A retrospective study: efficacy of an originator versus a generic formulation of simvastatin in patients who suffer from hyperlipidaemia.

BACKGROUND: South Africa is home to a multi-ethnic society with a large range of cultures and lifestyles. Cardiovascular disease is a major cause of morbidity and mortality. South Africa is known to have one of the highest incidence rates of hypercholesterolaemia in the world, especially among the Caucasian population. AIM: The aim of this retrospective chart review was to establish whether a multisource simvastatin (Simvotin®, Ranbaxy, a Sun Pharma company) maintained the cholesterol-lowering effect after switching from the innovator brand Zocor® (MSD South Africa) in the public-sector hospitals. Since prescribers often doubt the registration requirements of multisource products based on bioequivalence alone, this research was done to confirm similar clinical outcomes in a real-world setting. METHODS: More than 200 charts were identified from patients treated for hyperlipidaemia. Patients were treated for at least six months prior to and again six months after the switching of brands in order to meet criteria to be eligible for inclusion. The lipid values at initiation of therapy as well as before switching (visit 1 and 2) had to be available and again six months after treatment on the multisource product (visit 3). RESULTS: No significant change was observed in the lipid control after switching, confirming similarity. CONCLUSION: This real-world evidence should allay any fears of generic inferiority of this important medicine in the treatment and prevention of high cardiovascular risk in patients requiring lipid-lowering therapy.

Perindopril: do randomised, controlled trials support an ACE inhibitor class effect? A meta-analysis of clinical trials.

BACKGROUND: Due to the lack of face-to-face trials between ACE inhibitors, clinicians and third-party funders may assume they provide similar outcomes. As a result, ACE inhibitors may be prescribed interchangeably and deemed to provide the same outcomes for all patients when used chronically, that is for more than six months. OBJECTIVE: This meta-analysis aims to dispute the assumption of a class effect when prescribing ACE inhibitors (ACEIs), since the evidence from all the clinical trials is not uniform and therefore a direct comparison is impossible. METHODS: Published randomised, controlled trials were selected using an applicable literature search for all ACEIs, irrespective of drug combination, for any cardiovascular outcome (both composite and individual outcomes were included). The average length of ACEI exposure per trial had to be longer than six months). This meta-analysis was performed using odds ratios as the parameter of efficacy in a fixed-effects model. RESULTS/CONCLUSION: Perindopril resulted in significantly fewer patients reaching the primary endpoint versus all other ACEIs combined. The results were consistent for myocardial infarction, stroke and mortality (5 vs 11%, p = 0.0001). Perindopril alone or as part of combination therapy in clinical trials seemed to deliver clear and consistent outcome differences compared to other ACEI trials. In the presence of positive outcomes from robust randomised, controlled trials for perindopril, one cannot assume a class effect for all ACEIs.

Generic versus non-generic formulation of extended-release clarithromycin in patients with community-acquired respiratory tract infections: a prospective, randomized, comparative, investigator-blind, multicentre study.

BACKGROUND AND OBJECTIVE: There is a general concern about the use of multisource (generic) antibacterials in the clinical setting with registration based solely on bioequivalence data. In order to address this concern, two modified-release formulations of clarithromycin (i.e. the originator Klacid XL and the generic Klarithran MR) were compared in patients with acute community-acquired respiratory tract infections. METHODS: Patients presenting with tonsillopharyngitis, sinusitis or pneumonia were randomized to receive either of the test drugs provided they clinically qualified for empirical clarithromycin treatment. The study endpoints were clinical and bacteriological cure rates, tolerability and safety. The study was designed to test for non-inferiority with regard to cure rates. RESULTS: The main outcome of this study was that both agents had similar clinical (non-inferior) and bacteriological cure rates and demonstrated no difference in tolerability in patients. The study also demonstrated the clinical efficacy of clarithromycin when used as empirical treatment in patients with respiratory tract infections in community practice (i.e. 95% clinical cure rate). CONCLUSION: The clarithromycin extended-release multisource product (Klarithran MR) does not differ significantly from the originator (Klacid XL) and the clinical cure rate of the generic formulation is non-inferior to that of the originator. The two formulations are tolerated similarly.

Brown coal derived humate inhibits contact hypersensitivity; an efficacy, toxicity and teratogenicity study in rats.

