Moderate Decrease In Blood Pressure Research Articles

Electroconvulsive Therapy in Heart Transplant Patients: To Avoid or Embrace?

Patients with heart disease are at an increased risk of depression. Electroconvulsive therapy (ECT) is a highly effective treatment for severe depressive episodes. However, ECT may increase the risk for adverse outcomes in certain patients because of changes in blood pressure and heart rate secondary to an initial parasympathetic surge followed by a sympathetic surge and peripheral catecholamine release. In post-cardiac transplant patients, these acute hemodynamic changes on a denervated heart may bring clinical challenges. The available data on ECT in heart transplant patients are limited. The authors of this article present a summary of the available literature relating to ECT in heart transplant patients.The authors performed a literature search of 6 online databases yielding 6 English-language case reports of ECT in cardiac transplant patients. All patients experienced changes in hemodynamic variables during and immediately after ECT, ranging from moderate decrease in blood pressure to extreme hypertension. The cases did not report any serious cardiac complications during the course of ECT. In the 5 patients whose psychiatric responses to treatment were detailed, all had improvement in their depressive symptoms. Electroconvulsive therapy may be considered for severe cases of depression in patients with a history of cardiac transplant, but the potential benefit of ECT needs to be weighed against risks. In the limited number of cases reported in the literature, ECT seems to have been relatively safe and effective.

How Dexamethasone Used in Anti-COVID-19 Therapy Influenced Antihypertensive Treatment in Patients with SARS-CoV-2.

During the SARS-CoV-2 pandemic period, in the treatment approved by the WHO, along with antivirals, antibiotics, nonsteroidal anti-inflammatory drugs and anticoagulants, dexamethasone was always used. This study started from the professional concern related to the vasopressor effect of cortisone on blood pressure (BP). The study group was achieved by selecting, from a total of 356 patients hospitalized in the clinic, the patients with known hypertensive status at admission for SARS-CoV-2. Dexamethasone was part of the anti-COVID-19 treatment, with an administration of 4-6-8 mg/day, depending on bodyweight, for 10 days. All patients with hypertension received antihypertensive treatment in adjusted doses according to the recorded BP values. Monitoring of BP in hospitalized patients was performed daily, in the morning and evening. If on the 2nd day of treatment, 84% of the patients partially responded to the treatment with a moderate decrease in BP, on the 3rd therapy day, the situation clearly improved: more than 75% of the patients had values of BP that can be classified as high-normal (38.23%) and normal (40.03%). Dexamethasone for treatment of SARS-CoV-2 infection did not have a notable influence on increasing BP, because the doses were low-moderate and prescribed for a short time.

