Authority and ownership: the growth and wilting of medicine patenting in Georgian England.

Secret, owned, Georgian medicines were normally known as patent medicines, though few had a current patent. Up to 1830, just 117 medicines had been patented, whilst over 1,300 were listed for taxation as 'patent medicines'. What were the benefits of patenting? Did medicine patenting affect consumer perception, and how was this used as a marketing tool? What were the boundaries of medical patenting? Patents for therapeutic preparations provided an apparent government guarantee on the source and composition of widely available products, while the patenting of medical devices seems to have been used to grant a temporary monopoly for the inventor's benefit.

Relationship between central sympathetic drive and magnetic resonance imaging-determined left ventricular mass in essential hypertension.

BACKGROUND: Sympathetic activation has been implicated in the development of left ventricular hypertrophy (LVH). However, the relationship between sympathetic activation and LV mass (LVM) has not been clearly defined across a range of arterial pressure measurements. The present study was planned to determine that relationship, using cardiac magnetic resonance imaging to accurately quantify LVM, in hypertensive patients with and without LVH and in normal subjects. METHODS AND RESULTS: Twenty-four patients with uncomplicated and untreated essential hypertension (LVH[-]) were compared with 25 patients with essential hypertension and left ventricular hypertrophy (LVH[+]) and 24 normal control subjects. Resting muscle sympathetic nerve activity was quantified as multiunit bursts and single units. Cardiac magnetic resonance imaging-determined LVM was indexed to body surface area (LVM index); in the LVH[-] group, LVM index was 67+/-2.1 g/m2, a value between those of the LVH[+] (91+/-3.4 g/m2) and normal control (57+/-2.2 g/m2) groups, respectively. The sympathetic activity in the LVH[-] group (53+/-1.3 bursts per 100 cardiac beats and 63+/-1.6 impulses per 100 cardiac beats) was between (at least P<0.001) those of the LVH[+] (66+/-1.7 bursts per 100 cardiac beats and 77+/-2.2 impulses per 100 cardiac beats) and normal control (39+/-3.0 bursts per 100 cardiac beats and 45+/-3.4 impulses per 100 cardiac beats) groups. Significant positive correlation existed between sympathetic activity and LVM index in the LVH[-] and LVH[+] groups (at least r=0.76, P<0.0001) but not in the normal control group. However, no consistent relationship existed between arterial blood pressure and sympathetic activity or LVM index. CONCLUSIONS: These findings further support the hypothesis that central sympathetic activation is associated with the development of LVH in human hypertension.

Direct ambulance admission to the cardiac catheterization laboratory significantly reduces door-to-balloon times in primary percutaneous coronary intervention.

BACKGROUND: Primary percutaneous coronary intervention (PCI) is the preferred treatment for ST-segment elevation myocardial infarction (STEMI) provided it can be delivered within 90 minutes of hospital admission. In clinical practice this target is difficult to achieve. We aimed to determine the effect of direct ambulance admission to the cardiac catheterization laboratory on door-to-balloon and call-to-balloon times in primary PCI. METHODS: We performed a prospective evaluation of a new system of paramedic electrocardiogram diagnosis of STEMI and subsequent direct ambulance admission to the cardiac catheterization laboratory for primary PCI. Door-to-balloon and call-to-balloon times were recorded for all patients. Direct admissions were compared with admissions via the emergency room of the interventional center and of 2 referring hospitals. All times are quoted as medians. RESULTS: Five hundred and seventy-seven patients (70% male, age 63 +/- 13 years) underwent primary PCI between April 2005 and May 2007. After February 2006, 172 (44%) of 387 patients were admitted directly from the ambulance to the catheterization laboratory. Directly admitted patients had significantly reduced door-to-balloon (58 vs 105 minutes, P < .001) and call-to-balloon times (105 vs 143 minutes, P < .001). The 90-minute target for door-to-balloon time was achieved in 94% of direct admissions compared to 29% of patients referred from the emergency room. CONCLUSIONS: Direct admission of patients with suspected STEMI from the ambulance service to the catheterization laboratory significantly reduces time to treatment in primary PCI and allows the 90-minute door-to-balloon time target to be reliably achieved.