OBJECTIVES: The effects of two humate products were compared to that of prednisolone on a contact hypersensitivity rat model. METHODS: Rats, sensitized with dinitrofluorobenzene (DNFB), were placed on a daily oral treatment of 61 mg/kg BW of humate derived from either leonardite or bituminous coal or on prednisolone at one mg/kg BW and challenged 6 days later with a topical application of DNFB to the right ear. The inflamed ears were measured daily. In a toxicity study rats were exposed to daily oral treatment of leonardite humate at 1,000 mg/kg BW for 1 month. A teratogenicity study was done where pregnant rats were treated with 500 mg/kg BW on days 5 to 17 of pregnancy. RESULTS: Only the leonardite humate compared favourably with prednisolone in suppressing contact hypersensitivity. No signs of toxicity were observed and weight gain was normal during the 6-day and 1 month treatments and during the teratogenicity study with the leonardite humate. However, the rats on the other two products experienced slower weight gain. CONCLUSION: The identification of a naturally occurring nontoxic compound with anti-inflammatory activity is exciting and merits further evaluation in the treatment of patients suffering from inflammatory conditions.

Evaluation of cisplatin and a novel platinum polymer conjugate for drug toxicity and drug distribution in mice.

The toxicity and distribution of cisplatin and two novel platinum (Pt) polymer conjugates (Pt-6 and Pt-7) were determined in serum and tissue of BALB/c mice at specific time points after i.p. administration of a drug bolus containing identical Pt concentrations. Pt concentrations were determined in serum, liver and kidney at 5 and 15 min, respectively, after drug administration by inductively coupled plasma mass spectrometry. It was found that the Pt polymer Pt-7 gave rise to a considerably lower Pt concentration in serum and considerably higher concentration in liver and kidney than cisplatin. LD25 measurements indicated that the Pt-7 polymer is considerably less toxic than cisplatin. In vitro experiments and determination of IC50 values in a variety of human tumor cell lines, normal lymphocytes and fibroblasts confirmed that Pt-6 and Pt-7 polymers are 40-500 times more toxic for tumor cells than for normal cells, perhaps reflecting preferential uptake. The toxicity of cisplatin was found to be only 1.6-40 times more effective in tumor cells. These inter-relationships are supported by the observation that the tumor enrichment factor (TEF) for cisplatin is only in the region of 6, and much lower than for Pt-6 and Pt-7, where TEFs are in the region of 40 and 150, respectively. These results demonstrate that the Pt polymer conjugates exhibit greater tumor specificity than cisplatin, killing tumor cells more effectively while being considerably less toxic for normal cells. It is concluded that the Pt polymer conjugates may be superior for cancer therapy and warrant further testing to assess their full clinical potential.

Effect of betamethasone-loratadine combination therapy on severe exacerbations of allergic rhinitis : a randomised, controlled trial.

OBJECTIVE: Corticosteroids are effective in controlling the inflammatory component of allergic rhinitis; however, evidence for the clinical efficacy of systemic corticosteroids in this disease is sparse. It is further common practice to combine oral corticosteroids with antihistamines in the treatment of acute exacerbations of allergic rhinitis. The aim of this study was to investigate the effect of low-dose oral betamethasone alone and in combination with loratadine in a group of patients with allergic rhinitis with clinically significant obstruction. METHODS: In this parallel, double-blind, active controlled multicentre study, 299 patients with severe allergic rhinitis were randomly allocated to either betamethasone 1.0mg or betamethasone 1.0mg plus loratadine 10mg or betamethasone 0.5mg plus loratadine 10mg or loratadine 10mg alone for 5-7 days. Total symptom scores, nasal obstruction, and doctor and patient perception of improvement were measured as markers of disease severity. RESULTS: Although not statistically significant, both betamethasone 1.0mg regimens resulted in a total symptom score difference of at least 1 or more from loratadine (i.e. mean [SD] change in total symptom score of 4.10 [3.10] and 4.40 [3.62] vs 3.10 [3.30], respectively, for betamethasone 1.0 mg plus loratadine, betamethasone 1.0 mg and loratadine). All corticosteroid-containing regimens were significantly better than loratadine alone with regard to the patients' (p < 0.013) and doctors' (p < 0.009) perceptions of improvement. They significantly favoured loratadine in combination with betamethasone over single-drug therapy (i.e. odds ratio: investigator ratings 0.49, 0.36 and 0.45, and patient ratings 0.47, 0.40 and 0.43, respectively, for 0.5 mg and 1.0 mg betamethasone plus loratadine and betamethasone 1.0 mg alone vs loratadine alone). Betamethasone 1.0mg plus loratadine also resulted in significant reduction of the relapse rate compared with the other therapies. CONCLUSIONS: This study demonstrated the benefit of a short course of a systemic low dosage of corticosteroids with and without antihistamine therapy during acute severe exacerbations of allergic rhinitis. Combination treatment with betamethasone 1.0mg and loratadine 10mg was significantly better in relieving symptoms of hayfever as experienced by patients. This was the first study to give evidence of benefit of systemic low-dose corticosteroids with and without an antihistamine in patients with acute exacerbations of allergic rhinitis.

