Hemodynamic impact of isobaric levobupivacaine versus hyperbaric bupivacaine for subarachnoid anesthesia in patients aged 65 and older undergoing hip surgery.

BACKGROUND: The altered hemodynamics, and therefore the arterial hypotension is the most prevalent adverse effect after subarachnoid anesthesia. The objective of the study was to determine the exact role of local anesthetic selection underlying spinal anesthesia-induced hypotension in the elderly patient. We conducted a descriptive, observational pilot study to assess the hemodynamic impact of subarachnoid anesthesia with isobaric levobupivacaine versus hyperbaric bupivacaine for hip fracture surgery. DESCRIPTION: Hundred twenty ASA status I-IV patients aged 65 and older undergoing hip fracture surgery were enrolled. The primary objective of our study was to compare hemodynamic effects based on systolic blood pressure (SBP) and dyastolic blood pressure (DBP) values, heart rate (HR) and hemoglobin (Hb) and respiratory effects based on partial oxygen saturation (SpO2%) values. The secondary objective was to assess potential adverse events with the use of levobupivacaine versus bupivacaine. Assessments were performed preoperatively, at 30 minutes into surgery, at the end of anesthesia and at 48 hours and 6 months after surgery. Among intraoperative events, the incidence of hypotension was statistically significantly higher (p <0.05) in group BUPI (38.3%) compared to group LEVO (13.3%). There was a decrease (p <0.05) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at 30 minutes intraoperatively (19% in group BUPI versus 17% in group LEVO). SpO2% increased at 30 minutes after anesthesia onset (1% in group BUPI versus 1.5% in group LEVO). Heart rate (HR) decreased at 30 minutes after anesthesia onset (5% in group BUPI versus 9% in group L). Hemoglobin (Hb) decreased from time of operating room (OR) admission to the end of anesthesia (9.3% in group BUPI versus 12.5% in group LEVO). The incidence of red blood cell (RBC) transfusion was 13.3% in group BUPI versus 31.7% in group LEVO, this difference was statistically significant. Among postoperative events, the incidence of congestive heart failure (CHF) was significantly higher in group BUPI (8,3%). At 6 months after anesthesia, no differences were found. CONCLUSIONS: Given the hemodynamic stability and lower incidence of intraoperative hypotension observed, levobupivacaine could be the agent of choice for subarachnoid anesthesia in elderly patients.

La actividad de la renina plasmática. Papel de la inhibición directa de la renina / Plasma renin activity. Role of the direct renin inhibition

La renina es la enzima encargada de transformar el angiotensinógeno en angiotensina I, primer paso en la activación del sistema renina-angiotensina (SRA). La actividad de la renina plasmática (ARP) mide la capacidad de la renina para producir angiotensina I a partir de angiotensinógeno, se expresa como concentración de angiotensina I generada por unidad de tiempo (ng/ml/h) y se utiliza para valorar el grado de activación del SRA. Hay relación entre valores de ARP y enfermedad cardiovascular. Se ha descrito que valores de ARP alta se asocian con mayor incidencia de infarto agudo de miocardio, pérdida de función renal, peor pronóstico de la insuficiencia cardiaca y aumento de la mortalidad por causa cardiovascular. La inhibición del SRA con fármacos inhibidores de la enzima de conversión de la angiotensina o con antagonistas del receptor de la angiotensina incrementa la secreción de renina, y por lo tanto la ARP, como consecuencia de la interrupción del mecanismo de retroalimentación negativa que regula la secreción de renina a partir de las concentraciones de angiotensina II. Sin embargo, los inhibidores directos de la renina, como el aliskiren, aunque también interrumpen el mecanismo de retroalimentación y aumentan la secreción de renina, disminuyen la ARP porque bloquean su actividad catalítica. Esta característica diferencial de los inhibidores directos de la renina puede conferirles ventajas en cuanto a la reducción del riesgo cardiovascular (AU)