Gender-related differences in the sympathetic vasoconstrictor drive of normal subjects.

The risk of cardiovascular disease has been linked to sympathetic activation and its incidence is known to be lower in women than in men. However, the effect of gender on the sympathetic vasoconstrictor drive has not yet been established. In the present study, we investigated whether there is a gender difference in MSNA (muscle sympathetic nerve activity) and blood flow, and to determine the mechanisms involved. We examined 68 normal subjects, 34 women and 34 men, matched for age, BMI (body mass index) and waist circumference. MSNA was measured as the mean frequency of single units (s-MSNA) and as multi-unit bursts (m-MSNA) from the peroneal nerve simultaneously with its supplied muscle CBF (calf blood flow). Women had lower (P=0.0007) s-MSNA (24+/-2.0 impulses/100 cardiac beats) than men (34+/-2.3 impulses/100 cardiac beats), and a greater baroreceptor reflex sensitivity controlling efferent sympathetic nerve activity than men. The sympathetic activity was inversely and directly correlated respectively, with CBF (P=0.03) and CVR (calf vascular resistance; P=0.01) in men only. The responses of an increase in CVR to cold pressor and isometric handgrip tests were significantly smaller in women (P=0.002) than in men, despite similar increases in efferent sympathetic nerve activity. Women had a lower central sympathetic neural output to the periphery, the mechanism of which involved differences in central and reflex control, as well as a lower vasoconstrictor response to this neural output. It is suggested that this may partly explain the observed lower incidence of cardiovascular events in women compared with men.

The sympathetic drive after acute myocardial infarction in hypertensive patients.

BACKGROUND: Sympathetic activation occurs in hypertension (HT) and after acute myocardial infarction (AMI) and is related to greater cardiovascular risk. Also, AMI in patients with HT (AMI-HT) carries greater risk than that in normal subjects (AMI-NT). We therefore planned to determine whether the sympathetic activation and its duration after AMI are greater in patients with antecedent HT than in patients with normal arterial pressure (NT). METHODS: In 68 matched subjects with uncomplicated AMI-HT (n = 17), AMI-NT (n = 17), HT (n = 17), and NT (n = 17), we measured resting muscle sympathetic nerve activity (MSNA) as the mean frequency of multiunit bursts (m-MSNA) and single units (s-MSNA). In AMI groups data were obtained 2 to 4 days after AMI and then at 3-month intervals until MSNA returned to levels found in HT and NT. RESULTS: The AMI-HT had greater (at least P < 0.05; ANOVA) s-MSNA (99 +/- 3.5 impulses/100 cardiac beats) than AMI-NT (84 +/- 2.8 impulses/100 cardiac beats). During follow up, s-MSNA hyperactivity in AMI-HT was always greater than in AMI-NT, and returned to values found in HT and NT (84 +/- 3.5 impulses/100 cardiac beats and 62 +/- 4.4 impulses/100 cardiac beats, respectively) 9 months after AMI. Similar results were obtained for m-MSNA. CONCLUSIONS: AMI in hypertensives resulted in greater MSNA levels lasting at least 6 months longer than AMI in normotensives. This indicates that AMI further augmented the MSNA hyperactivity of HT and that this could be one mechanism involved in the reported worse prognosis in AMI-HT.

Time course of sympathetic neural hyperactivity after uncomplicated acute myocardial infarction.