NT‐proBNP as a diagnostic marker of dilated cardiomyopathy in dogs

In dogs of service breeds, cardiopathology is one of the most common diseases of non‐infectious etiology. Dilated cardiomyopathy (DCM) is frequently reported among other heart conditions in large and giant breed dogs. As a result of our previous work, it has been established that DCM of varying severity is recorded in no less than 25% of service dogs. The diagnosis at the later stages of development is not difficult ‐ an enlarged cardiac silhouette on the roentgenogram, enlarged cavities of the heart chambers with echocardiography, ventricular extrasystoles on the electrocardiogram, and a drop in blood pressure during tonometry. Treatment at the late stages of DCM is ineffective and prolongs the dog's lifespan by an average of 3 months. It is advisable to start treatment when the dog is in the early stages of DCM development. However, it is not so easy to identify the disease at the initial stage using visual diagnostics. Therefore, additional methods for diagnosing heart function are required, among which serological analysis for brain natriuretic peptide (NT‐proBNP) can be distinguished. The study aimed to determine the sensitivity of NT‐proBNP in large and giant breed dogs suspected of having DCM disease. Study inclusion criterion: dogs used in security and search work; large or giant breeds; age 2‐8 years; vaccination against rabies, leptospirosis, plague of carnivores, adenovirus infection, parvovirus enteritis, viral hepatitis; absence of diseases of infectious, invasive, and non‐infectious etiology for the last 3 months. In the experiment, 24 dogs were used, which were divided into three groups: group 1 ‐ dogs with significant dilatation of the heart cavities, rhythm disturbances, and a drop in blood pressure (n = 8); Group 2 ‐ dogs with moderate dilatation of the heart cavities, ECG changes, a moderate decrease in blood pressure (n = 8); Group 3 ‐ animals that had no abnormalities during ultrasound diagnostics in the state of the heart (n = 8). An enzyme‐linked immunosorbent assay determined the NT‐proBNP activity. Thus, in dogs of group 1, the NT‐proBNP activity was increased to 4381.7 ± 281.1 pmol / l, which is 20.5 times higher (p <0.05) than in healthy dogs. Severe DCM was confirmed in these dogs. In group 2 animals, the NT‐proBNP level exceeded the values of healthy animals and amounted to 831.7 ± 94.5 pmol / l, which is 3.9 times higher than the normal values. Despite the absence of changes detected during visual diagnostics of the heart, in 2 of 8 dogs of group 3, NT‐proBNP increased to 467.8 ± 15.4 pmol / L. It was increased 2.1 times, which suggested a violation of cardiac activity in these animals. Repeated diagnostics of these 2 dogs 9‐15 months after the start of the study revealed changes characteristic of DCM ‐ changes in the electrical activity of the heart, dilatation of the heart chambers, changes in blood pressure. Based on the experiment results, it was concluded that serological analysis for NT‐proBNP level is a sensitive test that can be included in the list of DCM differential diagnoses.

Evaluation of the effectiveness of statin and spironolactone by the influence on indicators of vascular stiffness in patients with arterial hypertension

Abstract Introduction The possibility of slowing down vascular remodeling in hypertensive patients with the combined effect of antihypertensive drugs and statins has been studied in unitary studies. The effect of spironolactone on vascular stiffness in relation to the severity of the hypotensive effect in combination therapy has also been insufficiently studied. The aim of the research was to study the dynamics vascular stiffness parameters in hypertension patients of high/very high cardiovascular risk in addition rosuvastatin or spironolactone to combined two-component amlodipine and lisinopril therapy. Methods 90 patients (46 men and 44 women aged 51.6±8.5) with hypertension were randomized into groups: the first group received a fixed combination of amlodipine/lisinopril, the 2nd one followed the same regimen of therapy with addition of 20 mg rosuvastatin, the third - in addition to the combination of amlodipine / lisinopril received 25 mg of spironolactone. The office and ambulatory blood pressure (BP), central (aortic) BP, augmentation index (AIx), carotid-femoral and carotid-radial pulse wave velocity (PWV) were evaluated before and after a 24-week follow-up period. Results The office and average daily blood pressure decreased against the background of all therapy regimens (all p<0.0001). The degree of decrease in the above parameters was more pronounced under the influence of spironolactone, compared with taking a combination of amlodipine / lisinopril (office systolic BP (SBP) p=0.04 and diastolic BP (DBP) p=0.002, average daily SBP p=0.02 and DBP p=0.014) and office DBP in comparison with the group of additional administration of rosuvastatin (p=0.02). A decrease in central BP and AIx was noted in all groups. A more pronounced decrease in AIx occurred in the statin supplementation group relative to the standard treatment group (−5.8% and −9.0%, respectively, p=0.036). Carotid-femoral PWV significantly decreased in all groups (−0.9±1.5 m/s, −0.7±1.4 m/s, −2.2±2.6 m/s, respectively), in greater degree in the spironolactone addition group compared with the statin supplementation group (p=0.036). Carotid-radial PWV to the same extent significantly decreased only in the second (from 9.5±1.8 to 8.8±1.1 m/s (p=0.034)) and the third (from 9.8±1.3 to 8.4±1.3 m/s (p=0.0002)) groups. Conclusions The addition of a statin to a two-component combination of amlodipine / lisinopril in the treatment of hypertensive patients had an additional effect on the elastic properties of the aorta, in the form of a decrease in the augmentation index, and peripheral arteries, in the form of a decrease in PWV. The addition of spironolactone to standard therapy was accompanied by a significant increase in the antihypertensive effect and a decrease in aortic stiffness in the form of a more pronounced decrease in PWV in the carotid-femoral and carotid-radial areas. Funding Acknowledgement Type of funding sources: None.

