Arsenic toxicity is enzyme specific and its affects on ligation are not caused by the direct inhibition of DNA repair enzymes

There is an increasing awareness that the exclusion of women from clinical trials may lead to inaccurate application of drug therapy in women. Gender and estrus cycle differences in the pharmacokinetics and pharmacodynamics of drugs in animals have been appreciated for over 60 years, but investigation into these differences in humans has only recently occurred. It is postulated that hormonal fluctuations within the menstrual cycle phase may be a primary cause of documented gender differences in the pharmacokinetics and pharmacodynamics of drugs. Existing data suggest that menstrual cycle variations do occur in renal, cardiovascular, haematological and immune systems. These physiological changes could potentially impact on the pharmacokinetics or pharmacodynamics of drugs by altering properties, such as protein binding or the volume of distribution, and thereby causing significant effects at various times during the menstrual cycle. However, systematic investigations of physiological variability throughout the menstrual cycle are limited. Fluctuations in symptom severity and clinical course coinciding with the menstrual cycle phase have been seen in some diseases. Hormonal fluctuations within the menstrual cycle have been postulated to cause disease exacerbation. They may also worsen disease severity by impacting on the pharmacokinetics or pharmacodynamics of the medication. Menstrual cycle hormonal changes may influence drug absorption, distribution, metabolism or excretion. In vivo data to demonstrate an effect of endogenous estrogen or progesterone on pharmacokinetics are limited and contradictory. Systematic investigations of specific pharmacokinetic and pharmacodynamic changes within the menstrual cycle are lacking. Most published studies have been conducted with small numbers of women and a limited numbers of menstrual cycle phases within 1 menstrual cycle. These design problems have resulted in incomplete data for assessing the effects of the menstrual cycle. To date, there are no demonstrated clinically significant changes that occur in the absorption, distribution or elimination of drugs. With respect to drug metabolism, data are exceedingly sparse and have been collected in a suboptimal fashion. Standardisation of study design and analyses in systematic investigations of the influence of the menstrual cycle on drug pharmacokinetics and pharmacodynamics are needed.     

Antiparkinsonian agents. Drug interactions of clinical significance

Within the past 3 decades revolutionary changes have taken place in the pharmacological management of Parkinson's disease. Used alone, or often in combination, antiparkinsonian agents can dramatically and meaningfully ameliorate the symptoms of Parkinson's disease. However, with the development of effective therapeutic agents has come the potential for drug interactions; these interactions can produce consequences that range from the inconsequential to incapacitating and even life-threatening. Drug-drug interactions are not a major problem with either the anticholinergic medications or amantadine. However, cumulative anticholinergic toxicity may occur when multiple drugs with anticholinergic properties are utilised concomitantly, and amantadine toxicity can be triggered by drugs that impair its renal clearance. Gastric emptying and levodopa absorption can be significantly altered by medications and dietary contents. A rather extensive array of medications can interfere with dopaminergic function and thus produce clinical parkinsonism or impair the effectiveness of levodopa. The effectiveness of direct dopamine agonists can also be affected by a small group of agents. As a selective monoamine oxidase type B (MAO-B) inhibitor, selegiline (deprenyl) is free of the 'cheese-effect' when employed in recommended dosages. However, potentially life-threatening drug interactions, with both pethidine (meperidine) and with fluoxetine and other antidepressant medications, have been described, presumably occurring via serotonergic mechanisms. Awareness of the potential for drug interactions with antiparkinsonian agents, and prompt recognition of them when they do occur, is vital for the optimum clinical management of Parkinson's disease.     