BACKGROUND: Little information is available on sympathetic activity after acute myocardial infarction (AMI), despite the belief that sympathetic drive is important in relation to morbidity and mortality. Indirect indices such as plasma catecholamines are transiently elevated after uncomplicated AMI, whereas other prognostically important autonomic indices may be affected longer. We planned to quantify central sympathetic output to the periphery after uncomplicated AMI and to investigate its progress over time. METHODS AND RESULTS: After uncomplicated AMI, 13 patients had muscle sympathetic nerve activity (MSNA) assessed from multiunit discharges and from single units with defined vasoconstrictor properties (s-MSNA). Measurements were obtained 2 to 4 days after AMI and were repeated after 3 and 6 months. We also examined 3 matched control groups comprising normal subjects, patients with coronary artery disease, and hospitalized patients without AMI. MSNA and s-MSNA after AMI (84+/-4.6 bursts/100 beats and 95+/-5.8 impulses/100 beats) were unchanged at 3 months but decreased (P<0.01 and P<0.001) after 6 months (75+/-4.0 bursts/100 beats and 80+/-4.4 impulses/100 beats). These were still greater (at least P<0.01) than values in normal subjects, patients with coronary artery disease, and hospitalized patients without AMI (51+/-3.9 bursts/100 beats, 58+/-4.7 impulses/100 beats; 56+/-2.2 bursts/100 beats, 61+/-2.2 impulses/100 beats; and 55+/-3.6 bursts/100 beats, 61+/-3.3 impulses/100 beats, respectively). This sympathetic hyperactivity was inversely correlated to left ventricular ejection fraction but not to changes in blood pressure. CONCLUSIONS: A protracted state of sympathetic hyperactivity was shown to occur after uncomplicated AMI. It is suggested that this hyperactivity may explain delayed cardiovascular morbidity and mortality and that it arises because of an impairment of reflexes from cardiac receptors.

Sympathetic drive in anterior and inferior uncomplicated acute myocardial infarction.

BACKGROUND: The sympathetic activation that follows acute myocardial infarction (AMI) has been associated with increased morbidity and mortality. Because the prognosis after anterior AMI (ant-AMI) is worse than that after inferior AMI (inf-AMI), we planned to determine whether the magnitude of sympathetic hyperactivity differs between the two. METHODS AND RESULTS: Thirty-nine patients with uncomplicated AMI, comprising 2 matched groups of 17 patients with ant-AMI, and 22 patients with inf-AMI were examined. Measurements were obtained 2 to 4 days after AMI and compared with 20 normal subjects (NC) who were matched in terms of age and body weight to the AMI groups. Resting muscle sympathetic nerve activity was quantified from multiunit bursts (MSNA) and from single units (s-MSNA). Both groups of AMI patients were matched with regard to hemodynamic variables, left ventricular function, and infarct size. Both groups had greater (at least P<0.01) sympathetic nerve activity than NC (60+/-4.3 bursts/100 cardiac beats and 68+/-4.9 impulses/100 cardiac beats), but the magnitude of sympathetic nerve hyperactivity in ant-AMI (81+/-4.0 bursts/100 cardiac beats and 91+/-4.9 impulses/100 cardiac beats) was similar (P>0.05) to that in inf-AMI (80+/-3.2 bursts/100 cardiac beats and 90+/-4.0 impulses/100 cardiac beats) CONCLUSIONS: Both ant-AMI and inf-AMI resulted primarily in a similar magnitude of sympathetic nerve hyperactivity. These findings suggest that the worse prognosis after ant-AMI compared with after inf-AMI would not be related primarily to the degree of sympathetic hyperactivity.

Impact of type 2 diabetes mellitus on sympathetic neural mechanisms in hypertension.