Discovery of a phenylpyrazole amide ROCK inhibitor as a tool molecule for in vivo studies

Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.

Gender differences in the effects of renin-angiotensin system inhibitors and calcium channel blockers in combination therapy with diuretics on indicators of arterial hemodynamics, vascular stiffness and structural and functional state of the heart

Objective — to compare the gender-associated effects of 6-month (М6) treatment of patients aged 0.05), except for a decrease in LVMI in men compared to 9.5 % for CCB (p 0.05).Conclusions. Treatment of patients with 1—2 degrees of AH during 6 months with ACE inhibitors/ARB ± inda­pamide or CCB ± indapamide, both men and women, resulted in the significant decrease in brachial and central blood pressure. However, regardless of the type of treatment, women achieved lower levels of brachial blood pressure than men. CCB-based therapy, compared to ACE inhibitors/ARB therapy, contributed to more pronounced decreased in central blood pressure in women, decreased the AP both men and women, AIx75 in women. In addition, 6-months antihypertensive therapy using CCB ± indapamide was reduce LVMI on 9.3 %, but only in men, which was not accompanied by changes in diastolic function, regardless of the type of treatment and gender.

Usefulness of Individual Shear Rate Therapy, New Treatment Option for Patients With Symptomatic Coronary Artery Disease

The aim of this study was to elucidate if patients with coronary artery disease (CAD), who fail to respond to revascularization procedures, can improve from individual shear rate therapy (ISRT). The ISRT is an adaptation of the external counterpulsation with lower individual treatment pressures based on Doppler-ultrasound measurements during counterpulsation. In contrast to the external counterpulsation therapy, the ISRT is based on the detection of the individual intra-arterial shear rate. Here we report about the first clinical trial of 31 patients with CAD who were enrolled for 30 sessions of ISRT. To determine the therapeutic effect of ISRT we measured the exercise capacity, the arterial stiffness, the aortic wave reflection, and the 24-hour blood pressure before and after 30 treatment sessions. After 6 weeks of accomplished ISRT the walking distance during the 6-minute walking test extended by 78 m (p = 0.007). The total exercise duration in the exercise stress electrocardiogram increased by 84 seconds (p = 0.012) but not the stress intensity (p = 0.086). The pulse wave velocity decreased by 1.2 m/s (p = 0.004) and demonstrated a decrease in arterial stiffness. Pulse wave analysis results demonstrated a progressive decrease in central blood pressure by 12 mmHg (p = 0.008), in pulse pressure by 9 mmHg (p = 0.005), and in augmentation pressure by 5.3 mmHg (p = 0.004). The 24-hour blood pressure decreased systolic by 15 mmHg (p <0.001) and diastolic by 8 mmHg (p = 0.033). The patients also benefited subjectively followed by New York Heart Association and Canadian Cardiovascular Society classifications. In conclusion, the ISRT is an effective treatment for patients with CAD to improve cardiac fitness, arterial stiffness, and to reduce blood pressure.

Comparison of lercanidipine plus hydrochlorothiazide vs. lercanidipine plus enalapril on micro and macrocirculation in patients with mild essential hypertension.

