Pharmacokinetics of cardiovascular drugs in children. Inotropes and vasopressors

Infants and children with congenital or acquired heart disease and children with systemic disease often require pharmacological support of their failing circulation. Catecholamines may serve as inotropic (enhance myocardial contractility) or vasopressor (elevate systemic vascular resistance) agents. Noncatecholamine inotropic agents, such as the cardiac glycosides or the bipyridines, may be used in place of, or in addition to, catecholamines. Developmental changes in neonates, infants and children will affect the response to inotropic or pressor therapy. Maturation of the gastrointestinal tract, liver and kidneys alters absorption, metabolism and elimination of drugs, although there are few clear examples of this among the vasoactive drugs considered in this review. Changes in body composition affect the volume of distribution (Vd) and clearance (CL) of drugs. Developmentally based pharmacodynamic differences also affect the responses to both therapeutic and toxic effects of inotropes. These pharmacodynamic differences are based in part upon developmental changes in myocardial structure, cardiac innervation and adrenergic receptor function. For example, the immature myocardium has fewer contractile elements and therefore a decreased ability to increase contractility; it also responds poorly to standard techniques of manipulating preload. Available data suggest that dopamine and dobutamine pharmacokinetics are similar to those in adults. Wide interindividual variability has been noted. A consistent relationship between CL and age has not been demonstrated, although one investigator demonstrated an almost 2-fold increase in the CL of dopamine in children under the age of 2 years. The CL of dopamine appears to be reduced in children with renal and hepatic failure. Fewer data are available regarding the pharmacokinetics of epinephrine (adrenaline), norepinephrine (noradrenaline) and isoprenaline (isoproterenol). Digoxin pharmacokinetics have been extensively evaluated in infants and children. The Vd for digoxin is increased in infants and children. Children beyond the neonatal period display increased CL of digoxin, approaching adult values during puberty. Although it was previously thought that children both needed and tolerated higher serum concentrations of digoxin than adults, more recent studies indicate that adequate clinical response can be achieved with serum concentrations similar to those aimed for in adults, with decreased toxicity. Evaluation of studies of digoxin pharmacokinetics is complicated by the presence of an endogenous substance with digoxin-like activity on radioimmunoassay. Limited studies of amrinone pharmacokinetics in infants and children indicate a dramatically larger Vd, and a decreased elimination half-life in older infants and children, compared with values observed in adults.     

New trends in the search for nootropic preparations

The paper describes the effects of the new nootropic agents nooglutyl and glycine N-phenyl-L-prolyl ethyl ester (GVS-111). Nooglutyl, a derivative of L-glutamic and oxynicotinic acids, that has glutamatergic effects is a highly active drug in treating disturbances of memory and learning, protecting against ischemic neuronal damage and brain injury. GVS-111 is a substituted prolyl dipeptide that has the properties of enhancing cognitive functions and is able to prevent the learning impairment provoked by shock, scopolamine, brain injury, and other damages. Multimodal mechanisms responsible for the nootropic effects of nooglutyl and GVS-111.     

The effect of the new nootropic dipeptide GVS-111 in different functional disorders of the escape reaction

Endothelium protector SOFTEL is developed by Ekran firm and Institute of Eye Diseases, Russian Academy of Medical Sciences. The drug was used in 157 patients aged 28-79 years. Perforating keratoplasty for corneal leukoma and keratoconus was carried out in 46 patients, cataract extraction with implantation of intraocular lens (IOL) in 94, and cataract extraction without IOL implantation in 17 patients. Two patients developed slight hypertension in the postoperative period, which resolved within 24 h, and four patients developed moderate corneal edema persisting for 1-2 days postoperation. The protective effect of softel is compatible with that of its foreign analog Healon. The drug is effective in cataract extractions with IOL implantation and perforating keratoplasty.     

Pharmacokinetics of acyclovir in the cat

To investigate the detoxification of bromobenzene-induced hepatic lipid peroxidation by Oenanthe javanica DC, the hepatic lipid peroxide level and the activities of enzymes responsible for production and removal of epoxide were studied. The level of lipid peroxide elevated by bromobenzene was significantly reduced by the methanol extract (250 mg/kg) and persicarin (5 mg/kg). The methanol extract and persicarin administered daily over 4 weeks before intoxication with bromobenzene did not affect the activities of aminopyrine N-demethylase, aniline hydroxylase, and glutathione S-transferase. Epoxide hydrolase activity was decreased significantly by bromobenzene, which was restored to the control level by pretreatment with persicarin. However, the identical pretreatment with isorhamnetin and hyperoside did not change the enzyme activity or lipid peroxide level. The results suggest that the reduction of bromobenzene-induced hepatic lipid peroxidation by O. javanica under our experimental conditions is effected through enhancing the activity of epoxide hydrolase, an enzyme removing bromobenzene epoxide. In addition, the bioactive component of this plant responsible for the detoxification of bromobenzene, at least in part, is thought to be persicarin.     