BACKGROUND: Essential hypertension (EHT) is a major cardiovascular risk factor, and the additional presence of type 2 diabetes mellitus (DM2) increases this risk. However, although the sympathetic nerve hyperactivity of EHT is known to play a role in cardiovascular risk, the level of sympathetic nerve activity is known neither in DM2 nor in hypertensive type 2 diabetic patients (EHT+DM2). Therefore, we planned to quantify the vasoconstrictor sympathetic nerve activity in patients with EHT+DM2 and with DM2 relative to that in matched groups with EHT and normal blood pressure (NT). METHODS AND RESULTS: In 68 closely matched subjects with EHT+DM2 (n=17), DM2 (n=17), EHT (n=17), and NT (n=17), we measured resting muscle sympathetic nerve activity as the mean frequency of multiunit bursts (MSNA) and of single units (s-MSNA) with defined vasoconstrictor properties. The s-MSNA in EHT+DM2 (97+/-3.8 impulses/100 beats) was greater (at least P<0.001) than in EHT (69+/-3.4 impulses/100 beats) and DM2 (78+/-4.1 impulses/100 beats), and all these were significantly greater (at least P<0.01) than in NT (53+/-3.3 impulses/100 beats) despite similar age and body mass index. The MSNA followed a similar trend. In addition, the level of insulin was also raised in EHT+DM2 (20.4+/-3.6 microU/mL) and DM2 (18.1+/-3.1 microU/mL; at least P<0.05) compared with HT or NT. CONCLUSIONS: Patients with EHT+DM2, EHT, or DM2 had central sympathetic hyperactivity, although plasma insulin levels were raised only in EHT+DM2 and DM2. The combination of EHT and DM2 resulted in the greatest sympathetic hyperactivity and level of plasma insulin, and this hyperactivity could constitute a mechanism for the increased risks of this condition.

Sympathetic neural mechanisms in white-coat hypertension.

OBJECTIVES: This study planned to establish whether sympathetic hyperactivity exists in white-coat hypertension (WHT) in the clinical setting, relative to matched groups with normotension (NT) and untreated essential hypertension (EHT). BACKGROUND: White-coat hypertension differs from EHT by the presence of normal ambulatory blood pressure. Sympathetic hyperactivity exists in patients with EHT in the clinical setting and is believed to contribute to the development of target organ damage. Similar organ damage has been reported in WHT, yet little is known about sympathetic neural activity in this condition. METHODS: Using microneurography, we examined groups of 12 matched subjects with WHT, EHT and NT during the same clinical setting to quantify muscle sympathetic nerve activity as multiunit discharge (MSNA) and single units (s-MSNA). RESULTS: The s-MSNA in WHT (54 +/- 4.2 impulses/100 beats) was greater (p < 0.05) than in NT (37 +/- 5.4 impulses/100 beats) despite similar age and body mass index (BMI). The EHT values of s-MSNA (73 +/- 5.2 impulses/100 beats) were significantly (p < 0.05) greater than in WHT despite similar age, BMI and blood pressure levels. The MSNA followed a similar trend. White-coat hypertension had a similar cardiac baroreceptor reflex sensitivity to NT, but this was impaired in EHT relative to both NT and WHT. CONCLUSIONS: It was shown, in the clinical setting, that central sympathetic hyperactivity exists in WHT, albeit to a lesser degree than EHT. These findings suggest that WHT may not be entirely benign and that the observed sympathetic hyperactivity may be responsible for development of target organ damage in this group of patients.

Relationship of neurovascular compression to central sympathetic discharge and essential hypertension.

OBJECTIVES: We planned to examine the relationship between neurovascular compression (NVC) of the rostral ventrolateral medulla (RVLM) and the magnitude of central sympathetic hyperactivity in normal subjects and in patients with untreated and uncomplicated essential hypertension (EHT). BACKGROUND: Previously it has not been possible to establish a definitive relationship between EHT and NVC of the RVLM, a location containing efferent sympathetic vasoconstrictor neurons. Furthermore, the relationship between NVC and magnitude of sympathetic nerve hyperactivity has not been adequately examined, despite the knowledge that hyperactivity varies according to EHT severity. METHODS: In 83 subjects, we used magnetic resonance imaging to detect NVC and, independently, peroneal microneurography to quantify muscle sympathetic nerve activity (MSNA), expressed as the mean frequency of multi-unit discharge (m-MSNA) and of single units (s-MSNA). Subjects were classified according to arterial pressure values into groups with normal (NT) (n = 24) or high-normal (HN) (n = 14) arterial pressure and mild (EHT-1) (n = 26) or severe (EHT-2/3) (n = 19) EHT. RESULTS: A significantly greater sympathetic activity was found in 23 subjects with NVC, compared with 60 subjects without NVC. The prevalence of NVC and the magnitude of sympathetic hyperactivity were greater in the EHT-1 group (p < 0.05) than in the other three groups. There was no significant difference in confounding variables between the groups. Although increased sympathetic activity was strongly predictive of NVC, this was not significantly related to baroreceptor sensitivity controlling the pulse interval (cardiac baroreceptor reflex sensitivity). CONCLUSIONS: Neurovascular compression of the RVLM may cause central sympathetic activation in normal and hypertensive populations and therefore has significant implications regarding the pathogenesis of EHT.