Role of the liver in interorgan homeostasis of glutathione and cyst(e)ine

There are many pathological changes in patients with cystic fibrosis (CF) which can lead to alterations in drug disposition. Although, in patients with CF, the extent of drug absorption varies widely and the rate of absorption is slower, bioavailability is not altered. Plasma protein binding for the majority of drugs studied did not differ in patients with CF compared with control groups. The difference in volume of distribution of most drugs between patients with CF and healthy individuals vanished when corrected for lean body mass. Despite hepatic dysfunction, patients with CF have enhanced clearance of many, but not all, drugs. Phase I mixed-function oxidases are selectively affected: cytochrome P450 (CYP) 1A2 and CYP2C8 have enhanced activity, while other CYP isoforms such as CYP2C9 and CYP3A4 are unaffected. Increased phase II activities are also demonstrated: glucuronyl transferase, acetyl transferase (NAT1) and sulfotransferase. The increased hepatic clearance of drugs in the presence of CF may be the consequence of disease-specific changes in both enzyme activity and/or drug transport within the liver. The renal clearance (CLR) of many drugs in patients with CF is enhanced although there has been no pathological abnormality identified which could explain this finding: glomerular filtration rate and tubular secretion appear normal in patients with CF. The precise mechanisms for enhanced drug clearance in patients with CF remain to be elucidated. The optimisation of antibiotic therapy in patients with CF includes increasing the dose of beta-lactams by 20 to 30% and monitoring plasma concentrations of aminoglycosides. The appropriate dosage of quinolones has not been definitively established.     

Treatment of concomitant illnesses in patients receiving anticonvulsants: drug interactions of clinical significance

As epilepsy often is a chronic condition requiring prolonged therapy with anticonvulsants, patients being treated for epilepsy can be at risk when they are prescribed other drugs for concomitant diseases. Pharmacokinetic interactions can occur at each step of drug disposition (absorption, distribution, metabolism and elimination). Although such interactions may occur frequently with some drugs, only some will be clinically relevant. Alterations in the hepatic biotransformation of metabolised drugs due to hepatic isoenzyme induction or inhibition is of particular concern. The consequences of pharmacokinetic interactions are either accumulation of the drug leading to toxicity, or lowering of plasma concentrations resulting in reduced efficacy. Clinically relevant interactions depend on the structure, dosage and duration of administration of interacting agents, and on the individual's genetic make-up. In the past, drug interactions have been analysed empirically. At present, at least for interactions between drugs that are biotransformed in the liver, the risk should be predicted by considering the individual cytochrome P450 isoforms involved in the metabolism of coadministered drugs. Although drug-drug interactions can be predicted, their extent cannot be due to large interindividual variability. Even if nearly all drug combinations could be used with close clinical surveillance and blood concentration determinations, drugs that are not metabolised and are not highly protein bound, as are several of the new anticonvulsants, such as gabapentin, lamotrigine and vigabatrin, have a clear advantage in terms of a lower interaction potential.     

Psychopharmacologic issues in organ transplantation. Part I: Pharmacokinetics in organ failure and psychiatric aspects of immunosuppressants and anti-infectious agents

This article discusses pharmacokinetics and pharmacodynamics during hepatic, renal, and cardiovascular insufficiencies. Hepatic metabolism of psychotropic drugs and of drugs commonly used in transplant patients that have neuropsychiatric side effects is discussed. Neuropsychiatric effects of immunosuppressant agents, including cyclosporine, corticosteroids, azathioprine, OKT3, and FK 506, are reviewed. Certain infections occur more often in immunosuppressed patients; their treatment with antiviral, antifungal, and antibiotic drugs may have neuropsychiatric consequences. Because of altered drug sensitivities and metabolism, drug interactions, and severe medical illness, most drugs are used in reduced doses.     

Warfarin resistance in a patient with short bowel syndrome

Drug therapy in short bowel syndrome can be complicated by inadequate or incomplete absorption of drugs in the small intestine. Many case reports claim that warfarin absorption is not affected by the syndrome. We treated a patient with oral warfarin for recurring deep vein thrombosis; up to 20 mg/day was administered with no increase in the international normalized ratio. Drug-drug interactions that may prevent absorption, increase metabolism, or antagonize the effects of warfarin were ruled out. Intravenous lipid administration, which is anecdotally reported to precipitate warfarin resistance, may have contributed to the condition, but dosing was less frequent than in published reports. The most probable explanation of warfarin resistance is the reduced surface area for drug absorption secondary to surgical removal of the patient's duodenum and gastrojejunostomy.     

