The clinical pharmacokinetics of cladribine

Cladribine is a new purine nucleoside analogue with promising activity in low-grade lymphoproliferative disorders, childhood acute myelogenous leukaemia and multiple sclerosis. Reversed phase high performance liquid chromatography and radioimmunoassay have been used for the analysis of the plasma pharmacokinetics of cladribine. The major (inactive) metabolite in plasma, chloroadenine, can only be detected by liquid chromatography. The oral bioavailability of cladribine is 37 to 51%, and that of subcutaneous administration is 100%. The terminal half-life varies from 5.7 to 19.7 hours and the apparent volume of distribution from 54 to 357 L/m2. The concentration in the cerebrospinal fluid is 25% of that in plasma in patients without central nervous system disease; in patients with meningeal disease, the cladribine concentration in the cerebrospinal fluid exceeds that in plasma. Cladribine is a prodrug and needs intracellular phosphorylation to active nucelotides. The intracellular concentration of these metabolites is several hundred-fold higher than that of cladribine in plasma and they are retained in leukaemia cells with half-lives between 9 and > 30 hours depending on diagnosis and sampling schedule. There is no correlation between the plasma concentration of cladribine and that of the intracellular metabolites. The renal clearance of cladribine is 51% of total clearance and 21 to 35% of an intravenously administered dose is excreted unchanged in the urine. Pretreatment with cladribine increases the intracellular accumulation of the active metabolite of cytarabine, cytosine arabinoside 5'-triphosphate, by 36 to 40%.     

Radiolunate fusion. The forgotten partial arthrodesis

Radiolunate fusion has been used successfully in the treatment of rheumatoid ulnar translation of the carpus and degenerative radiolunate arthritis. Fusing the lunate to the radius places the keystone of the carpus in an aligned and stable position. The use of radiolunate fusion has been introduced here for other treatment challenges including traumatic ulnar translation of the carpus, dynamic midcarpal instability, volar and static intercalated segment instability. Pain relief was excellent and preoperative range of motion was maintained with radiolunate fusion.     

Man's forgotten weapon.

"The forgotten weapon… is also our potentially most effective device for constructive advance. It is, simply, awareness, consciousness, man's awareness of himself and of the world around him… . we can, and must, deliberately exploit this characteristic… . its intentional development and use is as essential for our survival as men as it has been for our evolution into man. Consideration of the role that this has played in biological evolution in the past may give us some background for discussing its possibilities in the biological and cultural evolutuion of the futurue." Cultural evolutuion is "subject to conscious control." Psychologists must exploit awareness as a "weapon against disaster." (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Freud's forgotten evolutionary project.

In the last decades psychoanalysis has tended to recast itself as a hermeneutic discipline geared at the retelling of human lives, and Freud is recast as a great writer in the humanist tradition rather than as the scientist as which he saw himself. Although this reconceptualization has good reasons, it tends to obscure the fact that Freud primarily saw himself as a theorist of human nature. One of Freud's deepest convictions was that psychopathology needs to be explained on the basis of evolutionary biology. This paper argues that this may have been one of Freud's greatest ideas. The reason it has been "repressed" by psychoanalysis is that Freud based it on Lamarckian principles. The current flourishing of evolutionary psychology and psychiatry may well turn Freud into one of the precursors of the psychology of the future. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The relative distribution of soluble and insoluble cholinesterases in rat excitable tissues

Three ratios were studied here: bound to free AChE (R1), bound to free BChE (R2), and the ratios between these two (R3). The first one proved relevant in that it contributed to the division of the cholinergic tissues into 3 classes: high values (nicotinic tissues: skeletal muscle), low values (muscarinic tissues: small intestine, uterus, heart), and middle values (mixed, nicotinic and muscarinic cholinergic innervation: brain). The third ratio (R3) showed different values in the muscarinic tissues studied; no significant differences could, however, be found between the ratios of brain and skeletal muscle. Further exploration of this ratio should indicate whether it is of some importance for the characterization of excitable tissues.     

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.     

