Deltamethrin resistance in the sea louse Caligus rogercresseyi (Boxhall and Bravo) in Chile: bioassay results and usage data for antiparasitic agents with references to Norwegian conditions.

The sea louse Caligus rogercresseyi is a major threat to Chilean salmonid farming. Pyrethroids have been used for anticaligus treatments since 2007, but have shown reduced effect, most likely due to resistance development. Pyrethroid resistance is also a known problem in Lepeophtheirus salmonis in the Northern Hemisphere. This study describes the development of deltamethrin resistance in C. rogercresseyi based on bioassays and usage data for pyrethroids in Chilean aquaculture. These results were compared to bioassays from L. salmonis from Norway and to Norwegian usage data. Available deltamethrin bioassay results from 2007 and 2008, as well as bioassays from Norway, were collected and remodelled. Bioassays were performed on field-collected sea lice in region X in Chile in 2012 and 2013. Bioassays from 2007 were performed prior to the introduction of pyrethroids to the Chilean market. Both the results from 2008 and 2012 showed an increased resistance. Increased pyrethroid resistance was also indicated by the increased use of pyrethroids in Chilean aquaculture compared with the production of salmonids. A similar trend was seen in the Norwegian usage data. The bioassay results from Chile from 2012 and 2013 also indicated a difference in the susceptibility to deltamethrin between male and female caligus.

Single-dose field bioassay for sensitivity testing in sea lice, Lepeophtheirus salmonis: development of a rapid diagnostic tool.

Sea lice on farmed salmonids are often treated with chemicals. Sensitivity testing of sea lice can reduce the number of treatments by identifying substances the sea lice are susceptible to. This study describes a simpler protocol for field sensitivity testing than today's six-dose bioassay. The protocol, which uses a single dose of the delousing agents deltamethrin, azamethiphos and emamectin benzoate, was developed on four different strains of sea lice and their subsequent generations. A sensitive strain and a strain showing reduced sensitivity were identified for each chemical after performing traditional bioassays and small-scale treatments. The single doses for each chemical were established by modelling dose-response curves from 24-h bioassays on strains with differences in sensitivity. The largest difference between the lower 80% prediction interval for the sensitive strain and the upper 80% prediction interval for the strain showing reduced sensitivity was identified for each delousing agent. The concentration of the chemical and the % mortality corresponding to each of the 80% prediction intervals were subsequently established. To validate the protocol for field use, further studies on both sensitive and resistant strains of sea lice under field conditions are required.

Adenosine induces prolonged anti-beta-adrenergic effects in guinea-pig papillary muscle.

A sustained anti-beta-adrenergic effect of adenosine has been reported. This study was initiated to investigate this topic and especially elucidate the role of protein kinase C (PKC). Contractile force amplitude and action potential duration at 90% repolarization (APD90) were measured in guinea-pig papillary muscles before and after 5 min challenge with 5 nm isoproterenol. Protocols contained 30 min exposure to the test agents adenosine 33 microm (ado), adenosine + PKC-inhibitor bisindolylmaleimide 20 nM (ado + BIM), PKC-activator 1,2-dioctanoyl-sn-glycerol 10 microm (DOG) and alpha-agonist phenylephrine 5 microm (phe). Isoproterenol was given at the end of test exposure and after 15 min washout. Results are mean +/- SEM of percentage-change, P < or = 0.05 considered significant and labelled *. The first isoproterenol challenge significantly increased contractile force (27 +/- 7%*) in the control group. Responses in the test groups were 2 +/- 4 (ado), 1 +/- 5 (ado + BIM), 14 +/- 4* (DOG), 0 +/- 2% (phe). After washout of adenosine, DOG and phenylephrine, isoproterenol induced 3 +/- 8 (ado), 23 +/- 5* (ado + BIM), 13 +/- 5* (DOG), 15 +/- 7% (phe) increase in test groups compared with 22 +/- 5%* increase in contractile force in the control group. After 45 min washout of adenosine the inotropic response was still significantly reduced compared with control (29 +/- 4 vs. 79 +/- 8%*). Isoproterenol stimulation shortened APD90 in controls at both time points (5 +/- 1%* and 4 +/- 1%*), with no significant shortening in test groups. Adenosine induces sustained anti-beta-adrenergic effects on contractile force as well as APD90. A role for PKC in signal transduction is supported with respect to contractile force.

HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica.

We examined factors associated with high-grade squamous intraepithelial lesions (HSIL) and cervical cancer among human papillomavirus (HPV)-infected women in a prevalent case-control study conducted within a population-based cohort of 10 077 women in Costa Rica. We compared 146 women with HPV-positive HSIL or cancer (HSIL/CA) against 843 HPV-positive women without evidence of HSIL/CA. Subjects completed a risk factor questionnaire. We evaluated the associations between exposures and HSIL/CA among women positive for any HPV and restricted to those positive for high-risk HPV types. Risk of HSIL/CA increased with increasing number of live births (P(trend)= 0.04). Women who smoked 6+ cigarettes/day had a RR for HSIL/CA of 2.7 (95% CI = 1.1-6.7) compared to non-smokers. Current use of barrier contraceptives was associated with a reduction in risk of HSIL/CA (RR = 0.39; 95% CI = 0.16-0.96). Sexual behaviour and a self-reported history of sexually transmitted diseases (STDs) other than HPV were not associated with HSIL/CA. Oral contraceptive use was associated with HSIL/CA among women with <3 pregnancies. Effects were similar in analysis restricted to women positive for high-risk HPV types. Among women positive for high-risk HPV types, 44% of HSIL/CA could be attributed to multiparity (>/=3 pregnancies) and/or smoking. Among HPV-positive women, multiparity and smoking are risk factors for HSIL/CA. Oral contraceptive use may be associated with HSIL/CA in subgroups of women.

Cardiac effects of non-depolarizing neuromuscular blocking agents pancuronium,vecuronium, and rocuronium in isolated rat atria.

Pancuronium, vecuronium, and rocuronium produce different cardiac effects. Using spontaneously beating right and electrically stimulated left rat atria, while measuring developed force, effective refractory period, and heart rate, we determined and compared the concentration-dependent cardiac effects of the compounds. The preparations were exposed to five progressively increasing concentrations of these compounds (10(-9), 10(-8), 10(-7), 10(-6), and 10(-5) mol/L). Pancuronium increased heart rate; vecuronium and rocuronium produced positive inotropic effects; and vecuronium shortened refractoriness. These effects may be the result of a blockade of the M2 muscarinic receptors. However, the concentrations required to produce changes were higher than those observed in patients under neuromuscular blockade.

Diazepam-induced Ca(2+)-channel blockade reduces hypothermia-induced electromechanical changes in isolated guinea pig ventricular muscle.

Calcium-channel blockers reduce the in vitro effects of hypothermia and benzodiazepines have been reported to reduce inward calcium flow through L-type cardiac-calcium channels. Thus, this study was designed to determine if diazepam could reduce hypothermia-induced changes in ventricular papillary muscle electromechanical activity. Conventional microelectrode techniques were used while force was recorded using a miniature force transducer. Six experimental groups of electrically paced papillary muscles were formed (n = 6 per group). One was exposed to one microM nisoldipine and four were exposed to one of four diazepam concentrations (0.1, 1.0, 10 or 100 microM). A final group had no drug and provided a time-matched control. The effects were determined at 37 degrees C and then at 27 degrees C. At 37 degrees C, diazepam initially increased and then reduced inotropy and APD90. Nisoldipine reduced both APD90 and inotropy. At 27 degrees C, 100 microM diazepam and nisoldipine (1.0 microM) reduced the hypothermia-induced lengthening of APD and the increase in force. Although diazepam reduced the hypothermia-induced alterations, the concentration required to do so (100 microM) suggests that this effect has little role in clinical use.

Immune activation in cervical neoplasia: cross-sectional association between plasma soluble interleukin 2 receptor levels and disease.