Pharmacokinetics of the penicillins in man

The purpose of this article is to review and summarise those aspects of the pharmacokinetic behaviour of the penicillins that may be of particular interest to the clinician. While these antibiotics differ markedly in their acid stability and oral absorption, misleading inferences may be drawn from simple inspection of the maximal serum concentrations produced by a given dose administered orally. A more accurate picture emerges when serum protein binding and intrinsic activity of the drugs are taken into account. All of the penicillins are readily and actively secreted by the renal tubles and most are eliminated, almost completely unchanged, in the urine. The majority are excreted in small quantities in the bile, but this is a major route for elimination of nafcillin from the body. Distribution of the penicillins in 'non-specialised' sites is excellent. In contrast, penetration of the central nevous system and eye are poor, and of the prostate, minimal. Inflammation reduces the barries to penetration of these areas. However, quantitative data related to this phenomenon in man are few. Probenecid actively competes with the 'export' pump of the meninges and renal tubular cells. This results in an increase in concentrations of the penicillins in the blood and cerebrospinal fluid. The effect of this agent on active secretion of these antibiotics from the eye and biliary tract is minimal. While elimination of the penicillins from the body takes place largely via renal excretion, penicillin V and oxacillin are extensively degraded as well. In contrast to the situation with respect to 'natural' and 'broad-spectrum' penicillins, the serum half-life of the isoxazolyl congeners and nafcillin is only minimally prolonged in the presence of renal failure. These agents are only weakly haemodialyzable, while the other penicillins are rapidly removed from the circulation by this procedure.     

Pharmacokinetics of rapamycin

Based on the present findings, a number of preliminary conclusions can be made regarding the distribution, pharmacokinetics, and therapeutic range investigations with RAPA: (a) the majority of the drug is sequestered in erythrocytes, resulting in whole blood concentrations; (b) the drug has a relatively long half-life in both humans and animals with 24-hour trough concentrations being within the analytical range of HPLC when immunosuppressive doses are administered; (c) the drug exhibits a proportionality between trough concentrations and dose; (d) trough concentrations of the drug appear to be related to immunosuppressive efficacy and drug-related side effects. The studies described here should provide a basis for the establishment of therapeutic monitoring protocols for RAPA.     

The nootropic correction of disorders in learning and memory processes induced by extreme exposures

Experiments on rats demonstrated that the low-intensity electromagnetic field (12.6 cm, 2375 MHz, power density 1 mW/cm2), motion sickness, and electroconvulsive shock provoked the retrograde amnesia in the passive avoidance test. The oxyracetam (100 mg/kg, i.p.), aniracetam (50 mg/kg, i.p.), nooglutil (50 mg/kg, i.p.), meclofenoxate (50 mg/kg, i.p.), pyracetam (200 mg/kg, i.p.), and GABA (200 mg/kg, i.p) prevented the memory-impairing effect of all these extreme factors. On the contrary, the N-acetylglycinamide, semax, and other nootropic drugs were effective only under one or two extreme conditions.     

Pharmacokinetics of ipriflavone

Ipriflavone administered to rats orally is well absorbed from small intestine via the portal route, distributed widely in tissues, metabolized extensively by oxidation, and eliminated from the body preferentially in urine. The absorption of ipriflavone is less effective in dogs, than in rats. In dogs, the compound absorbed is metabolized in the same way as in rats and the metabolites formed are eliminated largely in faeces, together with unabsorbed ipriflavone. In human, ipriflavone administered orally is rapidly absorbed, and quickly metabolized. The dose is eliminated mainly via the urinary route as metabolites (57% of the dose), and the smaller fraction with the faeces, mostly as ipriflavone (40% of the dose). There is no significant change in the pharmacokinetics of ipriflavone even after multiple dose. In the serum, ipriflavone and its metabolites are primarily bound to albumin, the binding is 94-99% and totally reversible.     

Effect of the nootropic agent cerebrolysin in cerebral ischemia in rats with varying behavioral reactions in the open field test

Open field tests were made on 489 white male rats to distinguish subgroups by baseline higher nervous activity (HNA) to study the effects of cerebrolysin (EBEVE, Austria) on relationships between neuronal activity and cerebral blood supply in normal cerebral circulation (CC) and in acute brain ischemia. Local CC and EEG were measured by laser doppler flowmeter and read from the same point gauge. CC/EEG index was calculated. Cerebrolysin was injected i.p. in a dose 0.3 ml/100 g body mass. Brain ischemia was provoked by occlusion of the common carotid arteries. Neurological symptoms were estimated according to the McGrow scale. Also, 24-h lethality was registered. It was confirmed that cerebrolysin, as an active nootrop, enhances EEG. This effect takes place both in intact and brain ischemia rats. It was also found that cerebrolysin has different effectiveness dependent on the animal's behavior in the open field test, that blood supply to the brain does not increase in cerebrolysin-activated HNA. In stable circulation, this was compensated due to cerebral metabolic reserve, but in intensive EEG activation, recorded by CC/EEG index, cerebrolysin reduces cerebral blood supply aggravating acute brain ischemia.     