Renin is the enzyme responsible for the conversion of angiotensinogen into angiotensin I, the first step in the activation of the renin-angiotensin system (RAS). Plasma renin activity (PRA) provides a measure of the capacity of renin to produce angiotensin I from angiotensinogen and is expressed as the rate of increase in the angiotensin-I concentration (i.e. ng/mL per hour). The PRA level is used to evaluate the degree of activation of the RAS. There is a relationship between the PRA level and cardiovascular disease. It has been reported that a high PRA level is associated with an increased incidence of myocardial infarction, with the loss of kidney function, with a poor prognosis in patients with heart failure, and with increased mortality due to cardiovascular causes. Inhibition of the RAS by angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists increases renin secretion and, thereby, increases the PRA level. This is due to interruption of negative feedback mechanism that regulates renin secretion in accordance with the angiotensin-II concentration. However, direct renin inhibitors such as aliskiren, although they also interrupt the feedback mechanism and increase renin secretion, reduce PRA by blocking renin’s catalytic activity. This distinctive property of direct renin inhibitors could be advantageous in helping to reduce cardiovascular risk (AU)

Trans- but not cis-resveratrol impairs angiotensin-II-mediated vascular inflammation through inhibition of NF-κB activation and peroxisome proliferator-activated receptor-gamma upregulation.

Angiotensin II (Ang-II) displays inflammatory activity and is implicated in several cardiovascular disorders. This study evaluates the effect of cis- and trans (t)-resveratrol (RESV) in two in vivo models of vascular inflammation and identifies the cardioprotective mechanisms that underlie them. In vivo, Ang-II-induced arteriolar leukocyte adhesion was inhibited by 71% by t-RESV (2.1 mg/kg, i.v.), but was not affected by cis-RESV. Because estrogens influence the rennin-angiotensin system, chronic treatment with t-RESV (15 mg/kg/day, orally) inhibited ovariectomy-induced arteriolar leukocyte adhesion by 81%, partly through a reduction of cell adhesion molecule (CAM) expression and circulating levels of cytokine-induced neutrophil chemoattractant, MCP-1, and MIP-1alpha. In an in vitro flow chamber system, t-RESV (1-10 microM) undermined the adhesion of human leukocytes under physiological flow to Ang-II-activated human endothelial cells. These effects were accompanied by reductions in monocyte and endothelial CAM expression, chemokine release, phosphorylation of p38 MAPK, and phosphorylation of the p65 subunit of NF-kappaB. Interestingly, t-RESV increased the expression of peroxisome proliferator-activated receptor-gamma in human endothelial and mononuclear cells. These results demonstrate for the first time that the in vivo anti-inflammatory activity of RESV is produced by its t-RESV, which possibly interferes with signaling pathways that cause the upregulation of CAMs and chemokine release. Upregulation of proliferator-activated receptor-gamma also appears to be involved in the cardioprotective effects of t-RESV. In this way, chronic administration of t-RESV may reduce the systemic inflammatory response associated with the activation of the rennin-angiotensin system, thereby decreasing the risk of further cardiovascular disease.

Solifenacin pharmacology.

Antimuscarinics are the drugs of choice for the treatment of overactive bladder syndrome, and their benefit/risk ratio depends largely on selectivity for the different subtypes of muscarinic receptors. Solifenacin is the antimuscarinic that presents greatest selectivity for M3 bladder receptors, which may translate into a lower incidence of undesirable effects related to other receptor subtypes. Metabolic pathways of the antimuscarinics may impact efficacy and appearance of interactions. Solifenacin is metabolized only by the CYP3A4, giving three inactive metabolites and one with a similar activity to the original compound. However, other drugs in the group are also a substrate for the CYP 2D6 which presents polymorphisms, whereby their pharmacokinetics may be modified in slow metabolizers. The risk of interactions of solifenacin is low, and it is lower than that of the antimuscarinics which are also metabolized by the CYP 2D6. The unaltered fraction of solifenacin which is eliminated in urine, together with the active metabolite, can contribute to the therapeutic effect by acting on the urothelium receptors. It is not necessary to adjust doses of solifenacin in elderly patients or those with moderate liver or kidney impairment.