In a previous study (Tsukui et al., Cancer Res., 56: 3967-3974, 1996), we observed an inverse association between degree of cervical neoplasia and interleukin (IL) 2 production by peripheral blood mononuclear cells in response to human papillomavirus (HPV) 16 E6 and E7 peptides in vitro. This suggested that a Th1-mediated cellular immune response might be important in host immunological control of HPV infection and that a lack of such a response might predispose to progression of cervical disease. To follow up on these findings, we have conducted a cross-sectional study of women with various degrees of cervical neoplasia to investigate the association between overall immune activation and cervical disease. A total of 235 women were recruited into our study; 120 of these women were participants in our previous study in which IL-2 production in response to HPV-16-specific peptides was measured. The study population included 34 women with invasive cancer, 62 women with high-grade squamous intraepithelial lesions (HSILs), and 105 women with low-grade squamous intraepithelial lesions (LSILs). In addition, 34 cytologically normal women with no past history of squamous intraepithelial lesions despite confirmed HPV-16 infection in the 5 years preceding the study were selected as controls. As our measure of overall immune activation, serum samples obtained from study participants were tested for soluble IL-2 receptor (sIL-2R) level using an ELISA method. The mean sIL-2R levels were found to increase with increasing disease severity (Ptrend = 0.0002). Among cytologically normal, HPV-exposed women, the mean receptor level in serum was 465.8 units/ml compared to 467.6 units/ml among LSIL subjects, 514.9 units/ml among HSIL subjects, and 695.5 units/ml among women with invasive cervical cancer. Similarly, the proportion of women with elevated sIL-2R levels (defined as > or = 450 units/ml) increased with increasing disease severity from 35.2% among normal study subjects to 70.6% among cancer patients (Ptrend = 0.003). Among the subgroup of subjects for whom in vitro IL-2 production in response to HPV-16-specific peptides was measured, we examined the association between in vitro IL-2 production and serum levels of sIL-2R. sIL-2R levels were higher, on average, among those women who were positive in our IL-2 production assay compared to those who were negative, but the differences did not reach statistical significance (P > 0.05). We also observed a trend of increasing sIL-2R level with increasing disease severity both in women who were positive and in women who were negative for our IL-2 production assay, but the trend was only significant among those who were negative for IL-2 production (Ptrend = 0.01). Results from our studies suggest that although the immune system of women with cervical neoplasia is nonspecifically activated as disease severity increases, the ability of those women with HSILs or cancer to mount a Th1-mediated immune response to HPV peptides appears to decrease compared to women with LSILs or normal women infected with HPV. Increased overall activation along with decreased Th1 immune response among women with increasing cervical disease severity might be explained by an increased Th2-mediated immune response, a response that we hypothesize is ineffective in controlling the viral infection and its early cytological manifestations. Future studies should directly assess Th2-mediated responses to confirm this hypothesis. Also, future efforts should be aimed at determining whether the associations observed are causally related to disease progression or an effect of the disease.

Comparison of the hybrid capture tube test and PCR for detection of human papillomavirus DNA in cervical specimens.

The strong association of human papillomavirus (HPV) and cervical cancer makes it important to study HPV detection methods that may play a role in cervical cancer screening. We compared two DNA methods that are commonly used for HPV research in the United States: the MY09/MY11 L1 consensus primer PCR-based test and the first-generation Hybrid Capture tube method (HCT). Laboratory assays by each method were performed with 596 cervicovaginal specimens collected from participants in a large cohort study conducted in Portland, Oreg. Included were 499 specimens from women whose cytology was normal and 97 specimens from women with squamous intraepithelial lesions (SILs). The overall HPV DNA positivity for known types was 22.5% by PCR compared to 13.6% by HCT. When the analysis was restricted to the 14 HPV types detectable by both methods, the sensitivity of HCT, with PCR used as the standard for HPV status, was higher for specimens from women with concurrent SILs (81.0%) than for specimens from women with normal cytology (46.7%). Among specimens testing positive by both methods, 97.2% of the time the two methods agreed on whether specimens were positive for cancer-associated HPV types. Both of these HPV test methods provide information that supplements the information provided by the Pap smear. The PCR method has higher analytic sensitivity than HCT in detecting HPV, but HCT may be helpful in identifying women with concurrent SILs.

Design and methods of a population-based natural history study of cervical neoplasia in a rural province of Costa Rica: the Guanacaste Project.