Glycerol. Biochemistry, pharmacokinetics and clinical and practical applications

Glycerol is a naturally occurring 3-carbon alcohol in the human body. It is the structural backbone of triacylglycerol molecules, and can also be converted to a glycolytic substrate for subsequent metabolism. Serum glycerol concentrations approximate 0.05 mmol/L at rest, and can increase to 0.30 mmol/L during increased lipolysis associated with prolonged exercise or caloric restriction. When glycerol is ingested or infused at doses greater than 1.0 g/kg bodyweight, serum concentrations can increase to approximately 20 mmol/L, resulting in more than a 10 mOsmol/kg increase in serum osmolality. Glycerol infusion and ingestion have been used in research settings for almost 60 years, with widespread clinical use between 1961 and 1980 in the treatment of cerebral oedema resulting from acute ischaemic stroke, intraocular hypertension (glaucoma), intracranial hypertension, postural syncope and improved rehydration during acute gastrointestinal disease. Since 1987, glycerol ingestion with added fluid has been used to increase total body water (glycerol hyperhydration) by up to 700 ml, thereby providing benefits of improved thermoregulation and endurance during exercise or exposure to hot environments. Despite the small number of studies on glycerol hyperhydration and exercise, it appears to be an effective method of improving tolerance to exercise and other heat-related stressors.     

Leptin: its pharmacokinetics and tissue distribution

OBJECTIVE: The pharmacokinetics and tissue distribution of leptin in rats was investigated. DESIGN: A catheter was inserted in the right jugular vein of rats on the day prior to experiment. The next day, blood was sampled and then a tracer dose of radioiodinated hormone was administered via the catheter. Thereafter, small (200 microl) samples of blood were taken at regular intervals. Two experiments were conducted over different sampling times. TCA precipitated radioactivity was counted in samples of plasma and tissues. Pharmacokinetic parameters were calculated after fitting a bi-exponential equation describing a two-pool model of plasma leptin distribution. Selected time-point plasma samples were fractioned using size exclusion chromatography and the leptin distribution determined. RESULTS: The two pool model described the pharmacokinetics of leptin in two forms: an initial fast decaying pool (t(1/2) = 3.4 min) and a slower decaying pool (t(1/2) = 71 min) with an overall clearance rate of 6.16 ml/min/kg. Size exclusion chromatography showed a persistent peak (all time-points tested) of 125I-leptin corresponding to the plasma albumin peak. The size of the free 125I-leptin peak became diminished or absent in later time-point plasma samples. Tissue distribution of leptin at 60 min and 180 min time-points showed that the small intestine contained the highest concentration of leptin, almost four times the level found in kidneys, liver, stomach and lungs. 125I-leptin was least abundant in skin, muscle, heart, caecum and brain. CONCLUSION: The pharmacokinetics of leptin are affected by three important factors: 1) its ability to bind to a plasma carrier molecule which increases its half-life; 2) its association with abundant peripheral tissue binding sites which creates an additional pool of leptin and 3) the rate of synthesis of leptin which may be less important than originally believed as the prolonged half-life and the additional pool of tissue binding sites are important factors in determining its plasma concentration.     

Blood distribution and single-dose pharmacokinetics of leflunomide

Leflunomide (HWA 486, LEF) is a novel isoxazole derivative with potent immunosuppressive properties. LEF is converted to its active metabolite (A77 1726) after absorption. Presently, the blood distribution and pharmacokinetics of LEF have not been reported. Such information would prove invaluable in determining the appropriate medium for analysis and optimal immunosuppressive dosing regimes. In this study, A77 1726 was found to be primarily associated (> 95%) with the lipoprotein free fraction of plasma at all tested concentrations ranging from 0.4 to 100 mg/L. Detectable levels of A77 1726 (0.34 +/- 0.18 mg/L), analyzed by HPLC, were found in the plasma free fraction only at the highest tested concentration (100 mg/L). Single-dose pharmacokinetics of A77 1726 (i.v.) and HWA 486 (p.o.) were investigated in five healthy New Zealand white rabbits. The half-lives (t1/2) of A77 1726 i.v. and HWA 486 p.o. administration were 3.88 +/- 2.3 and 3.18 +/- 1.6 h, respectively. The volume of distribution by both routes of administration indicates minimal distribution into tissues (Vdss p.o. = 0.14 +/- 0.03 L/kg and Vdssi.v. = 0.09 +/- 0.02 L/kg). The mean residence time of A77 1726 was greater after oral administration of LEF (MRTp.o. = 10.54 +/- 2.6 h and MRTi.v. = 6.76 +/- 1.0 h). Identical areas under the curve suggest bioavailability was 100% (AUCp.o. = 421.16 +/- 204.5 mg.h/L and AUCi.v. = 399.75 +/- 126.9 mg.h/L).     

Husserl revisited: The forgotten distinction between psychology and phenomenology.