Farmacología de la solifenacina / Solifenacin pharmacology

Los antimuscarínicos son los fármacos de primera elección para el tratamiento del síndrome de vejiga hiperactiva y su relación beneficio/riesgo depende en gran medida de la selectividad por los distintos subtipos de receptores muscarínicos. Solifenacina es el antimuscarínico que muestra mayor selectividad por los receptores M3 vesicales, lo que puede traducirse en una menor incidencia de reacciones adversas relacionadas con otros subtipos de receptor. Las vías metabólicas de los antimuscarínicos pueden influir en la eficacia y en la aparición de interacciones. Solifenacina es metabolizada sólo por el CYP3A4 originando tres metabolitos inactivos y uno con actividad similar a la del compuesto original. Sin embargo, otros fármacos del grupo son también sustrato para el CYP 2D6 que presenta polimorfismos, por lo que su cinética se puede modificar en los pacientes metabolizadores lentos. El riesgo de interacciones de solifenacina es bajo, e inferior al de los antimuscarínicos que se metabolizan también por el CYP 2D6. La fracción inalterada de solifenacina que se elimina por orina junto con el metabolito activo pueden contribuir al efecto terapéutico actuando sobre los receptores del urotelio. No es necesario ajustar las dosis de solifenacina en pacientes de edad avanzada o con insuficiencia hepática o renal moderadas(AU)

Antimuscarinics are the drugs of choice for the treatment of overactive bladder syndrome, and their benefit/risk ratio depends largely on selectivity for the different subtypes of muscarinic receptors. Solifenacin is the antimuscarinic that presents greatest selectivity for M3 bladder receptors, which may translate into a lower incidence of undesirable effects related to other receptor subtypes. Metabolic pathways of the antimuscarinics may impact efficacy and appearance of interactions. Solifenacin is metabolized only by the CYP3A4, giving three inactive metabolites and one with a similar activity to the original compound. However, other drugs in the group are also a substrate for the CYP 2D6 which presents polymorphisms, whereby their pharmacokinetics may be modified in slow metabolizers. The risk of interactions of solifenacin is low, and it is lower than that of the antimuscarinics which are also metabolized by the CYP 2D6. The unaltered fraction of solifenacin which is eliminated in urine, together with the active metabolite, can contribute to the therapeutic effect by acting on the urothelium receptors. It is not necessary to adjust doses of solifenacin in elderly patients or those with moderate liver or kidney impairment(AU)

Drug utilization and off-label drug use among Spanish emergency room paediatric patients.

OBJECTIVE: To describe the use of medicines and to determine the frequency of off-label use in emergency room paediatric patients. PATIENTS AND METHODS: A prospective, observational and descriptive study was carried out in the setting of the paediatric emergency room of a Spanish general hospital. Medicines used by children <14 years prior to their emergency room visit were analysed based on information collected from parents/guardians and relatives for each drug prescription. Off-label use was defined as the utilization of a drug at an indication, dosage, frequency or route of administration that differed from the specifications in the Summary of Product Characteristics or by children outside the authorized age group. RESULTS: The patient cohort comprised 462 children, among whom 336 children had been prescribed 667 prescriptions. Of the medicines prescribed, 90% fell into only five 5 Anatomical Therapeutic Chemical Classification System groups. The most frequent active principles were ibuprofen and paracetamol. Of a total of 152 different formulations recorded, no paediatric information was provided for 40 formulations, and one formulation was contraindicated in children. Based on the established criteria, 338 prescriptions were off-label: no paediatric information or contraindication in children were available (82 prescriptions); the drug was used for an indication different from the authorized one (111 prescriptions); drug use was inconsistent with age recommendations (16 prescriptions); drug use was inconsistent with dose/frequency (129 prescriptions). Of the 152 formulations, 107 were occasionally used in an off-label manner. CONCLUSIONS: Although the mean number of drugs used in children is small, off-label use is frequent. Research efforts should target paediatric studies that allow a rational drug use in children.

[Drug-drug interactions. An update]. / Interacciones medicamentosas. Nuevos aspectos.

A drug interaction is the quantitative or qualitative modification of the effect of a drug by the simultaneous or successive administration of a different one. The simultaneous administration of several medicines to the same patient can facilitates their appearance. It is difficult to determine their incidence, but it is related to the number of drugs administered simultaneously. Although it is impossible to remember all the clinical relevant interactions, to bare in mind their existence and the possible mechanisms of production can help to identify them and to contribute to their prevention. The most frequent interactions related with clinical problems are the pharmacokinetic ones, mainly those related to the metabolism through the cytochrome P450 system or the presystemic clearance by means of the P-glycoprotein and other drug transporters. Interactions between drugs and grapefruit juice or St John's wort are frequent and it is important to bear in mind in clinical practice.