Dihydropyridine calcium channel blockers may possess antioxidant properties, and might improve micro and macrovascular structure and function. Combination treatment with an ACE inhibitor may have additional advantages, compared with a thiazide diuretic. The aim of the present study is to investigate the effects of a short-term treatment with lercanidipine, and to compare two combination treatments: lercanidipine+enalapril vs. lercanidipine+hydrochlorothiazide on structural alterations in retinal arterioles, on skin capillary density and on large artery distensibility. Thirty essential hypertension patients are included in the study, and treated for 4weeks with lercanidipine 20mg per day orally. Then, they were treated for 6months with lercanidipine+enalapril (n=15) or lercanidipine+hydrochlorothiazide (n=15) combinations. Investigations were performed on basal condition, after appropriate wash out of previous treatments, after 4weeks of lercanidipine monotherapy treatment, and at the end of the combination treatment. Non-invasive measurements of wall-to-lumen ratio (WLR) and other morphological parameters of retinal arterioles were performed using either scanning laser Doppler flowmetry or adaptive optics. Capillary density was evaluated by capillaroscopy, while pulse wave velocity was measured, and central blood pressures were assessed by pressure waveform analysis. A significant improvement of WLR and other indices of retinal artery structure is observed with both technical approaches after treatment with lercanidipine alone, with a further improvement after treatment with lercanidipine+enalapril, while after treatment with lercanidipine+hydrochlorothiazide, the improvement is partially blunted. Central systolic and diastolic blood pressures are similarly reduced by both therapeutic strategies. Capillary density is increased only after treatment with lercanidipine+enalapril. In conclusion, lercanidipine both in monotherapy and in combination with enalapril but not with hydrochlorothiazide is able to improve microvascular structure; on the other hand, a decrease in central blood pressure is observed with both therapeutic combinations.

Protective Angiotensin Type 2 Receptors in the Brain and Hypertension

The goal of this review is to assess the evidence that activation of angiotensin type 2 receptors (AT2R) in the brain can lower blood pressure and possibly constitute an endogenous anti-hypertensive mechanism. Recent studies that detail the location of AT2R in the brain, particularly within or near cardiovascular control centers, mesh well with findings from pharmacological and gene transfer studies which demonstrate that activation of central AT2R can influence cardiovascular regulation. Collectively, these studies indicate that selective activation of brain AT2R causes moderate decreases in blood pressure in normal animals and more profound anti-hypertensive effects, along with restoration of baroreflex function, in rodent models of neurogenic hypertension. These findings have opened the door to studies that can (i) assess the role of specific AT2R neuron populations in depressing blood pressure, (ii) determine the relevance of such mechanisms, and (iii) investigate interactions between AT2R and depressor angiotensin-(1-7)/Mas mechanisms in the brain.

The Impact of Hypoglycemia on the Cardiovascular System: Physiology and Pathophysiology.

Intensive glycemic control may increase cardiovascular (CV) risk and mortality due to hypoglycemia. The pathophysiology of glucose counter-regulation in patients with type 1 or type 2 diabetes for over 15 years is characterized by impairment of the defense mechanisms against hypoglycemia. Hypoglycemia causes pronounced physiological and pathophysiological effects on the CV system as consequences of autonomic system activation and counter regulatory hormones release. These effects provoke a series of hemodynamic changes that include an increase in heart rate and peripheral systolic blood pressure, a decrease in central blood pressure, reduced peripheral arterial resistance, and increased myocardial contractility and cardiac output. Cardiac electrophysiological changes including flattening or inversion of T waves, QT prolongation, and ST segment depression were observed in both insulin-induced and spontaneous hypoglycemia. Sympathoadrenal activation is the main cause of these changes through mechanisms that involve, but are not limited to, catecholamine-mediated hypokalemia. Hypoglycemia is also involved in platelet activation. There is growing concern about the long-term effects of hypoglycemia, especially as related to inflammation and atherogenesis.

Effects of renal sympathetic denervation on blood pressure and glycaemic control in patients with true resistant hypertension: results of Polish Renal Denervation Registry (RDN-POL Registry).