Argues that as phenomenology attracts growing attention in current psychology, it is increasingly important for psychologists to understand that phenomenology encompasses much more than a mere appreciation for subjective self-report data. The ideas of E. Husserl, the so-called founder of phenomenology, are reexamined to enlighten psychologists about phenomenology's contrasting approach to the study of consciousness. Whereas psychology studies actual subjective responses to actual environmental events (empirical data), phenomenology studies the essential character of consciousness in meaning-conferring acts (essential knowledge). Husserl proposed phenomenology as a positive alternative to the experimental methods of the new scientific psychology. Husserl believed phenomenology was needed to clarify the essential, but unanalyzed, pre-understandings of mental phenomena that guide psychology's experimental investigations. (36 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The impact of Katrina: Shedding light on things forgotten.

Volunteering on a disaster mental health team to assist the victims of Hurricane Katrina can affect a psychologist in a number of ways that cannot be known until after the experience has taken place. Such an event will have a unique impact based on who the person is, on his or her life experience, and on what activities he or she conducted. This article shares the impact this experience has had on a psychologist who had never before been involved in a disaster mental health effort. The focus is on how this experience has helped to shape and influence the author's present clinical work, both as a practitioner and program administrator. Rather than learning anything completely novel or foreign, instead, this experience has shed light on things known but that were in some ways forgotten or less fully appreciated. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Systemic antifungal agents. Drug interactions of clinical significance

There are 3 main classes of systemic antifungals: the polyene macrolides (e.g. amphotericin B), the azoles (e.g. the imidazoles ketoconazole and miconazole and the triazoles itraconazole and fluconazole) and the allylamines (e.g. terbinafine). Other systemic antifungals include griseofulvin and flucytosine. Most drug-drug interactions involving systemic antifungals have negative consequences. The interactions of amphotericin B, flucytosine, griseofulvin, terbinafine and azole antifungals can be divided into the following categories: (i) additive dangerous interactions; (ii) modifications of antifungal kinetics by other drugs; and (iii) modifications of the kinetics of other drugs by antifungals. Amphotericin B and flucytosine mainly interact with other agents pharmacodynamically. Clinically important drug interactions with amphotericin B cause nephrotoxicity, hypokalaemia and blood dyscrasias. The most important drug interaction of flucytosine occurs with myelotoxic agents. Hypokalaemia can precipitate the long QT syndrome, as well as potentially lethal ventricular arrhythmias like torsade de pointes. Synergism is likely to occur when either QT interval-modifying drugs (e.g. terfenadine and astemizole) and drugs that induce hypokalaemia (e.g. amphotericin B) are coadministered. Induction and inhibition of cytochrome P450 enzymes at hepatic and extrahepatic sites are the mechanisms that underlie the most serious pharmacokinetic drug interactions of the azole antifungals. These agents have been shown to notably decrease the catabolism of numerous drugs: histamine H1 receptor antagonists, warfarin, cyclosporin, tacrolimus, digoxin, felodipine, lovastatin, midazolam, triazolam, methylprednisolone, glibenclamide (glyburide), phenytoin, rifabutin, ritonavir, saquinavir, nevirapine and nortriptyline. Non-antifungal drugs like carbamazepine, phenobarbital (phenobarbitone), phenytoin and rifampicin (rifampin) can induce the metabolism of azole antifungals. The bioavailability of ketoconazole and itraconazole is also reduced by drugs that increase gastric pH, such as H2 receptor antagonists, proton pump inhibitors, sucralfate and didanosine. Griseofulvin is an enzymatic inducer of coumarin-like drugs and estrogens, whereas terbinafine seems to have a low potential for drug interactions. Despite important advances in our understanding of the mechanisms underlying pharmacokinetic drug interactions during the 1990s, at this time they still remain difficult to predict in terms of magnitude in individual patients. This is because of the large interindividual and intraindividual variations in the catalytic activity of those metabolising enzymes that can either be induced or inhibited by various drugs. Notwithstanding these variations, increasing clinical experience is allowing pharmacokinetic interactions to be used to advantage in order to improve the tolerability of some drugs, as recently exemplified by the use of a fixed combination of ketoconazole and cyclosporin.     

20,000 psychologists: Lost and forgotten.

Comments on J. M. Tuma's (see record 1989-27149-001) article concerning children's needs for mental health services and the shortage of trained professionals to provide services to this population. It is noted that Tuma failed to acknowledge the school psychologists working in this field. (PsycINFO Database Record (c) 2010 APA, all rights reserved)