Interacciones medicamentosas. Nuevos aspectos / Drug-drug interactions. An update

Se denomina interacción farmacológica a la modificación cuantitativa o cualitativa del efecto de un fármaco causada por la administración simultánea o sucesiva de otro. La polimedicación facilita la aparición de interacciones cuyo resultado puede ser una reacción adversa o la pérdida de efecto terapéutico. La incidencia es difícil de determinar, pero se relaciona fundamentalmente con el número de fármacos administrados conjuntamente al mismo paciente. Aunque es imposible recordar todas las interacciones de interés clínico, conocer su existencia y mecanismos de producción ayuda a identificarlas y prevenirlas. Las que con mayor frecuencia causan problemas son las de tipo farmacocinético, sobre todo las relacionadas con el metabolismo a través del sistema del citocromo P450 o el aclaramiento presistémico por la glucoproteína P u otros transportadores. Las interacciones entre fármacos y zumo de pomelo o hierba de San Juan son cada vez mejor conocidas y deben tenerse en cuenta en la práctica diaria

A drug interaction is the quantitative or qualitative modification of the effect of a drug by the simultaneous or successive administration of a different one. The simultaneous administration of several medicines to the same patient can facilitates their appearance. It is difficult to determine their incidence, but it is related to the number of drugs administered simultaneously. Although it is impossible to remember all the clinical relevant interactions, to bare in mind their existence and the possible mechanisms of production can help to identify them and to contribute to their prevention. The most frequent interactions related with clinical problems are the pharmacokinetic ones, mainly those related to the metabolism through the cytochrome P450 system or the presystemic clearance by means of the P-glycoprotein and other drug transporters. Interactions between drugs and grapefruit juice or St John's wort are frequents and it is important to bare in mind in clinical practice

Effects of dopamine in isolated rat colon strips.

The aim of the present work is to investigate the effects of dopamine on isolated rat colon strips, and whether dopamine receptors are involved in these effects. Experiments on spontaneous motility and under potassium contraction were performed with dopamine and isoprenaline, both in the absence and presence of antagonists (distal colon strips, isotonic recording, Tyrode solution, 31 degrees C, 1 g of resting tension). At higher concentration (10(-4) mol/L), dopamine abolished spontaneous motility of the rat colon and this effect was not modified by antagonists. In isolated rat colon strips that were depolarized with potassium, dopamine produced concentration-dependent relaxation, without significant differences in reserpinized rats. Preincubation with sulpiride or Sch 23390, dopamine antagonists, did not modify the effects of dopamine. Propranolol shifted the concentration-response curve to the right, though in a noncompetitive manner. Prazosin and yohimbine (alpha-antagonists) did not modify the response to dopamine. Isoprenaline produced a concentration-dependent relaxant response to the KCl-induced contraction antagonized by propranolol, but not by prazosin, in a noncompetitive manner. In conclusion, dopamine exhibits a relaxant effect on the isolated rat colon, which is not mediated by specific dopamine receptors or alpha-adrenoceptors but it may be mediated by atypical beta-adrenoceptors.

[Antihypertensive drug-drug interactions]. / Interacciones farmacológicas de los fármacos antihipertensivos.

A drug interaction is the quantitative or qualitative modification of the effect of a drug by the simultaneous or successive administration of a different one. Hypertensive patients, mainly the more elderly ones, frequently present concomitant diseases that require the administration of several medicines which facilitates the appearance of interactions. The lack of effectiveness of the antihypertensive treatment is a relatively frequent fact that sometimes is due to interactions of antihypertensive drugs with other treatments. It is difficult to determine the incidence of interactions, but it is related to the number of drugs administered simultaneously. Between 37 and 60% of hospital-admissions are treated with potentially dangerous drug associations and up to a 6% of fatal events are due to this circumstance. Among antihypertensive drugs, diuretics and angiotensin converting enzyme inhibitors are less affected by drug-interactions. Lipophilic beta-blockers agents may present some clinical relevant interactions, whereas calcium channel blockers, especially the non-dihydropiridinic ones, are implied in clinically relevant pharmacokinetic interactions. Among the angiotensin receptor blockers there are differences that would have to be considered when they are used in patients who receive other drugs. Although it is impossible for the doctor to remember all the clinical relevant interactions, it is important to bear in mind their existence and the possible mechanisms of production which can help to identify them and to contribute to their prevention. The most frequent interactions related with clinical problems are the pharmacokinetic ones, mainly those related to the metabolism through the cytochrome P450 system or the presystemic clearance by means of the P-glycoprotein. Enzymes of the cytochrome P450 system may present polymorphisms that can explain the individual differences in the response to drugs or the appearance of drug-interactions.