Ameliorative influence of a nootropic drug on motor activity of rats after bilateral carotid artery occlusion

The effects of the peptidergic nootropic drug Cerebrolysin on spatial memory and motor activity were examined in intact and ischemic rats. Ischemic-hypoxic damage was induced by injection of Na-cyanide followed by bilateral occlusion of common carotid arteries. Immediately afterwards Cerebrolysin or saline was administered, either by continuous intraventricular (i.v.) infusion or by daily intraperitoneal (i.p.) injection. Rats were tested for spatial memory and motor activity in the Morris water maze on days 3 and 4 post-surgery. The best dose of the substance for i.p. administration was known from previous studies. Therefore we had to investigate the dose-response-relationship and tolerability of the drug after i.v. administration in intact rats. Infusion (i.v.) of a high dose of Cerebrolysin (0.57 mg/day) decreased motor activity and spatial memory of intact rats (p < 0.01 and p < 0.05, respectively) but low dose of Cerebrolysin was well tolerated in the intact animals. Ischemia led to deterioration of motor activity in control rats (p < 0.01). Cerebrolysin significantly counteracted deleterious motor changes due to ischemia up to the level of intact controls after both i.v. infusion (0.0057 mg/day) and daily i.p. drug administration (100 mg/kg bw and day) indicating an accelerating recovery after ischemia.     

The EAA-ergic modulation of the brain dopaminergic system as a basis for creating new nootropic agents with stress-protective activity

The paper provides theoretical evidence for and practical confirmation of the possible use of three lipophilic derivatives of N-acetyl-aspartic acid (EAA-AKF-94; AKF-92-10, and PIR-87-6-0). These compounds were shown to display pronounced nootropic activity to correct behavioral, memory, and cognitive disorders in rats exposed to emotional stress. Evidence is provided for the fact that modulation of monoaminergic brain activity mediated by heterosynaptic activation of EAA receptors.     

Pharmacokinetics of thiamphenicol in dogs

OBJECTIVE: To determine pharmacokinetic parameters of thiamphenicol (TAP) after IV and IM administration in dogs. ANIMALS: 6 healthy 2- to 3-year-old male Beagles. PROCEDURE:IN a crossover design study, 3 dogs were given TAP IV, and 3 dogs were given TAP IM, each at a dosage of 40 mg/kg of body weight. Three weeks later, the same dogs were given a second dose by the opposite route. At preestablished times after TAP administration, blood samples were collected through a catheter placed in the cephalic vein, and TAP concentration was determined by use of a high-performance liquid chromatography. Results-Kinetics of TAP administered IV were fitted by a biexponential equation with a rapid first disposition phase followed by a slower disposition phase. Elimination half-life was short (1.7+/-0.3 hours), volume of distribution at steady state was 0.66+/-0.05 L/kg, and plasma clearance was 5.3+/-0.7 ml/min/kg. After IM administration, absorption was rapid. Peak plasma concentration (25.1+/-10.3 microg/ml) was reached about 45 minutes after drug administration. The apparent elimination half-life after IM administration (5.6+/-4.6 hours) was longer than that after IV administration probably because of the slow absorption rate from the muscle. Mean bioavailability after IM administration was 96+/-7%. CONCLUSION: The pharmacokinetic profile of TAP in dogs suggests that it may be therapeutically useful against susceptible microorganisms involved in the most common infections in dogs, such as tracheobronchitis, enterocolitis, mastitis, and urinary tract infections.     

Pharmacokinetics of phenolsulfonphthalein in sheep

Pharmacokinetic variables of phenolsulfonphthalein (PSP) were determined in sheep after rapid IV injection and IV infusion to steady state. In Suffolk wethers, an average of < 75% of an IV administered dose was eliminated in urine, indicating that measures of systemic clearance overestimate renal clearance in this species. Furthermore, PSP elimination from plasma was more rapid in Suffolk than Rambouillet wethers and, in Suffolk ewes, systemic clearance decreased from mean +/- SD 7.8 +/- 0.3 ml/min/kg of body weight to 4.7 +/- 1.1 ml/min/kg at steady-state plasma concentration of 2.4 +/- 0.3 and 151.3 +/- 31.8 micrograms/ml, respectively. These observations indicate that, similar to that in other species, systemic clearance of PSP in sheep is concentration-dependent and that significant differences may exist between breeds.