This paper reports on the enrollment phase of a population-based natural history study of cervical neoplasia in Guanacaste, a rural province of Costa Rica with consistently high rates of invasive cervical cancer. The main goals of the study are to investigate the role of human papillomavirus (HPV) infection and its co-factors in the etiology of high-grade cervical neoplasia, and to evaluate new cervical cancer screening technologies. To begin, a random sample of censal segments was selected and enumeration of all resident women 18 years of age and over was conducted with the aid of outreach workers of the Costa Rican Ministry of Health. Of the 10738 women who were eligible to participate, 10049 (93.6%) were interviewed after giving written informed consent. After the interview on cervical cancer risk factors was administered, a pelvic examination was performed on those women who reported previous sexual activity. The pelvic examination included a vaginal pH determination and collection of cervical cells for cytologic diagnosis using three different techniques. Additional cervical cells were collected for determination of the presence and amount of DNA from 16 different types of HPV, and two photographic images of the cervix were taken and interpreted offsite by an expert colposcopist. Finally, blood samples were collected for immunologic and micronutrient assays. Women with any abnormal cytologic diagnosis or a positive Cervigram, as well as a sample of the whole group, were referred for colposcopy, and biopsies were taken when lesions were observed. The enrollment screening will serve as the basis for a prevalent case-control study, and the members of the cohort free from serious disease will be followed actively, at intervals of no more than a year, to study the natural history of HPV infection and the origins of high-grade squamous intraepithelial lesions (HSIL). Details of the field operation are outlined, with particular reference to the realization of this kind of study in developing countries. Descriptive data on the prevalence of disease and exposure to various risk factors are also presented.

Cervical specimens collected in liquid buffer are suitable for both cytologic screening and ancillary human papillomavirus testing.

BACKGROUND: Several new techniques have been developed to improve the sensitivity of cervical carcinoma screening and reduce equivocal cytologic diagnoses referred to as atypical squamous cells of undetermined significance (ASCUS). This study evaluates the effectiveness of combining two newly introduced diagnostic techniques: preparation of thin-layer cytologic slides from ThinPrep liquid buffer and selected Hybrid Capture testing for human papillomavirus (HPV) DNA. Because HPV DNA detection has been strongly associated with the presence of a cervical carcinoma precursor ("squamous intraepithelial lesion," or SIL), HPV testing might be useful for identifying women with ASCUS who have an underlying SIL. METHODS: Two hundred specimens demonstrating diverse cervical abnormalities were selected from a prospective population-based study of 9174 women conducted in Costa Rica. The entire cohort had been screened with conventional cervical smears; ThinPrep slides made from liquid buffer, PAPNET, a computerized slide reading system; and Cervicography. Patients with any abnormal screening test were referred for colposcopy, punch biopsy, and loop excision of cases with high grade cytologic abnormalities not explained by punch biopsy. For this investigation, the results of ThinPrep cytology and HPV testing alone and in combination were compared with the final diagnoses, with an emphasis on the detection of carcinoma and high grade SIL. RESULTS: The 200 subjects studied included 7 women with a final diagnosis of carcinoma, 44 with high grade SIL, 34 with low grade SIL, 51 with a variety of equivocal diagnoses, and 64 with normal diagnoses. A ThinPrep cytologic diagnosis of SIL or carcinoma was made in 39 (76%) of the 51 women with final diagnoses of high grade SIL or carcinoma. Hybrid Capture testing detected carcinoma-associated types of HPV DNA in 100% of women with carcinoma, 75% with high grade SIL, 62% with low grade SIL, 20% with equivocal final diagnoses, and 12% of normal women. If colposcopy referral had been limited to women with a ThinPrep diagnosis of SIL or a diagnosis of ASCUS associated with the detection of carcinoma-associated HPV DNA from the same vial, 100% of women with carcinoma and 80% with high grade SIL would have been examined. To achieve this high sensitivity in the entire population of 9174 women would have required the referral of about 7% of the population. The combined screening strategy would have performed marginally better than optimized conventional screening with referral of any abnormal cytology (ASCUS and above). CONCLUSIONS: A cervical carcinoma screening technique which uses a single sample for cytopathology and HPV testing to triage equivocal diagnoses may be promising if it proves to be cost-effective.

Influence of hypothermia on the cardiac effects of propranolol observed in isolated rat atria.

UNLABELLED: 1. The purpose was to determine if hypothermia influences cardiac responses to propranolol. 2. Rat atria were used and 11 test groups were created; 3 control groups were maintained at 35, 28 or 20 degrees C. Two additional groups, at each temperature, were exposed to 1.2 or 40 mumol/l propranolol. Developed force and effective refractory period (ERP) were measured. 3. At 35 degrees C, propranolol decreased developed force and lengthened ERP. At 28 degrees C, propranolol did not affect developed force, but ERP was lengthened. At 20 degrees C, 1.2 microM propranolol neither affected developed force or ERP, but 40 microM reduced developed force and lengthened ERP. CONCLUSION: hypothermia reduced propranolol's usual negative inotropic effect.