Short-course, low-dose oral betamethasone as an adjunct in the treatment of acute infective sinusitis : a comparative study with placebo.

OBJECTIVE: To assess the effect of a short course of low-dose oral corticosteroid used as an adjunct to antimicrobials in patients with acute infective sinusitis. STUDY DESIGN AND PATIENTS: Double-blind, randomised, placebo-controlled study including 42 patients with a clinical diagnosis of acute infective sinusitis. The study was performed at three primary healthcare sites in South Africa during the period January-November 2003. INTERVENTION: Two equal groups received either betamethasone 1mg orally (n = 21; the treatment group) or placebo tablets (n = 21; the placebo group) once a day in the morning for five consecutive days. All patients received amoxicillin-clavulanic acid 625mg orally, three times daily for 5 days. MAIN OUTCOME MEASURE: Patients rated symptoms on a daily symptom score card for 5 days and were examined by the investigator at diagnosis (day 0) and on the second visit (day 6). RESULTS: Headache, facial pain, nasal congestion and dizziness improved significantly from baseline in the treatment group compared with the placebo group over 5 days of treatment (p = 0.028, p

Arylamine N-acetyltransferase (NAT2) genotypes in Africans: the identification of a new allele with nucleotide changes 481C>T and 590G>A.

This study was carried out to characterize the distribution of NAT2 allelic variants among a sample of three African populations. We determined the frequencies of major NAT2 allele clusters (NAT2*4, *6, *7 and *14) using PCR/restriction fragment length polymorphism and sequencing techniques. The genotypes predict slow acetylator phenotypes of 49, 38 and 52% among Tanzanians, Venda and Zimbabweans, respectively. The most common genotype was NAT2*4/*5. NAT2* 5 was the most common allele while NAT2* 7 was the least common. A new allele with two base changes occurring together, 481C>T and 590G>A, is reported. The frequency of the occurrence of the combination 481C>T and 590G>A, was found to be 9% (30/326), 7% (14/192) and 8% (18/234) among Zimbabweans, Venda and Tanzanians, respectively. The allele has been named NAT2*6E. Among Africans, the change 481C>T is not only associated with 341C>T (i.e. the NAT2* 5 allele cluster) as in other populations, but also with 590G>A on the same allele.

Genetic polymorphism of CYP2D6 and CYP2C19 in east- and southern African populations including psychiatric patients.

OBJECTIVES: The study was carried out to investigate the distribution of cytochrome P450 2D6 (CYP2D6) and CYP2C19 genotype frequencies in three African populations and to compare these frequencies between healthy individuals and psychiatric patients. METHODS: Three hundred and eighty-four subjects from South Africa (Venda), Tanzania, and Zimbabwe who consented to the study were genotyped for CYP2D6 (CYP2D6*1, *2, *3, *4, *5, and *17) and CYP2C19 (CYP2C19*1, *2, and *3) by PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) techniques. RESULTS: The genotypes for CYP2D6 predicted a poor metabolizer frequency of 2.3% (2/88) in Tanzanian psychiatric patients, 1.9% (2/106) in Tanzanian healthy controls and 2.6% (2/76) in the South African Venda. The low-activity CYP2D6*17 allele frequency was higher in psychiatric patients (30%, 53/176) than in healthy individuals (20%, 43/212) in Tanzanians. The frequencies for CYP2C19*2 genotypes were predictive of a low prevalence of poor metabolizers (PMs). The CYP2C19*3 allele was absent in the three populations studied. There was no difference in CYP2D6 or CYP2C19 PM genotype frequencies between psychiatric patients and healthy subjects. CONCLUSION: The genotype results predict a low prevalence of people with deficient CYP2D6 and CYP2C19 activity among linguistically (Bantu) related populations of East and Southern Africa. The high frequency of the low-activity CYP2D6*17 allele predicts that the Bantu people have a reduced capacity to metabolise drugs that are CYP2D6 substrates.

Some neural and behavioural aspects of electrical and mechanical stunning in ostriches.