Relationship between central sympathetic activity and stages of human hypertension.

BACKGROUND: The magnitude of sympathetic hyperactivity in essential hypertension (EHT) varies with its severity and complications. There are no data on sympathetic nerve activity in borderline (BHT) or white-coat hypertension (WHT) relative to the various stages of EHT, despite suggestions that both lead to established EHT and organ damage through sympathetic mechanisms. We planned to determine the magnitude of sympathetic nerve activity in patients with BHT and WHT in relation to normality and various stages of sustained EHT. METHODS: We examined 90 untreated subjects comprising matched groups with BHT (n = 13), WHT (n = 12), Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure EHT stage 1 (EHT-1 n = 12), EHT stages 2 and 3 (EHT-2/3 n = 14), high-normal pressure (HN n = 14), and normal pressure (NT n = 13), as well as a group with EHT complicated by left ventricular hypertrophy (EHT+LVH n = 12). We quantified muscle sympathetic nerve activity as the mean frequency of multiunit discharge (MSNA) and that of single-units (s-MSNA). RESULTS: We found a greater (at least P <.01) mean central sympathetic frequency in BHT (75 +/- 5.8 impulses/100 beats), EHT-1 (76 +/- 4.0 impulses/100 beats), and EHT+LVH (79 +/- 4.3 impulses/100 beats) than in EHT-2/3 (57 +/- 3.1 impulses/100 beats), WHT (52 +/- 3.6 impulses/100 beats), HN (42 +/- 3.9 impulses/100 beats), and NT (33 +/- 3.6 impulses/100 beats). BHT hyperactivity was closer to that of EHT, whereas WHT was closer to NT. CONCLUSIONS: Central sympathetic activity was greatest in BHT, early stage, and complicated EHT, and as such is likely to play an integral role in the development of hypertension and its complications. Sympathetic hyperactivity occurs in WHT, but to a lesser extent than in BHT.

Sympathetic neural activation in nondiabetic metabolic syndrome and its further augmentation by hypertension.

Hypertension is a major cardiovascular risk factor in the metabolic syndrome (MS) in which the presence of insulin resistance, glucose intolerance, abnormal lipoprotein metabolism, and central obesity all confer an increased risk. Because essential hypertension (EHT), insulinemia, and visceral fat are associated with sympathetic hyperactivity, which is itself known to increase cardiovascular risk, the aim of this study was to see if MS is a state of sympathetic nerve hyperactivity and if the additional presence of EHT intensifies this hyperactivity. In 69 closely matched subjects, comprising hypertensive MS (MS+EHT, 18), normotensive MS (MS-EHT, 17), hypertensives without MS (EHT, 16), and normotensive controls without MS (NC, 18), we measured resting muscle sympathetic nerve activity (MSNA) as assessed from multiunit discharges and from single units with defined vasoconstrictor properties (s-MSNA). The s-MSNA in MS+EHT (76+/-3.1 impulses/100 beats) was greater (at least P<0.01) than in MS-EHT (62+/-3.2 impulses/100 beats) and in EHT (60+/-2.3 impulses/100 beats), and all these were significantly greater (at least P<0.01) than in NC (46+/-2.7 impulse/100 beats). The multi-unit MSNA followed a similar trend. These findings suggest that MS is a state of sympathetic nerve hyperactivity and that the additional presence of hypertension further intensifies this hyperactivity. The degree of sympathetic hyperactivity seen in this study could be argued at least partly to contribute to the higher cardiovascular risk and metabolic abnormalities seen in MS+EHT patients.

