidine, and intravenous pentolinium. Heart rate was unchanged after ANG II. There were no changes in back skin or rectal temperature. There was a nonsignificant fall in plasma norepinephrine and no change in epinephrine after ANG II. These results demonstrate that the acute pressor response to intravenous ANG II is mediated by its direct vascular effects and is not dependent on central or ganglionic stimulation of the sympathetic nervous system, in contrast to the effect of ANG II on cutaneous ear vasoconstriction, which is predominantly caused by a centrally mediated increase in sympathetic nervous activity. Our results separate, in conscious rabbits, the direct vascular effects of ANG II from its indirect vascular actions, which are mediated by central sympathetic stimulation in the brain.

Angiotensin II↗
PubMed1996

Effect of meal size on post-prandial blood pressure and on postural hypotension in primary autonomic failure.

In chronic autonomic failure, food ingestion causes a profound and rapid fall in supine blood pressure and aggravates postural hypotension. Food volume and caloric load are important determinants of gastric emptying and postprandial splanchnic hyperaemia, which appears to be a major contributor to hypotension. We therefore compared the cardiovascular effects of three large meals with six small meals providing an identical daily caloric intake, in seven subjects with primary autonomic failure. Daytime ambulatory blood pressure (BP) was measured by Spacelabs 90207 every 30 min with additional recordings while lying, sitting and standing, 30 min after each meal. Systolic and diastolic BP were lower in all three positions after large meals; systolic 131 versus 151 mmHg (large versus small), p = 0.005, 109 versus 124 mmHg, 89 versus 103 mmHg and diastolic 76 versus 90 mmHg, p = 0.02, 66 versus 78 mmHg, p = 0.07 and 50 versus 66 mmHg, p = 0.06 for lying, sitting and standing, respectively. Between meals, BP fell to lower levels with large meals, 88 (20) mmHg versus 104 (19) mmHg, p = 0.002 and 48 (13) mmHg versus 63 (13), p = 0.0001 mmHg for systolic and diastolic pressure respectively. Five subjects had more symptoms of postural dizziness after large meals. In primary autonomic failure, smaller and more frequent meals reduce postprandial hypotension and diminish postural symptoms post-meal. This is likely to be a useful non-pharmacological method in the management of postprandial hypotension.

Aged↗
PubMed1996

Neurohumoral, peptidergic and biochemical responses to supine exercise in two groups with primary autonomic failure: Shy-Drager syndrome/multiple system atrophy and pure autonomic failure.

The neurohumoral, peptidergic and biochemical responses to supine leg exercise were studied in two groups with primary autonomic failure: Shy-Drager syndrome (SDS, n = 15) and pure autonomic failure (PAF, n = 15), to determine if these accounted for exercise-induced hypotension and the greater blood pressure (BP) fall in PAF. Responses were compared to normal subjects (controls, n = 15), in whom BP rose with exercise. Resting plasma noradrenaline (NA) was higher in controls than SDS, and was lowest in PAF. With exercise, NA increased in controls, with a small rise in SDS, but no change in PAF. Resting plasma adrenaline (A) was higher in controls and SDS than PAF, with no change during exercise. Plasma dopamine was unrecordable at all stages in all groups. Resting plasma renin activity (PRA) was higher in controls than SDS and PAF, and was unchanged with exercise in all groups. Plasma insulin, C-peptide and serum growth hormone (GH) were similar at rest and with exercise in the three groups. Plasma glucose was higher at rest in SDS and PAF, and increased with exercise in all three groups. In conclusion, neither exercise-induced hypotension, nor the differences between SDS and PAF could be related to abnormalities in the release of A, PRA, insulin, glucose or GH. The abnormal NA response to exercise was consistent with the BP fall being due to inadequate compensatory sympathetic activity. In SDS, the small NA increase, in the presence of supersensitivity, may have reduced their BP fall as compared to PAF. These results suggest that impaired sympathetic neural activity is a key factor in exercise-induced hypotension.

Autonomic Nervous System Diseases↗