Different electrical and mechanical stunning procedures were studied in ostriches to determine the effectiveness of the method. Fifty-eight South-African Black ostriches were equipped with EEG electrodes and stunned with three different electrical head-only methods and with a new captive needle pistol, using air pressure. The first stunning procedure consists of two trials. In the first trial a total of 45 ostriches were stunned with a voltage of 200V (spiked electrodes) during 1s. Unfortunately, in 10 animals the electrodes were disconnected. A general epileptiform insult on the EEG followed by recovery was observed in 20 ostriches. Another eight animals died after recovery and five showed an iso-electric line and were dead. The total duration of the insult was 25±10s. The measured current was 463±120mA. In the second trial a constant current of 400mA was administered to 13 ostriches. In one animal the electrodes were disconnected. Eight out of 12 animals showed a general epileptiform insult, two of them showed an iso-electric line and two did not show the characteristics of a general epileptiform insult. The total duration of the insult on the EEG was 21±8s. The measured current was 365±91mA and the voltage 191±27V. During the second stunning procedure four and seven ostriches were stunned with 200V (spiked electrodes) and 48V (blunt electrodes), respectively, during approx. 6s. They all died. In addition, a group of 20 ostriches stunned with captive needle pistol using air pressure showed unconsciousness after stunning by the appearance of theta and delta waves tending to an iso-electric line on the EEG trace. It is recommended to use at least 500mA to stun ostriches effectively and to use a short stun-stick interval or to kill them by a long stunning duration. The captive needle pistol, using air pressure, can be an alternative for electrical head-only stunning.

Effect of levamisole on the immune response of patients with schistosomiasis after treatment with praziquantel.

Successful therapy with praziquantel in schistosomiasis is dependent on a normal host immune system, i.e. the recognition of parasite antigen, to be effective in eradicating the parasite. Levamisole, a nonspecific immunomodulator, has been hypothesised to normalise deficient cell-mediated immunity. The aim of this study was to investigate the effect of levamisole on the immune response seen after presumed curative doses of praziquantel. After ethical approval, 29 male volunteers infected with Schistosoma haematobium were recruited and randomised to receive orally either (a) levamisole 5 mg/kg for 2 consecutive days, plus praziquantel 40 mg/kg as a single dose, (b) levamisole 5 mg/kg for 2 days, or (c) praziquantel 40 mg/kg as a single dose. Blood samples were collected on day 0 and again 3 months later for differential counts and specific IgG and IgE to whole-worm-antigen, as well as for the detection of eosinophil cationic protein (ECP). Levamisole treatment alone resulted in a significant drop in circulating eosinophil counts, i.e. a median (95% confidence interval) drop of 6.0 (1;7)%. Eosinophil counts did not change significantly after praziquantel therapy alone. ECP values were significantly reduced with levamisole alone and praziquantel alone, i.e. respective median (95% confidence interval) drops of 33.58 (18.94; 55.9) and 16.54 (3.6; 33.5) microg/L (p < 0.05). The group receiving combination therapy demonstrated significant increases in specific IgG values (p = 0.02) with no decline in ECP levels and eosinophil counts compared with baseline values. Levamisole alone had no effect on egg counts. In conclusion, levamisole inhibited circulating eosinophils and eosinophil activation when given alone, but caused immune stimulation when combined with praziquantel. The exact mechanism of action still needs to be determined.

Effects of pretreatment with dexfenfluramine and fluoxetine on metoclopramide-induced aldosterone secretion in healthy volunteers.

OBJECTIVE: The present placebo-controlled study was designed to compare the effect of acute pretreatment with dexfenfluramine and fluoxetine on the plasma aldosterone response to metoclopramide. STUDY PARTICIPANTS AND DESIGN: Ten healthy ambulatory male volunteers participated. Following a single-blind, randomised design, each volunteer received metoclopramide as an intravenous bolus of 10mg at 0700 hours on each experimental day. Participants were pretreated at 2200 hours the previous evening and 0500 hours in the morning with one of the following: fluoxetine 20mg, dexfenfluramine 30mg, or placebo. RESULTS: In response to metoclopramide administration, the maximum concentration was significantly higher (p = 0.004) than baseline with placebo, fluoxetine and dexfenfluramine. The area under the curve of dexfenfluramine was significantly larger than that with both placebo (p = 0.007) and fluoxetine (p = 0.004), while that of fluoxetine was significantly larger than that of placebo (p = 0.01). CONCLUSION: Acute pretreatment with both dexfenfluramine and fluoxetine caused an enhancement of metoclopramide-induced aldosterone secretion, probably by augmenting serotonergic neurotransmission via serotonin (5-HT)(4) receptors. The plasma aldosterone levels were significantly higher with dexfenfluramine compared with fluoxetine, probably as a result of larger 5-HT concentrations being available for stimulation of glomerulosa cell activity.