Alteration of the cardiac effects of isoproterenol and propranolol by hypothermia in isolated rat atrium.

1. Hypothermia alters the myocardial response to some inotropic maneuvers. By measuring developed force and effective refractory period in isolated left atrial preparations, we determined whether hypothermia affected the cardiac response to isoproterenol and propranolol. 2. Twelve experimental groups were formed, each consisting of 6 atrial preparations. Three groups maintained at either 35, 28 or 20 degrees C served to determine the effects of hypothermia alone. 3. At each temperature, 3 additional groups were exposed to 1.0 microM isoproterenol alone or in combination with either 0.3 or 10.0 microM propranolol. At 35 degrees C, isoproterenol produced an increase in developed force and decreased effective refractory period. Propranolol reversed these isoproterenol-induced effects in a concentration-dependent manner. 4. Decreasing temperature to either 28 or 20 degrees C significantly increased developed force and effective refractory period. At 28 degrees C, isoproterenol no longer produced a significant increase in developed force, although effective refractory period was still decreased. At 20 degrees C, isoproterenol significantly reduced both developed force and effective refractory period. These effects of isoproterenol were reversed by the addition of propranolol, so that the effective refractory period was increased and developed force was not different from that observed at 20 degrees C in the absence of isoproterenol. 5. These effects of isoproterenol might be explained by effects on Na+/Ca(2+)-exchange.

Alteration of the cardiac effects of midazolam by hypothermia in rat isolated atria.

Hypothermia produces marked changes in cardiac activity and response to different anesthetic interventions. Isolated spontaneously beating right, or electrically stimulated left rat atria were examined while heart rate, sinus node recovery time, developed force, and effective refractory period were measured at 35 and 20 degrees C. Thus, we wanted to investigate the influence of low temperature on the cardiac effects of midazolam. The preparations were exposed to seven progressively increasing concentrations of midazolam. At 35 degrees C, midazolam produced a concentration-dependent positive inotropic effect and had a biphasic effect (shortening followed by lengthening) on the effective refractory period. These effects are best explained as due to a release of endogenous catecholamines, since the positive inotropy was completely blocked by propranolol. In reserpinized animals, there was no effect of midazolam. Midazolam, however, significantly decreased heart rate and increased the sinus node recovery time; these responses are believed to be direct effects. At 20 degrees C, midazolam had no effect on the developed force but, when a high concentration was administered, it significantly reduced the effective refractory period. Heart rate values were first increased and the reduced to control values. No effect on the sinus node recovery time was observed. Thus, hypothermia may reduce the catecholamine release and mask the effect of midazolam on cardiac tissue by mechanisms not yet fully understood.

Influence of atrial natriuretic factor on intravascular volume displacement in pigs.

The present study was undertaken to quantitate the influences of transcapillary fluid loss, urine output, and the capacity vessels on volume displacement toward and away from the right heart during atrial natriuretic factor (ANF) administration. In eight anesthetized pigs undergoing carotid denervation, cervical vagotomy, and splenectomy, blood was drained from the venae cavae to an extracorporeal reservoir and returned to the right atrium at a constant rate so that volume displacement toward and away from the heart could be recorded as change in reservoir volume. Human ANF-(99-126) (0.1 micrograms.kg-1.min-1) for 15 min was associated with a decrease in reservoir volume of 2.7 +/- 0.4 ml/kg (P less than 0.05), which resulted from a decrease in total blood volume of 8.6 +/- 1.0 ml/kg (P less than 0.05) and a displacement from the capacitance vasculature of 5.9 +/- 1.3 ml/kg (P less than 0.05). Since urine output increased only slightly, virtually all of the total blood volume decrement was due to a displacement of fluid into the extravascular space. Thus ANF acts to displace volume away from the right heart. The displacement is due almost entirely to an increase in transcapillary fluid loss; however, volume displacement from the capacity vessels to the right heart partially counteracts this transcapillary influence.

Influence of angiotensin on total intravascular capacity in the anaesthetized pig.

