Angiotensin Converting Enzyme Inhibitors: Animal Experiments Suggest a New Pharmacological Treatment for Alcohol Abuse in Humans

The prevalence of heavy alcohol consumption is a major problem of increasing proportions throughout the world. Although alcohol sensitizing drugs and more recently serotonin uptake inhibitors are drug interventions with some following, their long term beneficial consequences have yet to be demonstrated. In recent years, we have demonstrated that manipulating activity in the renin-angiotensin system will dramatically alter voluntary alcohol consumption in rats. Based on these findings, the present study evaluated the ability of a class of drugs known as the angiotensin converting enzyme inhibitors to reduce voluntary alcohol drinking in laboratory animals. These drugs prevent the conversion of angiotensin I to angiotensin II. They have been licensed for use in Europe and North America and are indicated in the treatment of hypertension. Our experiments showed that both captopril (Capoten, Squibb) and enalapril (Vasotec, Merck Sharpe & Dohme) can reduce alcohol drinking in both normotensive and hypertensive animals regardless of whether the pattern of intake is in a bout or of a less exaggerated nature. Furthermore, this change in alcohol intake can occur without concomitant changes in blood pressure, plasma renin activity, overall fluid balance, or the distribution and metabolism of alcohol. Taken together these findings suggest that the angiotensin converting enzyme inhibitors should be evaluated in a clinical setting for they may prove to be a useful new treatment or treatment adjunct for alcohol abuse in humans.     

Differences in the fiber composition of the pyramidal tract in two- and 14-month-old rats

The present study is aimed at an electron-microscopic morphometrical analysis of the pyramidal tract of 14-month-old rats at the level of the pyramis medullae and the second cervical segment, and a comparison with data obtained for rats of two months of age. Between 2 and 14 months of age there is, at the level of the pyramis medullae of the left pyramidal tract, a statistically significant increase of the number of myelinated fibers, from 91,000 to 118,000, whereas the total number of unmyelinated fibers decreases from 133,000 to 101,000. On the right side at the same level there is no statistically significant change in the number of myelinated fibers, whereas there is a significant decrease of unmyelinated fibers at this side, from 148,000 to 89,000. At the second cervical level, a statistically significant increase in the number of myelinated fibers has been noted at both sides (from 43,000 to 60,000) between 2 and 14 months, whereas the mean total number of unmyelinated fibers at this level decreases somewhat (from 35,000 to 28,000), but is not statistically significant. Several processes which might be involved in the age-related changes observed are discussed, including the possibility of a shift from unmyelinated fibers to myelinated ones, withdrawal of corticobulbar fibers and ongoing outgrowth of myelinated corticofugal fibers after two months of age, and a summarizing scheme is presented. We conclude that the pyramidal tract of the rat changes in composition after the age of two months and that continuing outgrowth of myelinated corticospinal fibers is an important aspect of this continuing development.     

The Effect of Antiepileptic Drugs on Cognition: Patient Perceived Cognitive Problems of Topiramate versus Levetiracetam in Clinical Practice

Summary:  Introduction: Neurocognitive complaints may interfere with long-term antiepileptic drug (AED) treatment and are an important issue in clinical practice. Most data about drug-induced cognitive problems are derived from highly controlled short-term clinical trials. We analyzed such cognitive complaints for the two most commonly used AEDs in a clinical setting using patient perceived problems as primary outcome measure.
Method: All patients of the epilepsy center Kempenhaeghe that received topiramate (TPM) or levetiracetam (LEV) from the introduction to mid 2004 were analyzed using a medical information system, an automated medical file. Patients were analyzed after 6, 12, and 18 months of treatment.
Results: Four hundred and two patients used either TPM (n = 260) or LEV (n = 142); 18 months retention showed a statistically significant difference, revealing 15% more patients that continued LEV compared to TPM: 18 months retention 46% for TPM and 61% for LEV [F (1.400) = 3.313, p = 0.043]. Neurocognitive complaints accounted for a significant number of drug discontinuations and especially the high frequency of neurocognitive complaints in the first period of TPM treatment appeared to be significant different from LEV [F(2,547) = 3.192, p = 0.042]. In the remaining patients, the difference in neurocognitive complaints was not statistically significant.
Conclusion: cognitive complaints are common in TPM treatment and frequently lead to drug withdrawal. The impact of LEV on cognitive function is only mild. This leads to a much higher (15%) drug discontinuation rate for TPM compared to LEV.     