Interacciones farmacológicas de los fármacos antihipertensivos / Antihypertensive drug-drug interactions

Se denomina interacción farmacológica a la modificación cuantitativa ocualitativa del efecto de un fármaco por la administración simultánea o sucesiva de otro. Los pacientes con hipertensión arterial, sobre todo los ancianos, presentan con frecuencia enfermedades concomitantes que requieren la administración conjunta de varios medicamentos, lo que facilita la aparición de interacciones. La falta de eficacia del tratamiento antihipertensivoes un hecho relativamente frecuente que, en ocasiones, se debe a interacciones de los fármacos antihipertensivos con otros tratamientos concomitantes. La incidencia de las interacciones es difícil de determinar, pero se relaciona con el número de fármacos administrados conjuntamente. Entre el 37 y el 60% de los pacientes que ingresan en un hospital están tratados con asociaciones de medicamentos potencialmente peligrosas y hasta un6% de acontecimientos mortales son debidos a esta circunstancia. Entre los fármacos antihipertensivos, los diuréticos y los inhibidores de la enzima conversiva de la angiotensina (IECA) son los menos afectados por las interacciones. Los bloqueadores beta adrenérgicos liposolubles pueden presentar algunas con interés clínico, mientras que el grupo de los antagonistas del calcio, en especial los no dihidropiridínicos, es el más implicado en interacciones farmacocinéticas que pueden tener importancia clínica. Los antagonistas del receptor de la angiotensina II (ARA II) presentan diferencias entre ellos que deberían ser tenidas en cuenta al administrarlos apacientes que reciben otros medicamentos. Aunque para el médico práctico es imposible recordar todas las interacciones de interés clínico, tenerlas presentes y considerar los posibles mecanismos de producción puede ayudar a identificarlas y contribuir a su prevención. Las interacciones que con mayor frecuencia causan problemas son las de tipo farmacocinético, sobre todo las relacionadas con el metabolismo a través del sistema del citocromo P450 o el aclaramiento presistémico por medio de la P-glucoproteína. El hecho de que algunas isoformas del citocromo puedan presentar polimorfismos explican las diferencias interindividuales en la respuesta a algunos fármacos o en la presentación de interacciones

A drug interaction is the quantitative or qualitative modification of the effect of a drug by the simultaneous or successive administration of a differentone. Hypertensive patients, mainly the more elderly ones, frequently present concomitant diseases that require the administration of several medicines which facilitates the appearance of interactions. The lack of effectiveness of the antihypertensive treatment is a relatively frequent fact that sometimes is due to interactions of antihypertensive drugs with other treatments. It is difficult to determine the incidence of interactions, but it is related to the number of drugs administered simultaneously. Between 37and 60% of hospital-admissions are treated with potentially dangerous drug associations and up to a 6% of fatal events are due to this circumstance. Among antihypertensive drugs, diuretics and angiotensin converting enzymein hibitors are less affected by drug-interactions. Lipophilic beta-blockers agents may present some clinical relevant interactions, whereas calcium channel blockers, especially the non-dihydropiridinic ones, are implied in clinically relevant pharmacokinetic interactions. Among the angiotensin receptor blockers there are differences that would have to be considered when they are used in patients who receive other drugs. Although it is impossible for the doctor to remember all the clinical relevant interactions, it is important to bear in mind their existence and the possible mechanisms of production which can help to identify them and to contribute to their prevention. The most frequent interactions related with clinical problems are the pharmacokinetic ones, mainly those related to the metabolism through the cytochrome P450 system or the presystemic clearance by means of the P-glycoprotein. Enzymes of the cytochrome P450 system may present polymorphisms that can explain the individual differences in the response to drugs or the appearance of drug-interactions

The KARTAN study: a postmarketing assessment of Irbesartan in patients with hypertension.