Influence of gender on the pharmacokinetics and pharmacodynamics of drugs

Historically, women, the elderly, and minorities were underrepresented in clinical drug trials. Information on possible gender-related differences in the pharmacokinetics of drugs is often lacking, although for some drugs significant differences could be demonstrated. In women, absorption, protein binding, volume of distribution, and metabolism of drugs may differ due to hormonal influences on physiological functions. Sex-related differences could be shown for phase I (cytochrome P450) as well as phase II (especially glucuronidation) reactions. Since many women world-wide take oral contraceptives, data should be provided to determine to what extent other drugs are influenced by estrogens and progestogens or to what extent the other drugs may attenuate the contraceptive efficacy. Moreover, estrogens interact with various enzymes and receptors, e.g. at the endothelial function as well as dopaminergic receptor sites, and may therefore attenuate or enhance drug effects or even drug side-effects. For a number of drugs it is well recognized, that women suffer more frequently from side-effects, however, it is often not clear, if this is due to gender differences in the pharmacokinetics or pharmacodynamics of the responsible drug. Very little is known about these gender-related differences and the possibility that women may show a different pattern of treatment response than men. As a result, drug approval authorities now require more data on the pharmacokinetics of novel drugs in women as well as a sufficient accrual of women in efficacy and outcome trials.     

Modulation of chemosensitivity through altered expression of cell cycle regulatory genes in cancer

Alterations in the expression of genes affecting cell cycle progression occur in all human cancers. These may occur either by overexpression of genes such as cyclin D1, mutation of regulatory genes such as p16, or abrogation of checkpoints following DNA damage as in the cases of mutation or deletion of the p53 gene. Perturbation of the normal functions of these genes has a profound effect on cellular proliferation, differentiation and apoptosis. There is increasing evidence that such alterations may modulate the cellular response to treatment with chemotherapeutic agents. In many cases genetic alterations may induce resistance to drug treatment as in the case of mutations of the p53 gene. However, the deregulated expression of cell cycle genes may also increase sensitivity to treatment by directly altering the expression of the target for chemotherapeutic drugs as in the case of deletion of the retinoblastoma gene. It is crucial to understand the interactions between drug mechanisms of action and the genetic alterations in cancer to exploit potential areas in which the alterations found in tumors may constitute potential vulnerability.     

Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics

Cytochrome P450 3A4 (CYP3A4), the major phase I drug metabolizing enzyme in humans, and the MDR1 gene product P-glycoprotein (P-gp) are present at high concentrations in villus tip enterocytes of the small intestine and share a significant overlap in substrate specificity. A large body of research both in vitro and in vivo has established metabolism by intestinal CYP3A4 as a major determinant of the systemic bioavailability of orally administered drugs. More recently it has been recognized that drug extrusion by intestinal P-gp can both reduce drug absorption and modulate the effects of inhibitors and inducers of CYP3A-mediated metabolism. There is relatively little data regarding the effects of CYP3A and P-gp on peptide drugs; however, studies with the cyclic peptide immunosuppresant cyclosporine as well as peptidomimetics such as the HIV-protease inhibitor saquinavir (Invirase) and a new cysteine protease inhibitor K02 (Morpholine-Urea-Phe-Hphe-Vinyl sulfone; Axys Pharmaceuticals) provide some insight into the impact of these systems on the oral absorption of peptides.     

Influence of foods on the absorption of antimicrobial agents]