The assessment of percutaneous renal sympathetic denervation (RDN) efficacy in patients with true-resistant hypertension (true-RH) in a newly established net of Polish centres (RDN-POL Registry). Forty-four patients with true-RH (23 men, mean age 52.3 years) with daytime systolic blood pressure (SBP) in ambulatory blood pressure monitoring (ABPM) ≥ 135 mm Hg, on ≥ three antihypertensive agents, including diuretic, underwent RDN and completed 12-month follow-up. Mean reductions of office SBP/diastolic blood pressure were -23.8/-10.0, -12.5/-4.6, and -12.6/-6.1 mm Hg at 3, 6, and 12 months, respectively (all significant except diastolic at 6 months). Diabetes was the only predictor of office SBP reduction at 6 months (OR 9.6, 95% CI 1.4-66.5, p < 0.05). Mean 24-h SBP change was -8.3 mm Hg at 6 months and -4.6 mm Hg at 12 months. Increased 2 h-glucose in oral glucose tolerance test was the only predictor of 24-h SBP reduction at 6 months (OR 1.24 for 10 mg/dL glucose increase, 95% CI 1.04-1.48, p < 0.05). At 12 months, 24-h SBP change predictors were: baseline office SBP (OR 4.93 for 10 mm Hg SBP increment, 95% CI 1.01-24.1, p < 0.05) and 2 h-glucose (OR 1.47, 95% CI 1.08-2.00, p < 0.05). In ABPM responders, significant reduction of 2 h glucose was found as compared to the non-responders (-45.8 vs. -7.7 mg/dL, p < 0.005). The RDN-POL Registry demonstrated moderate blood pressure decrease after RDN. The predictors of blood pressure reduction were diabetes, 2 h-glucose, and baseline office SBP. Analysis of ABPM responders indicates a probable positive impact of RDN on glycaemic control.

Relationship between Blood Pressure and Outcomes in Acute Ischemic Stroke Patients Administered Lytic Medication in the TIMS-China Study.

ObjectiveIncreased blood pressure (BP) management following acute ischemic stroke (AIS) remains controversial. This study aimed to identify the association between BP and clinical outcomes in AIS patients administered lytic medication in the TIMS-China (thrombolysis implementation and monitor of acute ischemic stroke in China) database.MethodsThe sample comprised 1128 patients hospitalized within 4.5 hours (h) of AIS for intravenous recombinant tissue plasminogen activator (i.v. rt-PA) thrombolysis. Systolic BP (SBP) and diastolic BP (DBP) at baseline, 2 h and 24 h after treatment, and changes from baseline were analyzed. The study outcomes comprised a favorable outcome (modified Rankin Scale 0–1 at 90 days) and symptomatic intracerebral hemorrhage (SICH), analyzed using logistic regression, with low BP as the reference group.ResultsLower BP (baseline, 2 h, and 24 h) was beneficial in AIS patients and significantly related to a favorable outcome (P<0.05). A substantial BP decrease at 24 h after rt-PA thrombolysis was significantly associated with a favorable outcome compared with a moderate BP decrease (P = 0.0298). A SBP >160 mmHg 2 h after rt-PA thrombolysis was significantly associated with SICH compared with a SBP <140 mmHg (P = 0.0238). An increase or no change (>25 mmHg) in SBP was significantly associated with SICH (P = 0.002) compared with a small SBP decrease (1–9 mmHg).ConclusionsThis study provides novel evidence that lower BP within the first 24 h is associated with a more favorable outcome and less frequent SICH in AIS patients administered lytic medication. Routine BP-lowering treatment should be considered in AIS patients following lytic medication.

Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis

BackgroundCalcific uremic arteriolopathy (CUA) or calciphylaxis is a severe complication of advanced chronic kidney disease (CKD) and dialysis. Few effective treatments are available and the mortality rate is high. We report 4 cases in which sodium thiosulfate therapy was rapidly effective. CasesSodium thiosulfate therapy was given to 4 Caucasian patients (3 females and 1 male aged 49 to 91 years) with CUA. The causes of end-stage CKD were nephroangiosclerosis (n=2) and diabetic nephropathy (n=2). The lesions developed 1 to 6.5 years after the initiation of hemodialysis and involved the lower limbs in 2 patients, the fingers in 1 patient, and a breast in the remaining patient. They were responsible for pain and skin necrosis in all 4 patients. Local superinfection occurred in 3 patients. Intravenous sodium thiosulfate was given in a dosage of 12.5 to 25g after each hemodialysis session, for 12 to 24 weeks. The pain and trophic disorders resolved fully in all 4 patients. The side effects consisted of nausea and vomiting (n=2) and a moderate blood pressure decrease (n=1). No recurrences were noted during the follow-up of 5 to 17 months after treatment discontinuation. ConclusionThe findings from this small case-series suggest that sodium thiosulfate may hold promise for the treatment of CUA.

Lifestyle modification increases serum testosterone level and decrease central blood pressure in overweight and obese men.

Obesity has reached global epidemic proportions and is associated with multiple comorbidities, including cardiovascular disease. A novel predictor of cardiovascular disease is elevated central systolic blood pressure. In fact, lifestyle modifications have been shown to decrease the central systolic blood pressure in overweight and obese men. The mechanism underlying these changes has yet to be fully elucidated. Interestingly, testosterone has been found to have cardioprotective effects. Moreover, serum testosterone levels are lower in obese men than in normal weight men. However, it is still unclear whether testosterone participates in the decrease of central blood pressure in overweight and obese men following lifestyle modifications. So, the purpose of the present study was to investigate the effect of testosterone on central systolic blood pressure in overweight and obese men before and after the 12-week lifestyle modification program. Forty-four overweight and obese men completed a 12-week lifestyle modification program (aerobic exercise training and dietary modifications). For all participants, central systolic blood pressure and serum testosterone levels were measured before and after the program. After the program, central systolic blood pressure was significantly decreased while serum total testosterone levels were significantly increased in overweight and obese men. Moreover, we also found a significant negative relationship between the change in serum testosterone levels and that in central systolic blood pressure. The present study suggests that increased serum testosterone levels likely contribute to a decrease in central blood pressure in overweight and obese men.

Alcohol-Medication Interactions: The Acetaldehyde Syndrome

Medications that inhibit aldehyde dehydrogenase when coadministered with alcohol produce accumulation of acetaldehyde. Acetaldehyde toxic effects are characterized by facial flushing, nausea, vomiting, tachycardia and hypotension, symptoms known as acetaldehyde syndrome, disulfiram-like reactions or antabuse effects. Severe and even fatal outcomes are reported. Besides the aversive drugs used in alcohol dependence disulfiram and cyanamide (carbimide), several other pharmaceutical agents are known to produce alcohol intolerance, such as certain anti-infectives, as cephalosporins, nitroimidazoles and furazolidone, dermatological preparations, as tacrolimus and pimecrolimus, as well as chlorpropamide and nilutamide. The reactions are also observed in some individuals after the simultaneous use of products containing alcohol and disulfiram-like reactions inducers. Depending on the pharmacological inducer, reactions may occur several days after treatment completion. Disulfiram-alcohol reaction includes moderate decrease in blood pressure, but severe life-threatening arterial hypotension and shock sometimes develop. Myocardial infarction secondary to disulfiram-alcohol reaction has been also reported. For severe hypotension resulting from a disulfiram-ethanol reaction, adrenaline or noradrenaline have been employed as the pressor agent of choice. Fomepizole, an alcohol dehydrogenase inhibitor, may be a safe and effective treatment of severe reactions. When medications that produce antabuse effects are prescribed or dispensed, patients should be instructed to avoid medicines and other products containing alcohol, such as syrups, fermented vinegar, sauces and lotions. It is essential that doctors, nurses and pharmacists instruct patients to avoid alcohol during treatment with aversive drugs and disulfiram-like reactions inducers. Likewise, even when scientific evidence is inconclusive, such instructions should be provided in leaflets, which are often the only source of information for patients and a guide for health professionals.