Sex and age specific prediction formulas for estimating body composition from bioelectrical impedance: a cross-validation study

In 827 male and female subjects, with a large variation in body composition and an age range of 7-83 years, body composition was measured by densitometry, anthropometry and bioelectrical impedance. The relationship between densitometrically determined fat free mass (FFM) with body impedance (R), body weight (W) and body height (H) was analysed, taking age and sex into account. The intercept of the regression equation FFM = a x H2/R + b was found to be age, and (at older ages) sex dependent, increasing from age 7 to age 15, and slowly decreasing after age 16. Therefore the population was subdivided into two age categories, the one 15 years and younger, and the other 16 years and older. Each age category was randomly divided into two groups, A and B. In each age category the developed prediction formula for group A was cross-validated in group B, and vice versa. No statistically and biologically meaningful differences between predicted and measured FFM were observed in either group. Therefore the data of group A and B in each age category were combined. The best fitted prediction formula at ages less than or equal to 15 was: FFM = 0.406 x 10(4) x H2/R + 0.360 W + 5.58 H + 0.56 Sex - 6.48: n = 166, R2 = 0.97, SEE = 1.68 kg (cv% = 4.9 percent); and at ages greater than or equal to 16: FFM = 0.340 x 10(4) x H2/R + 15.34 H + 0.273 W - 0.127 age + 4.56 sex - 12.44: n = 661, R2 = 0.93, SEE = 2.63 kg (cv% = 5.0 percent).(ABSTRACT TRUNCATED AT 250 WORDS)     

Gentamicin kills intracellular Listeria monocytogenes.

The purpose of the experiments described here was to test whether membrane-impermeant antibiotics present in the extracellular milieu could kill bacteria within macrophages. For this, mouse macrophage hybrids and elicited mouse peritoneal macrophages first were allowed to phagocytose the facultative intracellular bacterium Listeria monocytogenes. The cells were incubated with or without gentamicin, and their bactericidal activity was measured. The results show that gentamicin caused normally nonbactericidal macrophages to kill L. monocytogenes. In addition, gentamicin caused listericidal cells to kill significantly more bacteria. To determine whether gentamicin accumulated within macrophages during culture, we tested whether lysates of macrophage hybrids cultured for 72 h in gentamicin-containing medium and then washed could kill Listeria cells. When cultured with 50 to 100 micrograms of gentamicin per ml, but not when cultured with 0 to 5 micrograms of gentamicin per ml, cell lysates were extremely listericidal, demonstrating the presence of intracellular gentamicin. Because gentamicin does not penetrate cell membranes, we hypothesized that it can be internalized by the cell through pinocytosis and can enter the same intracellular compartment as does phagocytosed L. monocytogenes. To test this, macrophages which had phagocytosed L. monocytogenes were incubated with the fluorochrome lucifer yellow to trace pinocytosed medium. About half of the Listeria cells within the macrophages were surrounded by lucifer yellow, indicating delivery of pinocytosed fluid, which could contain antibiotics, to phagosomes containing bacteria. The experiments described here indicate that membrane-impermeant antibiotics can enter macrophages and kill intracellular bacteria. Thus, the use of gentamicin in macrophage bactericidal assays can interfere with the results and interpretation of experiments designed to study macrophage bactericidal activity.     

Regulation and selection of patients

During the past decades health legislation and regulation have been on the increase in most industrialized countries. The growing role of government in the provision and financing of health care, the need to correct given aspects of health care and the mandate to protect the underprivileged have been some of the many reasons for increased regulation. Different regulatory approaches and their respective advantages and disadvantages are reviewed in this paper. Particular attention is given to the crucial issue of how to regulate the access to scarce resources and how to cope within a legislative approach with the resulting patient selection.     

Polytrauma management - What is new and what is true in 2020 ?

This is a review of changes in the practice of treating polytrauma managemtent within the years prior to 2020. It focuses on five different topics, 1. The development of an evidence based definition of Polytrauma, 2. Resuscitation Associated Coagulopathy (RAC), 3. neutrophil guided initial resuscitation, 4. perioperative Scoring to evaluate patients at risk, and 5. evolution of fracture fixation strategies according to protocols^1,2 (Early total care, ETC, damage control orthopedics, DCO, early appropriate care, EAC, safe definitive surgery, SDS).     

Multitrauma patients: principles of 'damage control surgery'

The principles of damage control surgery were applied in the cases of three severely injured multitrauma patients, men aged 47 and 33 years who had a motorcycle accident and a 66-year-old man who had a car crash. Victims of major trauma suffer from a worsening physiologic derangement manifested by the triad of acidosis, hypothermia and coagulopathy. This often leads to a vicious cycle that heralds imminent death or organ failure. Damage control surgery involves three distinct stages. The first consists of rapid temporary measures to control bleeding and contamination, followed by rapid closure of the abdomen. The second involves aggressive correction of the lethal triad in the intensive care unit. The third is the planned re-operation for the definitive repair of the injuries. As shown in these three patients, the appropriate use of this strategy can lead to a decrease in the morbidity and mortality in complex trauma patients.     