Lack of effect of amitriptyline on risperidone pharmacokinetics in schizophrenic patients.

The interaction between plasma concentrations of the tricyclic antidepressant amitriptyline and the metabolism of the new antipsychotic risperidone was studied in 12 patients with chronic schizophrenia. Each patient received 3 mg risperidone twice a day for 28 days. Amitriptyline was coadministered at doses of 50 mg/day on day 15 and 100 mg/day on days 16 to 21. Amitriptyline did not significantly affect the mean plasma concentrations or pharmacokinetics of risperidone in schizophrenic patients or influence the antipsychotic fraction (the total concentration of risperidone and 9-hydroxyrisperidone, its primary and biologically active metabolite). These results suggest that risperidone dose need not be adjusted when coadministered with amitriptyline at doses up to 100 mg/day in schizophrenic patients.

Effects of calcitriol on eosinophil activity and antibody responses in patients with schistosomiasis.

OBJECTIVE: Parasitic infestations are known to elicit T-helper lymphocyte type 2 (Th-2) reactions, characterized by a pronounced eosinophila and high IgE levels. In humans both elevated specific IgE levels and eosinophil counts are associated with resistance to reinfection with schistosomiasis. This study aimed to establish whether the Th-2 reaction could be enhanced with calcitriol (vitamin D3). Calcitriol has been shown to cause a shift from Th-1 to Th-2 type reactions when applied locally to the skin. METHODS: Fifty-nine patients with Schistostoma haematobium infection were randomized to one of four treatment modalities, i.e. (a) praziquantel (PZQ) 60 mg.kg-1 orally on day 1, (b) PZQ 60 mg.kg-1 on day 1 plus calcitriol 1 microgram per day orally for 5 consecutive days, (c) calcitriol 1 microgram per day for 5 consecutive days or (d) placebo. Blood for differential counts, eosinophil cationic protein (ECP), specific IgE and IgG to whole-worm antigen, as well as urine samples for egg counts, were collected on days 0 and 21. RESULTS: Baseline values did not differ significantly between the groups. Calcitriol alone resulted in significant increases in circulating lymphocytes (median increase of 5.5%) and the percentage of eosinophil vacuolization (mean increase 28%). It, however, significantly decreased ECP levels (mean decrease 46%). PZQ in combination with calcitriol significantly enhanced production of specific IgE (mean increase 213%) and IgG (mean increase of 170%) and tended to increase eosinophil vacuolization (mean increase 22%). All these changes also differed significantly from those in the placebo group. The specific IgE and IgG levels were also significantly higher than the already increased levels seen with PZQ treatment only. ECP levels were, however, not significantly affected by combination therapy, whereas PZQ alone significantly enhanced ECP production (mean increase 93%). CONCLUSIONS: The increases in specific IgE responses and percentage of eosinophil vacuolization favour a Th-2 type of reaction. The ECP values viewed in isolation may, paradoxically, indicate a Th-1 response; this could, however, have been an artefact due to the method of ECP detection ex vivo. Finally, it would seem that calcitriol does cause some immune augmentation when combined with PZQ therapy in patients with schistosomiasis. However, long-term follow-up is needed to prove that these findings would translate into resistance against re-infection.

Lack of bioavailability of mebeverine even after pretreatment with pyridostigmine.

OBJECTIVE: After the oral administration of mebeverine to animal or human, measurable concentrations of the drug have never been found in the plasma. The ex vivo hydrolysis of mebeverine can be blocked by esterase inhibitors. In the present study, human volunteers were pretreated with pyridostigmine to attempt to improve the bioavailability of the parent drug. METHODS: Following a single-blind, random design, 12 normal human volunteers received orally either placebo or 60 mg pyridostigmine, followed 2 h later by 405 mg mebeverine. Blood samples were drawn intermittently for 4 h and were spiked immediately with neostigmine in order to block ex vivo hydrolysis. RESULTS: Even after pretreatment with pyridostigmine, the plasma samples failed to reveal detectable concentrations of mebeverine. Pyridostigmine pretreatment mediated a significantly higher peak concentration of veratric acid, the acid moiety resulting from hydrolysis of mebeverine. CONCLUSION: As mebeverine seemingly undergoes complete presystemic hydrolysis, it seems unlikely that the effects of the drug could be mediated centrally. Furthermore, as it is unlikely that sufficient mebeverine traverses the intestine to exert a local effect on the colon (i.e., the time-course of veratric acid plasma levels does not support such a conclusion), the therapeutic effect of the drug, if any, has to be ascribed to an active metabolite. However, the hydrolysis products of mebeverine are not known to be pharmacologically active.