Arterial pressure lowering effect of chronic atenolol therapy in hypertension and vasoconstrictor sympathetic drive.

Although the beta1-adrenergic blocking agent atenolol is an established antihypertensive therapy, its effect on peripheral sympathetic vasoconstrictor drive has remained controversial. In patients with hypertension, atenolol therapy has been reported to either increase or have no effect on peripheral vascular resistance, despite other reports showing no change or a decrease in peripheral sympathetic drive. This study was designed, in patients with untreated essential hypertension (EHT), to quantify changes in simultaneously measured peroneal muscle sympathetic nerve activity (MSNA) and calf vascular resistance (CVR) accompanying atenolol therapy. MSNA was quantified as the mean frequency of single units (s-MSNA) and as multiunit bursts (MSNA bursts) using the technique of microneurography, and CVR was measured using a standard plethysmographic technique. Firstly, by comparing two age- and body weight- matched groups, each of 14 patients with hypertension, we found that the group on atenolol therapy (treated-HT) had similar MSNA values counted over the same number of cardiac beats and similar CVR levels (at least P>0.40) to the group without therapy (untreated-HT). Secondly, we examined 10 EHT patients before and after 8+/-0.4 weeks of oral atenolol therapy (HT-A) in comparison to seven control patients with hypertension and no treatment (HT-C) who were examined over a similar period of time. We found that the measures of MSNA and CVR did not significantly change in both groups. We conclude that the arterial pressure lowering effect of atenolol was not related to significant changes in central vasoconstrictor sympathetic drive to the periphery.

Sympathetic neural hyperactivity and its normalization following unstable angina and acute myocardial infarction.

Impaired autonomic function occurs after AMI (acute myocardial infarction) and UA (unstable angina), which may be important prognostically. However, the pattern of sympathetic nerve hyperactivity has been investigated only after AMI. We aimed to quantify central sympathetic output to the periphery in patients with UA, investigate its progress over time relative to that after uncomplicated AMI and to explore the mechanisms involved. Muscle sympathetic nerve activity (MSNA) assessed from multiunit discharges and from single units (s-MSNA) was obtained in matched patients with UA ( n =9), AMI ( n =14) and stable CAD (coronary artery disease, n =11), patients with chest pain in which AMI was excluded (NMI, n =9) and normal controls (NCs, n =14). Measurements were obtained 2-4 days after UA or AMI, and repeated at 3 monthly intervals until they returned to normal levels. The respective MSNA and s-MSNA early after UA (72+/-4.0 bursts/100 beats and 78+/-4.2 impulses/100 beats respectively) were less than those after AMI (83+/-4.4 bursts/100 beats and 93+/-5.5 impulses/100 beats respectively). Relative to the control groups of NCs (51+/-2.7 bursts/100 beats and 58+/-3.4 impulses/100 beats respectively) and patients with CAD (54+/-3.7 bursts/100 beats and 58+/-3.9 impulses/100 beats respectively) and NMI (52+/-4.5 bursts/100 beats and 59+/-4.9 impulses/100 beats respectively), values returned to normal after 6 months in UA (55+/-5.0 bursts/100 beats and 62+/-5.5 impulses/100 beats respectively) and 9 months after AMI (60+/-3.8 bursts/100 beats and 66+/-4.2 impulses/100 beats respectively). In conclusion, both UA and AMI result in sympathetic hyper-activity, although this is of smaller magnitude in UA and is less protracted than in AMI. It is suggested that this hyperactivity is related to the degree of left ventricular dysfunction and reflexes.