Brain renin-angiotensin system and ouabain-induced sympathetic hyperactivity and hypertension in Wistar rats.

In Dahl salt-sensitive rats on a high salt diet or normotensive rats with chronic central infusion of sodium, increased brain "ouabain" results in sympathetic hyperactivity and hypertension, possibly by activating the brain renin-angiotensin system. In the present study, we tested whether the hypertension caused by exogenous ouabain also depends on activation of brain renin-angiotensin system. In Wistar rats, ouabain (50 micrograms/d) was infused subcutaneously for 14 days with the use of osmotic minipumps. Concomitantly, in one group, the angiotensin II type 1 receptor blocker losartan (1 mg/kg per day) was infused intracerebroventricularly. On day 15, mean arterial pressure, heart rate, central venous pressure, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air-jet stress, intracerebroventricular injection of the alpha(2)-agonist guanabenz (25 and 75 micrograms) or angiotensin II (30 ng), acute volume expansion, and ramp changes of blood pressure by +/-50 mm Hg with phenylephrine and nitroprusside. Compared with control rats, in rats treated with ouabain, resting mean arterial pressure was significantly increased (111+/-4 versus 93+/-3 mm Hg; P<0.05), and increases or decreases in mean arterial pressure, heart rate, and renal sympathetic nerve activity in response to air stress or guanabenz were enhanced significantly. These effects of ouabain were prevented when losartan was given concomitantly. Maximal slopes of arterial baroreflex control of renal sympathetic nerve activity and heart rate tended to be decreased in ouabain-treated versus control rats and were significantly increased in ouabain-treated rats with versus without losartan. No differences in cardiopulmonary baroreflex function were detected. It seems that by day 14 to 15, the central effect of ouabain on baroreflex control prevails over its peripheral sensitizing effect on baroreceptors, leading to a tendency of desensitization. These results indicate that chronic administration of ouabain activates the brain renin-angiotensin system, resulting in decreased sympathoinhibition and increased sympathoexcitation, impairment of baroreflex function, and hypertension.     

Prevention of hypertension by irbesartan in Dahl S rats relates to central angiotensin II type 1 receptor blockade

Hypertension in Dahl S rats on high-salt intake is in general considered a model of "low-renin hypertension," unresponsive to treatment with blockers of the renin-angiotensin system. However, direct central administration of an angiotensin II type 1 (AT(1)) receptor blocker prevents both the sympathoexcitation and hypertension caused by high-salt intake in Dahl S rats. In the present study, we tested the hypothesis that chronic peripheral administration of an AT(1) receptor blocker inhibits the salt-induced hypertension relative to the extent of central AT(1) receptor blockade that is induced. Dahl S rats received a high-salt (1370 micromol Na(+)/g) or regular (101 micromol Na(+)/g) diet from 4 to 8 weeks of age. In 3 different sets of experiments, Dahl S on high salt were randomized to intracerebroventricular (ICV) treatment with control infusion versus irbesartan at 50 or 250 microg. kg(-1). d(-1), oral treatment with control versus irbesartan at 125 or 500 mg. kg(-1). d(-1) once daily by gavage, or subcutaneous treatment with control versus irbesartan at 50 or 150 mg. kg(-1). d(-1) by once daily injection. At 8 weeks of age, MAP was measured in conscious rats at rest and in response to angiotensin II ICV or IV. On high-salt intake, Dahl S developed the anticipated marked increase in MAP to approximately 160 mm Hg. Irbesartan ICV did not affect pressor responses to angiotensin II IV, but irbesartan administered subcutaneously or by gavage markedly inhibited these responses. Irbesartan ICV or by gavage partially inhibited pressor responses to angiotensin II ICV and the development of hypertension. Irbesartan subcutaneously at the higher dose more completely inhibited pressor responses to angiotensin II ICV and fully prevented the salt-induced hypertension. The degree of central but not peripheral AT(1) receptor blockade parallels the antihypertensive effect of irbesartan, indicating that inhibition of the brain renin-angiotensin system can contribute to a significant extent to the therapeutic effectiveness of AT(1) receptor blockers such as irbesartan when administered in sufficiently high doses to cause central AT(1) receptor blockade.