Understanding the interaction between foods and antimicrobial agents is an aspect of therapy which may have an important clinical repercussion, which is why it must not be forgotten. This study reviews the interactions of foods with the anti-microbial agents which occur at the level of absorption, considering the mechanisms involved. The food-drug interaction can cause an increase, a decrease, or a delay in the bio-availability of the anti-microbial agents; foods may have no affect on the absorption of the anti-microbial agents, or they may improve the gastrointestinal tolerance. The Food and Drug Administration's bioequivalency criteria for considering whether or not there is an alteration in absorption have an orientative function, as generally all studies are conducted on healthy volunteers, but in clinical practice one must consider the physiological and pathological condition of the patient. The composition of the diet as well as the volume of liquid administered are other aspects which should be considered, as these may exert a different effect depending on the type of drug. After ingesting fatty foods, there is an increased absorption of albendazole, griseofulvin, itraconazole, and mebendazole. All foods but especially carbohydrates reduce the absorption of isoniazide. Among the anti-HIV drugs, the following must be administered on an empty stomach: didanosine, indinavir zalcitabine , and zidovudine ; lamivudine can be administered either on an empty or on a full stomach, because although food delays the absorption, it does not affect the amount absorbed; the absorption of stavudine is not affected by foods; ritonavir should be administered together with tile meals, and saquinavir must be administered after ingestion of food. It is advisable to administer clarithromycin together with foods, and azythromycin on an empty stomach; the same holds true for perfloxacin and rifabutine as for lamivudine.     

The effect of certain vitamin deficiencies on hepatic drug metabolism

There is increasing evidence that the liver microsomal drug metabolizing system is affected by various vitamins such as ascorbic acid, riboflavin, and alpha-tocopherol. In regard to ascorbic acid deficiency there is a decrease in the quantity of hepatic microsomal electron transport components such as cytochrome P-450 and NADPH-cytochrome P-450 reductase, as well as decreases in a variety of drug enzyme reactions such as N-demethylation, O-demethylation, and steroid hydroxylation. In addition, young animals given high supplements of vitamin C have increased quantities of electron transport components and overall drug metabolism activities. Kinetic studies indicate no change in the apparent Km of N-demethylase, O-demethylase or hydroxylase for drug substrates in animals depleted or given high amounts of the vitamin. However, there are qualitative changes in both type I and II substrate-cytochrome P-450 binding. Ascorbic acid is not involved in microsomal lipid peroxidation or in any qualitative or quantitative change in phosphatidylcholine. Replenishing vitamin C-deficient animals with ascorbic acid required 3 to 7 days for the electron transport components and drug metabolism activities to return to normal levels. Induction with phenobarbital and 3-methylcholanthrene is not impaired in the deficient animal since drug metabolism activities are induced to the same extent as normal controls; however, the administration of delta-aminolevulinic acid, a precursor of heme synthesis, to deficient animals caused an increase in the quantity of cytochrome P-450. The effects of riboflavin deficiency on electron transport components and drug metabolism activities have been noted only in adult animals after prolonged periods of deficiency. Decreases in drug metabolism activities occur with both type I (aminopyrine and ethylmorphine) and type II (aniline) substrates. As was found with ascorbic acid deficiency, drug enzyme induction occurred to the same extent with phenobarbital in deficient and normal animals. In addition, it required from 10 to 15 days for the drug metabolism activities to return to normal levels when deficient animals were replenished with riboflavin. The effect of vitamin E on drug metabolism is specific in N-demethylase activities decrease while O-demethylase activities are not affected in the deficient state. This vitamin differs from ascorbic acid and riboflavin in that several laboratories have reported no quantitative decrease in cytochrome P-450, although there are some reports that it and delta-aminolevulinic acid dehydratase are lowered quantity of cytochrome in E-deficient animals. The effect of vitamin E, if any, on the P-450 is unresolved; an important question that requires further clarification. As with ascorbic acid there is no difference in the apparent Km of N-demethylase enzymes for varous substrates and the protective effect of vitamin E does not appear to be one of an antioxidant inhibiting microsomal lipid peroxidation.     

Drug interactions: keeping it straight

Drug interactions are common causes of treatment failure and adverse reactions. Patients who have a number of chronic disorders, patients who take many medications or patients who have impaired renal function are at increased risk for these problems. Special attention must be given to drugs that require blood level monitoring, because these agents have a narrow margin of safety. Drug interactions are especially likely to occur with enzyme inhibitors such as erythromycin, cimetidine, ciprofloxacin and metronidazole. Mechanisms of drug interactions include problems with absorption secondary to binding by antacids or other cations, interference with the distribution of drugs secondary to the displacement of highly protein-bound drugs, differences in metabolism secondary to variability of the cytochrome P450 enzyme system, and interaction-related problems with drug excretion by renal tubules. Antagonistic and synergistic reactions also need to be considered. Finally, the time course in which a given drug interaction is likely to occur must be taken into account when deciding whether the interaction is responsible for an adverse effect or treatment failure.     