Kakao und dunkle Schokolade zur kardiovaskulären Prävention?

It has been shown that the consumption of cocoa has a positive influence on a number of cardiovascular surrogate parameters such as arterial vasodilatation and a moderate decrease in blood pressure in humans. In the blood, a decrease in platelet aggregation and an increase in angiogenetic progenitor cells was noted. Furthermore, anti-inflammatory effects, an amelioration of the lipid profile and glucose metabolism was described. An increase of endothelial NO production following the ingestion of the antioxidant cocoa flavanols catechin and epicatechin seems to be the leading mechanism causing these effects. In animal studies of myocardial reperfusion, a decrease in infarct size was noted. In several prospective cohort studies from Europe and the United States, a 50 % reduction of mortality mostly due to a reduction of myocardial infarction was published. Consumption up to about 25 g daily of a flavanol rich dark chocolate (ca. 85 % cocoa content) can be recommended for cardiovascular prevention. In this moderate dosage, the potentially harmful effects due to weight gain and cadmium intake will be minimal. However, controlled randomized trials with well defined clinical endpoints are needed to prove the positive effects described so far. At this point, in time based on the information described in this article, a moderate consumption of flavanol rich cocoa products seems to be effective in the prevention of coronary artery disease and myocardial infarction.

Comparison of the sedative effects of morphine, meperidine or fentanyl, in combination with acepromazine, in dogs

This study aimed to compare the sedative effects of morphine, meperidine and fentanyl, in combination with acepromazine (ACP) and their effects on physiologic values in dogs. Six healthy beagle dogs were randomly assigned to four treatments with 7-day washout intervals. In three treatments, ACP (0.05mg kg-1) was administered and 20 minutes later, the dogs received administration of 0.5mg kg-1 of morphine (ACPMOR), 5mg kg-1 of meperidine (ACPMEP) or 5µg kg-1 of fentanyl (ACPFEN). In treatment ACP HD MOR, 0.1mg kg-1 of ACP was administered in combination with 0.5mg kg-1 of morphine. All drugs were administered intravenously. Sedation scores were evaluated by a numeric descriptive scale (NDS: 0-3) and a simple numeric scale (SNS: 0-10). All variables were evaluated for 120 minutes. The administration of ACP caused mild to moderate sedation. Sedation was improved in all treatments after opioid administration, but significant differences were detected only in ACPMOR and ACP HD MOR. More dogs presented intense sedation (NDS=3.0) after administration of morphine (3/6 and 4/6 dogs in ACPMOR and ACP HD MOR versus 1/6 in other treatments). Duration of sedation was longer in ACPMOR and ACP HD MOR. Mild to moderate decreases in blood pressure, respiratory rate and temperature were observed in all treatments but decreased HR was observed only in ACPMOR and ACP HD MOR. No significant differences were observed in the aforementioned variables when twice the dose of ACP was used (treatment ACP HD MOR). Under the conditions of this study, administration of morphine, in combination with ACP, results in greater and longer sedation than meperidine and fentanyl. Increasing the dose of ACP, in combination with morphine, does not improve the degree of sedation. All combinations used were considered to be safe for healthy dogs.

Severe Hypotension and Ischemic Stroke after Disulfiram-Ethanol Reaction

Disulfiram (tetraethylthiuram disulfide) has been used for almost 60 years in the treatment of alcohol addiction. It causes aversive behavior due to disulfiram-ethanol reaction (DER). The classical DER includes flush, sweating, tremor, nausea, vomiting, tachycardia, moderate decrease in blood pressure and restlessness. Complete recovery is the usual outcome in clinical settings. Life-threatening reactions are rare but sometimes occur. We present a case of a 53-year-old man developing severe hypotension and ischemic stroke as a result of disulfiram treatment and ethanol intake. Use of adrenalin as a drug of choice in this critical condition, together with other therapeutic approaches led to stabilization of hemodynamics and reversal of neurological symptoms. Our case had a favorable outcome, but it should be remembered that patients unable to comply to the strong restrictions in treatment for alcohol rejection are not eligible for this therapeutic modality used in the management of alcohol dependency.