BACKGROUND: An important purpose of postmarketing surveillance of drugs is to better characterize the safety profile of drug therapy in the clinical setting. Another goal is to confirm the effectiveness of these drugs in patients who are candidates for antihypertensive therapy and who may have been excluded from Phase III studies. Irbesartan is a long-acting angiotensin II-receptor blocker specific for the angiotensin 1-receptor subtype that, in clinical trials in patients with hypertension, reduces blood pressure. OBJECTIVES: The KARTAN (this word was derived from the first and last syllables of Karvea [trademark of Bristol-Myers Squibb Group, Madrid, Spain] and irbesartan) study was designed to confirm and extend the findings from previous clinical trials using data from a large number of patients with hypertension treated with irbesartan in routine clinical practice. The primary goal was to assess the types and incidences of adverse drug reactions (ADRs) occurring at a low frequency (<0.05%) with irbesartan. The secondary objectives were to study the effect of irbesartan as an antihypertensive agent, to assess the types and incidences of the most frequent ADRs (>/=0.05%) occurring in routine clinical practice, and to detect possible interactions between irbesartan and other drugs frequently used in the primary care setting. METHODS: This 6-month, observational, open-label, uncontrolled, national, longitudinal, prospective study was conducted by 852 primary care physicians across Spain. Men and women aged >/=18 years with mild to moderate hypertension who, in their physicians' opinion, should have been treated with irbesartan were included. Each patient was followed up for 6 months, attending visits at baseline (ie, the start of treatment) and 1, 3, and 6 months after the start of treatment. A sample size of 3219 patients was calculated for the detection of >/=1 low-incidence (<0.05%) ADR. After the baseline visit, therapy typically was begun with irbesartan 150 mg/d. The initial dose was titrated up, at 300-mg increments based on the patient's response, at each visit as needed to achieve the treatment goals (systolic blood pressure, <140 mm Hg; diastolic blood pressure, <90 mm Hg). Information regarding ADRs was collected on case-report forms designed for each visit and analyzed by the scientific committee of the study. All recruited patients were included in the tolerability analysis. RESULTS: A total of 4887 patients were enrolled (2165 men, 2 772 women; mean [SD] age, 61.1 [11.0] years [range, 19-94 years]; 23.3% of patients were aged >70 years); 4612 were assessable for efficacy. One hundred eight patients (2.2%) experienced ADRs over the 6-month treatment period; 3 of these patients (0.1%) experienced >1 ADR. Of the total number of clinical manifestations of ADRs, 24 occurred at an incidence <0.05%. Irbesartan produced reductions in blood pressure that were statistically significant from the first visit (all p < 0.001), and 39.9% of the patients achieved the treatment goal at the end of the follow-up period. CONCLUSION: In this postmarketing surveillance study of patients with hypertension treated in routine clinical practice, irbesartan showed a satisfactory tolerability profile that was consistent with that seen in randomized, controlled trials.

El diseño y las conclusiones del estudio ALLHAT / Design and conclusions of the ALLHAT study

No disponible

Reactivity of isolated human chorionic vessels: analysis of some influencing variables.

The aim of the study was to determine whether 24 h of cold storage of samples, mode of delivery, and gestational age influenced in vitro human chorionic vascular reactivity (35 arteries and 34 veins). The following groups were compared: (i) fresh versus 24-h cold-stored (4 degrees C in Krebs-Henseleit solution) chorionic vascular rings from normal term placentas, (ii) fresh chorionic vascular rings from normal term placentas obtained after vaginal delivery versus those obtained after elective caesarean section, and (iii) fresh chorionic vascular rings from normal term placentas versus those obtained from preterm deliveries. Isometric recording of the concentration-response curve to KCl (5-120 mM) was assessed in each group. In vitro human chorionic vascular reactivity was influenced negatively by the 24-h cold storage of samples, with only 30% of stored samples being weakly reactive to KCl. Human chorionic vascular reactivity to KCl was unaffected by the mode of delivery. However, the response to KCl was gestational-age dependent. Thus, preterm vascular rings exhibited a significantly (P<0.05) decreased response (Emax=9.8 +/- 0.0 mN; EC50=26.0 +/- 1.3 mM) compared with term samples (Emax=21.6 +/- 2 mN; EC50=13.9 +/- 1.6 mM). In conclusion, this study provides evidence that fresh term vascular rings are the tissues of choice for studying human chorionic vascular reactivity.