Gamma-irradiation and UV-C light-induced lipid peroxidation: a Fourier transform-infrared absorption spectroscopic study

Metabolism of most drugs influences their pharmacological and toxicological effects. Drugs particularly affected are those with a narrow therapeutic window and that are subjected to considerable first-pass metabolism. Much of the interindividual and interethnic differences in effects of drugs is now attributable to genetic differences in their metabolism. Genetic polymorphisms have been described for many drug-metabolising enzymes in Caucasian and Oriental populations, the most well-characterised being those for cytochrome P450 2D6, cytochrome P450 2C19, glutathione S-transferases, and N-acetyl transferase 2. African populations have been studied to a lesser extent, but it is apparent that populations within Africa are heterogeneous with respect to these polymorphisms. In addition, although some allelic variants are common to all populations throughout the world (e.g., CYP2D6*5), some allelic variants are specific for an African population (e.g., CYP2D6*17). The polymorphisms give rise to enzymes with changed or no activity towards drug substrates. Two of the most important enzymes for metabolism of neuroleptics and other psychoactive drugs are CYP2D6 and CYP2C19. This article compares the current information on polymorphisms of these two enzymes in African and other populations and discusses the implications of these polymorphisms for neuropharmacotherapy.     

A new approach to the understanding of the mechanism of ischemia/reperfusion damage in the heart and the effects of anti-ischemic drugs

The classical understanding of the mechanism of anti-anginal or anti-ischemic drugs is an increase in blood supply to the heart and/or a decrease in oxygen consumption of the heart, maintaining energy balance in the heart between supply and demand and hence maintaining the tissue levels of high-energy phosphates. This scheme is reasonable. During reperfusion following ischemia, however, there is more serious damage to the heart, although the tissue levels of high-energy phosphates increase. This is probably because toxic substances are generated in the heart during ischemia/reperfusion. We propose that both lysophosphatidylcholine and palmitoyl-L-carnitine that accumulate in the myocardium during ischemia/reperfusion are candidates for the toxic substances that accelerate ischemia/reperfusion damage to the heart. Therefore, drugs that have anti-lysophosphatidylcholine and/or anti-palmitoyl-L-carnitine effects are promising for the treatment of ischemic heart diseases. We found that K-7259, a novel derivative of dilazep having a minimal effect on the normal heart, is a drug that attenuates the deleterious effects of both lysophosphatidylcholine and palmitoyl-L-carnitine on the heart, and therefore attenuates the ischemia/reperfusion damage.     

Drug administration in chronic liver disease

Cirrhosis encompasses a range of pathophysiological changes that may alter drug disposition. Drugs that are dependent primarily on the liver for their systemic clearance are more likely to be subject to reduced elimination and subsequent accumulation. Drug accumulation may lead to excessive plasma drug concentrations and adverse effects, if the adverse effects of the drug are concentration-dependent. The effects of hepatic insufficiency on the pharmacokinetics of drugs are not consistent or predictable. Furthermore, the influence of hepatic disease on the disposition of various drugs can vary, even though those drugs may share the same apparent metabolic pathway. Problems in forecasting drug kinetic behaviour are further enhanced by the additional impairment of kidney function (frequently encountered in patients with advanced liver disease) and by the unpredictability of the glomerular filtration rate using customary methods in patients with cirrhosis. Accordingly, dosages are generally adapted empirically, with the help of serum drug concentrations, when applicable. However, drugs eliminated predominantly by hepatic metabolism are not among those most commonly inducing adverse drug reactions or causing severe complications in patients with cirrhosis. Electrolyte disturbances and the hepatorenal syndrome produced by furosemide (frusemide)-the disposition of which is not substantially modified in liver disease-appear to be the most frequent adverse drug reactions in patients with liver disease. Furthermore, clinically significant alterations in the action of medications at concentrations generally considered to be in the normal therapeutic range are not uncommon. Tissue responsiveness to the pharmacological action of some drugs may be modified, as evidenced by the increased susceptibility of the brain in patients with cirrhosis to the action of many psychoactive agents. Another example is the greater susceptibility of such patients to the nephrotoxic potential of aminogly-cosides, which should not be used in this patient group. Drugs may also interfere with adaptive physiological processes induced by liver disease. ACE inhibitors and nonsteroidal anti-inflammatory drugs counteract the enhanced activity of the renin-angiotensin system in advanced liver disease, thereby generating a high risk of excessive hypotension or acute renal failure, respectively. These drugs are best avoided in patients with cirrhosis. Finally, there may be pharmacological effects that overlap with some pathophysiological modifications related to the process of liver disease, such as increased portal pressure produced by some calcium antagonists, or hypoprothrombinaemia related to the inhibition of synthesis of vitamin K-dependent clotting factors by some beta-lactam antibacterials (especially moxalactam and cefamandole). Accordingly, the use of these drugs should be avoided in advanced liver disease. It is noteworthy that reduced drug metabolism in patients with liver disease does not seem to have a significant impact on the frequency of hepatotoxicity. Special caution should be exercised, however, in patients with alcoholic liver disease because excessive alcohol intake may potentiate the hepatotoxic effect of paracetamol (acetaminophen).     