The present study examined the influence of angiotensin on total intravascular capacity. In eight anaesthetized pigs, splenectomy, carotid sinus denervation and cervical vagotomy were performed. Blood was drained from the venae cavae to an extracorporeal reservoir and returned to the right atrium at a constant rate so that changes in total intravascular volume could be recorded as the inverse of changes in reservoir volume. Angiotensin administration at 0.2 microgram kg-1 min-1 i.v. for 5 min was associated with a decrease in total intravascular volume of 57 +/- 6 ml (P less than 0.05) and an increase in aortic pressure from 96 +/- 5 to 119 +/- 6 mmHg (P less than 0.05). With subsequent angiotensin administration in five of the animals, the responses were not attenuated. In five of the animals, angiotensin was associated with a decrease in intravascular volume of 72 +/- 8 ml (P less than 0.05) before abdominal evisceration and 33 +/- 13 ml (P less than 0.05) after evisceration. These responses were significantly different from each other. In four of these eviscerated animals, angiotensin was associated with a decrease in intravascular volume of 35 +/- 17 ml (P less than 0.05) before ligation of all four limbs and a decrease of 36 +/- 4 ml (P less than 0.05) after limb ligation. Thus, angiotensin acts directly to decrease total intravascular volume. The decrease is due to decreases in both splanchnic and extrasplanchnic volume. The extrasplanchnic volume decrement is not due to decreases in skeletal muscle or cutaneous tissue intravascular capacity in the limbs.

Placebo-controlled comparison of single intramuscular doses of ketorolac tromethamine and pethidine for post-operative analgesia.

The analgesic efficacy and safety of single doses of 10 mg and 30 mg ketorolac tromethamine and 100 mg pethidine were evaluated in a double-blind, parallel-group study. The drugs were administered intramuscularly to patients experiencing moderate, severe or very severe pain immediately following major abdominal surgery. A total of 129 patients were randomly assigned to receive either active drug (n = 32 for each treatment group) or placebo (n = 33), and the patients assessed pain intensity and pain relief on a visual analogue scale at regular intervals over the following 8 h. During the first 2 h, pethidine had a more rapid onset of action than ketorolac or placebo, and thereafter 100 mg pethidine and 30 mg ketorolac were equally effective. Ketorolac, at a dose of 10 or 30 mg, and 100 mg pethidine were clinically and statistically more effective than placebo, with 30 mg ketorolac having a similar efficacy to 100 mg pethidine over the 8-h study period and 10 mg ketorolac being slightly less effective than 30 mg ketorolac. No serious adverse events were reported.

Inotropic effect of meperidine: influence of receptor and ion channel blockers in the rat atrium.

Meperidine increases developed force in isolated rat atria. We initiated this study to determine if this positive inotropic effect was attenuated by commonly used receptor- and ion channel blockers. Neither naloxone (opioid blocker), phentolamine (alpha-adrenoceptor blocker), propranolol (beta-adrenoceptor blocker), polaramine (H1-receptor blocker), ranitidine (H2-receptor blocker), verapamil (calcium-channel blocker), nor lidocaine (fast sodium-channel blocker) attenuated the positive inotropic effect of meperidine. However, after lidocaine pretreatment meperidine increased contractile force by 57% (27%-80%) (median and 95% confidence interval), which is significantly more (P less than 0.001) than the 21% (13%-35%) increase seen after pretreatment with saline. After Na,K-pump inhibition by ouabain, meperidine caused no further increase in contractility, but the atria still responded to isoproterenol with an increase in developed force. Conversely, meperidine prevented the positive inotropic effect of ouabain. These findings suggest that the positive inotropic effect of meperidine is mediated by an increase in intracellular sodium activity and not by regulation of the slow inward calcium channel.

Prolonged action potential duration of guinea-pig heart muscle after pethidine.

Since recent experiments indicated class III antiarrhythmic properties of pethidine in vitro, we studied cardiac effects of pethidine in vivo. Monophasic action potentials at different pacing rates were recorded from the left ventricular epicardium of pentobarbital anaesthetized guinea-pigs by means of suction electrode catheter. Intravenous injection of pethidine 2 mg/kg prolonged the action potential duration, and increased left ventricular developed pressure and dP/dt max, compared to animals receiving saline only. It is concluded that pethidine appears to have class III antiarrhythmic properties.