Effects of metoclopramide and tropisetron on aldosterone secretion possibly due to agonism and antagonism at the 5-HT4 receptor.

OBJECTIVE: Part of the prokinetic activity of metoclopramide can possibly be ascribed to agonist activity at 5-HT4 receptors. The 5-HT3 antagonist tropisetron is thought to act as an antagonist at 5-HT4 receptors. In the present study aldosterone secretion in response to the administration of these two drugs was explored to examine the role of the 5-HT4 receptor in aldosterone secretion. METHODS: Following a single-blind, random design, ten normal male volunteers received one of the following regimens on three occasions, with at least 2-week intervals: metoclopramide 10 mg i.v.; tropisetron 5 mg by slow i.v.i., or; tropisetron by slow i.v.i., followed by 10 mg metoclopramide i.v. RESULTS: In response to metoclopramide alone the mean plasma aldosterone level rose significantly to 149% of basal level and remained significantly elevated for the next 20 min. With tropisetron alone, there was a significant 37.8% drop at 60 min and the aldosterone levels remained low for the duration of the experiment. Metoclopramide reversed the decline mediated by tropisetron significantly at 30 and 90 min. Aldosterone levels after the latter regimen also did not differ significantly from baseline at any time period. CONCLUSION: These results would suggest the existence of a tonic stimulatory influence of 5-HT via 5-HT4 receptors on aldosterone secretion, which could be augmented by metoclopramide and blocked by tropisetron. However, the effect of tropisetron per se should be interpreted with caution given the lack of a saline group.

The proportional cumulative area under the curve of paracetamol used as an index of gastric emptying in diabetic patients with symptoms of gastroparesis.

1. The foreshortened 2 h method of measuring liquid gastric emptying (i.e. the proportional cumulative area under the curve of paracetamol) was utilized in diabetic patients in order to detect both gastroparesis and the influence of metoclopramide, a known prokinetic drug, on this condition. 2. Metoclopramide, 10 mg intravenously, caused a significant increase in the median PCAUC from 20 min onwards. 3. In this study delayed gastric emptying was defined as a %PCAUC without pretreatment lower than the 5% percentile at 40, 60 and 90 min for normal volunteers. According to this criterion seven of the 10 patients with clinical symptoms of gastroparesis and/or peripheral neuropathy had delayed gastric emptying. 4. The PCAUC method would therefore seem to be a reliable model for investigating gastric emptying in diabetics and the effects of various prokinetic drugs on this condition.

A noninvasive evaluation of baroreceptor sensitivity with the Valsalva maneuver and phenylephrine methods.

In a double-blind crossover study, we compared baroreceptor sensitivity (BS) and latency, derived from the phenylephrine method with BS and latency derived from phase IV of the Valsalva maneuver (VM), using the Finapres, a noninvasive blood pressure monitor. Ten healthy volunteers were enrolled in the study and BS was determined with placebo, atropine (0.03 mg/kg) and atenolol (10 mg) and was expressed as the linear relation between the change in RR interval following the blood pressure rise induced by either phenylephrine or phase IV of the VM (i.e., after cessation of straining). Baseline baroreceptor sensitivity (p<0.001) and baroreceptor sensitivity in the presence of atropine (p<0.02) was smaller with the VM but no differences in baroreceptor sensitivity between the two methods were evident after atenolol. Although no linearity existed between the two methods under any of the experimental conditions, baroreceptor sensitivity in the presence of atropine was significantly smaller (p<0.01)(and latency delayed (p<0.08)) compared to atenolol-induced changes with both methods. We found excellent correlation between baroreceptor sensitivity derived from the ECG tracing and Finapres recorded beat-to-beat pulse intervals (p<0.001; r>0.8, under all conditions) although the correlation after atropine was not as close (p<0.01; r=0.7). The smaller baroreceptor sensitivity induced by the Valsalva maneuver with placebo and atropine, but not with atenolol, suggests a parasympathetically influenced vasodilation, and sympathetically medicated tachycardia during phase IV of the VM.