Pharmacokinetic/pharmacodynamic consequences of space flight

As astronauts prepare for long-term space missions, the question arises of whether drug medication in a zero gravity environment will have the same effects as under normal gravity. There are two potential kinds of changes that must be evaluated: alterations of pharmacokinetics and pharmacodynamics. Pharmacokinetic changes will affect the drug concentrations produced by a certain dosage regimen. They can be caused by changes in: (1) intrinsic clearance (e.g., enzyme activity and renal function), (2) drug binding (e.g., protein binding and tissue binding), (3) blood flow (e.g., liver blood flow and renal blood flow), and (4) bioavailability (e.g., rate and extent of absorption). Pharmacodynamic changes will affect the response that is produced by a given drug concentration. They can be caused by changes in drug-receptor interaction or changes in disease characteristics. Studies of pharmacokinetic and pharmacodynamic changes in microgravity are limited, and predictions of any alterations are mainly extrapolated from known relationships between certain physiologic parameters and their effects on pharmacokinetics in normal gravity. Almost no data is available on changes in pharmacodynamics. Also, no information is available on the relationship between pharmacokinetics and pharmacodynamics. More studies are needed to elucidate the changes in pharmacokinetics and pharmacodynamics in microgravity to ensure the optimum use of drug therapy during space flight.     

Respiration and circulation after total hip replacement surgery. A comparison between parenteral analgesics and continuous lumbar epidural block

The cardiopulmonary effects of two different types of postoperative analgesic regimes were compared in 31 cardiorespiratorily healthy patients subjected to total hip replacement surgery. The investigation was performed preoperatively on the morning of the day of surgery and during the first 3 days postoperatively. All patients received continuous lumbar epidural analgesia preoperatively, during surgery and up to the end of the first measurement period, which started 2.5 h after surgery. Ten patients were subseuqently given pentazocine (Fortalgesic) intramuscularly on demand for pain relief throughout the investigation, while 14 patients received 0.4% plain lidocaine (Xylocain), and seven patients 0.4% lidocaine with adrenaline (1/400,000) as a continuous lumbar epidural drip for analgesia thorughout the investigation. It was confirmed that the operative procedure itself did not significantly influence the postoperative arterial oxygenation, while the type of postoperative analgesic regimen was of considerable importance in this respect. Thus, patients given pentazocine showed a significant increase in pulmonary venous admixture, due both to an increase in true shunt and to an increase in ventilation/perfusion disturbances. This pattern of poor pulmonary function still persisted on the third postoperatively. In patients given an epidural block no significant changes in pulmonary venous admixture were noted postoperatively, and thus there was no reduction in PaO2. All patients, irrespective of the type of analgesic regimen used, had a significantly increased cardiac index and oxygen uptake postoperatively, although patients given an epidural block showed a greater increase in cardiac index, and thus a tendency towards a more hyperkinetic circulation than those given pentazocine.     