Low-dose versus a Higher-dose Bupivacaine Spinal Anesthesia for Cesarean Delivery

Low-dose <i>versus</i> a Higher-dose Bupivacaine Spinal Anesthesia for Cesarean Delivery

Oblimersen (OBL; Genasense®), a Phosphorothioate (PS) Bcl-2 Antisense Oliogonucleotide (ASO), Can Be Safely Administered by Bolus Subcutaneous (SC) Injection and Brief IV Infusion.

Background: Oblimersen (OBL) is an 18-mer PS-ASO that down-regulates Bcl-2 and amplifies the activity of cytotoxic drugs in patients (pts) with chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and melanoma. PS-ASOs like OBL are commonly administered by continuous intravenous infusion (CIV) in order to avoid high peak plasma concentrations that have been associated with cardiovascular collapse, complement activation, and death in primates. However, we consistently observed no such reactions in patients who received inadvertent overdoses of OBL. Furthermore, preclinical studies in xenograft tumors in mice indicated that intratumoral uptake and retention of OBL was enhanced with short IV infusion. Given the inconvenience of CIV and based on recent preclinical data, we evaluated the safety and pharmacokinetics (PK) of OBL administered as weekly subcutaneous (SC) injection, a brief 2-hr IV infusion for 5 days, and a weekly 2-hr infusion.Methods: Eligible pts had: advanced solid tumors; no available standard therapy; adequate organ function; and ECOG performance status of 0 to 2. In the SC study, single doses of 75, 150, and 225 mg were given to 8 pts, followed by a multiple dose study at 150 mg, 225 mg, and 300 mg. Pts received OBL by 2-hr IV infusion once weekly for 3 weeks (Days 1, 8, 15) starting at a dose of 300 mg and increasing in increments of 100 mg to the maximum tolerated dose (MTD). Blood samples were obtained for complement, Bcl-2, and PK analyses. Dose escalation utilized an accelerated dose escalation schedule.Results: Single pt cohorts were treated at each 2-hr dose level ranging from 300 to 800 mg. Syncope occurred in 1 pt treated with 900 mg, but treatment of 2 additional pts at this dose was uneventful. At the 1000 mg dose level, all pts experienced fever, chills, and moderate decreases in blood pressure, generally limited to the first infusion, which were not felt to be dose-limiting. The PK were dose-proportional over the 300 to 900 mg dose range. AUC and Cmax levels nearly were dose-proportional, and dose-normalized AUC and Cmax values were constant. Cmax values at 900 mg were > 50 μg/mL, and exceeded by >10-fold the Css of CIV schedules in solid tumor pts. There was no change in metabolism or plasma clearance with increasing doses. Large inter-patient variability was observed; however, intra-patient variability was low, as indicated by a coefficient of variation of < 20% for Cmax values obtained on Days 1, 8, and 15. No consistent pattern in complement activation was observed. One patient with metastatic NSCLC remains on study at 14 weeks with a 10% reduction in tumor size. OBL given by SC injection was associated with a Grade 1 erythematous rash at the injection site in all pts, which resolved within 7 days. AUC0–24 exposure at the 225-mg SC dose was similar to previously established 24-h steady-state AUCs after 3 mg/kg by CIV infusion.Conclusions: OBL AUC exposure from a single SC injection is similar to that observed using the 3mg/kg daily dose level administered by CIV to pts with CLL. OBL can also be administered safely by 2-hr IV infusion at weekly doses up to 1,000 mg. Corticosteroids are being tested to evaluate whether constitutional reactions can be ameliorated, and then a twice-per-week schedule will be designed to examine OBL-induced down-regulation of Bcl-2 alone and in combination with cytotoxic drugs in specific diseases.