Pathophysiology of infection with Ostertagia ostertagi in cattle

Infection with the abomasal nematode, Ostertagia ostertagi, is an important cause of impaired productivity in young cattle in temperate parts of the world. Such losses have been associated with marked changes in feed intake, gastrointestinal function, protein, energy and mineral metabolism, and in body composition. The reduction in feed intake is an important factor in the pathogenesis of infection and may account for a large part of the difference in weight gain between ad libitum fed control and infected calves. Despite the obvious importance of inappetance, only recently has an association been made between reduced intake, altered gut motility and elevated levels of certain gastrointestinal hormones, such as gastrin. It has been suggested that the elevated gastrin levels accompanying abomasal parasitism may impair reticulo-ruminal motility and slow down abomasal emptying, leading to a stasis of ingesta and a reduction in feed intake. The rise in blood gastrin levels may also be partly responsible for the marked hyperplasia of the fundic mucosa seen in abomasal infections. Pronounced changes in protein metabolism have also been associated with Ostertagia infection. Radioisotopic studies have demonstrated increased losses of albumin into the gastrointestinal tract which are accompanied by an increase in the rate of synthesis in the liver. Dietary protein breakdown in the abomasum is also likely to be impaired, although there is evidence of a compensatory increase in protein digestion in the lower gut of parasitised calves. Increased losses of albumin are not always accompanied by increases in faecal nitrogen, suggesting that albumin is broken down and recycled as ammonia. Radioisotopic studies in animals with intestinal nematode infections have demonstrated a marked reduction in muscle protein synthesis and an increase in protein synthesis in gastrointestinal tissue. Such changes in the balance of protein synthesis are likely to be brought about by alterations in the balance of certain metabolic hormones. Marked changes in energy metabolism also accompany Ostertagia infection. Parasitised calves exhibit a marked increase in non-esterified fatty acid levels, resulting from the mobilisation of adipose tissue, and a reduction in digestive efficiency of energy, probably associated with the increase in cycling of protein through the gastrointestinal tract and the compensatory increases in protein synthesis. Mineral metabolism may also be affected although relatively little work has been conducted in cattle. Changes in body composition reflect a reduction in deposition of muscle protein and fat, and an increase in bone content and water retention.     

Fourier transform infrared spectroscopic study of ion binding and intramolecular interactions in the polar head of digalactosyldiacylglycerol

The study describes the changes in basic hemodynamic parameters after long-term antihypertensive therapy with cilazapril--a new ACE inhibitor lacking a sulfhydryl group--in hypertensive patients and the drug effects on renal function, glucose tolerance and lipid metabolism. 30 patients (18 males, 12 females, mean age: 53.3 +/- 18 years) with mild to moderate essential hypertension were studied. The following determinations were performed in patients, before and after 4.5 months of cilazapril monotherapy at a dose of 5 mg/24 h: (a) antihypertensive action of the drug (arterial pressure at rest and during a 24-hour recording); drug effects on left ventricular (LV) mass index; its contractility indexes (%FS, EF) and the left atrial emptying index were studied by means of echocardiography; (b) plasma insulin concentration during oral glucose tolerance tests, in the fasting state, after the administration of 75 g glucose per os, as well as the changes in the insulinogenic index and the 6-keto-PGF1 alpha/TXB2 ratio, and (c) drug effect on renal function (urea, creatinine, uric acid, plasma electrolytes), blood lipid profile (total cholesterol, triglycerides, HDL-CH) and serum transaminases. Long-term drug administration exhibits an effective antihypertensive action, without causing reflex tachycardia and also reduces the LV mass index without affecting its EF, while improving its diastolic function. It does not significantly affect the various biochemical parameters, and achieves glucose regulation, both in the fasting state and after glucose loading, with a decrease in the insulinogenic index, and simultaneously increases the 6-keto-PGF1 alpha/TXB2 ratio. The existence of a direct cause-effect relationship between the changes in the above hormone systems is possible.