Long-term plasma levels of leptin and adiponectin in Rett syndrome.

OBJECTIVE: Rett syndrome is a progressive neurological disorder affecting almost exclusively females after age 6 months and characterised by acquired microcephaly, psychomotor retardation, growth failure, purposeless hand movements, autistic-like behaviour and wide-based and stiff legged gait. Leptin and adiponectin, peptides secreted by adipose tissue, are involved in the regulation of body weight and energy expenditure. DESIGN AND PATIENTS: We investigated in patients with Rett syndrome the variations of plasma leptin and adiponectin and their relation over a 2-year period. Sixteen female patients, mean age at the basal time 9.4 +/- 4.3 years, with classical Rett syndrome were enrolled. Controls were 16 healthy female subjects, mean age at the basal time 9.9 +/- 3.4 years. MEASUREMENTS: Blood samples were withdrawn in the morning at the baseline, 12 months after and 24 months after; plasma leptin and adiponectin concentrations were detected by ELISA. RESULTS: In patients, leptin concentrations significantly increased, while adiponectin concentrations significantly decreased. Both leptin and adiponectin values were significantly higher than those found in controls at each time. Leptin significantly correlated with adiponectin in patients, while there was not a significant correlation in controls. CONCLUSION: Since all patients were not obese, we might hypothesize that in Rett syndrome leptin and adiponectin might participate to clinical manifestations other than weight balance.

Rett syndrome and plasma leptin levels.

OBJECTIVE: To describe in patients with Rett syndrome (classic and preserved-speech variant) plasma leptin levels and their relationship to BMI (body mass index) and age. STUDY DESIGN: Female patients (n = 48; age range 3-20 years) affected by classic Rett syndrome were enrolled into the study. Eleven female patients, age range 3 to 20 years, with preserved-speech variant Rett syndrome were included in the study. Controls were 24 healthy female subjects, age range 3 to 20 years. Blood samples (3 mL) were withdrawn from an antecubital vein in the morning; plasma leptin concentrations were detected by enzyme-linked immunosorbent assay method. RESULTS: Patients with classic Rett syndrome and preserved-speech variant had leptin values significantly higher than controls. Leptin concentrations did not significantly differ between patients with classic Rett and preserved-speech variant. Leptin values positively correlated with age and BMI. CONCLUSIONS: Because in all patients the increased leptin concentrations were not associated to obesity, we hypothesize that in patients with Rett syndrome leptin might participate to clinical manifestations other than weight balance.

Pharmacokinetics and pharmacodynamics of neutrophil-associated ciprofloxacin in humans.

OBJECTIVE: To study the possibility that the penetration of the antibiotic ciprofloxacin into polymorphonuclear leukocytes (PMN) may be associated with some changes in cell reactivity. DESIGN: Superoxide anion and chemiluminescence generation induced by formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) were studied ex vivo in 12 healthy volunteers (mean age, 53.15 +/- 16.3 years; mean body weight, 71.23 +/- 6.9 kg) at fixed intervals up to 72 hours from the administration of a single oral dose of 250 mg ciprofloxacin. Cytosolic free calcium levels ([Ca2+]i) in resting and stimulated cells were also evaluated. The dynamic parameters of the effects on PMNs were compared with the kinetic profile of the drug in plasma and in PMNs. RESULTS: Superoxide generation induced by the stimulating agents increased significantly, reaching a peak after 12 hours (+116% [p < 0.001] for fMLP and +66% [p < 0.05] for PAF). Similarly, chemiluminescence production showed a threefold increase in the response to the stimulating agents 12 hours after drug administration (p < 0.001). The increase in [Ca2+]i in stimulated PMNs was significantly potentiated (p < 0.001). The mathematic analysis of the effects of ciprofloxacin showed that time to maximal activity was between 10.4 hours (PAF-dependent [Ca2+]i increase), and 15 hours (fMLP-induced superoxide anion and chemiluminescence production). The ratio of PMNs to plasma ciprofloxacin concentration increased progressively, from 0.5 at 30 minutes to 10.4 after 24 hours. In addition, time to maximal activity and half-life differed in PMNs and in plasma (4.66 versus 1.90 hours and 13.03 versus 7.28 hours, respectively). CONCLUSIONS: Ciprofloxacin administration induced a long-lasting enhancement of PMN reactivity to fMLP and PAF. The levels of the drug in the cells were greater and more sustained in the time than those in plasma.

QTc interval prolongation during infusion with dipyridamole or adenosine.

The aim of our study was to discover whether there was a relationship between the QTc interval prolongation on the standard 12-lead electrocardiogram (ECG) and provoked myocardial ischemia. Since the increase of adenosine plasma levels, obtained either with adenosine or dipyridamole (an adenosine reuptake inhibitor) infusion, has been used to test the coronary artery reserve in patients affected by coronary artery disease, the QTc interval modifications during dipyridamole or adenosine echocardiographic stress test were evaluated. Twenty-five patients admitted to our Institute for evaluation of chest pain of suspected myocardial origin underwent an echocardiographic dipyridamole stress test (0.84 mg/kg over 10 min) after discontinuation of antianginal treatment. Of these patients, 10 underwent an echocardiographic adenosine stress test (scalar doses of 50, 75, 100, 140 micrograms/kg/min) after 48-72 h. The Bazett formula was used to evaluate the QTc interval. After dipyridamole and adenosine administration, a significant prolongation of the QTc interval was observed only in those patients who had positive test results. Our data suggested that QTc interval prolongation during pharmacological stress tests might be considered a marker of myocardial ischemia.

A short introduction to pharmacokinetics.

Phamacokinetics is proposed to study the absorption, the distribution, the biotransformations and the elimination of drugs in man and animals. A single kinetic profile may be well summarized by Cmax, Tmax, t 1/2 and AUC and, having more than one profile, 8 parameters at least, the mean and standard deviation of these parameters, may well summarize the drug kinetics in the whole population. A more carefull description of the data can be obtained interpolating and extrapolating the drug concentrations with some mathematical functions. These functions may be used to reduce all the data in a small set of parameters, or to verify if the hypotheses incorporated in the functions are confirmed by the observations. In the first case, we can say that the task is to get a simulation of the data, in the second to get a model. The functions used to interpolate and reduce the pharmacokinetic data are the multiexponential functions and the reference models are the compartmental models whose solutions are just the multiexponential functions. Using models, new meaningfull pharmacokinetic parameters may be defined which can be used to find relationships between the drug kinetic profile and the physiological process which drive the drug absorption, distribution and elimination. For example, compartmental models allow to define easily the clearance which is dependent on the drug elimination process, or the volume of distribution which depends on the drug distribution in the tissues. Models provide also an easy way to get an estimate of drug absorption after extravasculare drug administration (bioavailability). Model building is a complex multistep process where, experiment by experiment and simulation by simulation, new hypothesis are proven and disproven through a continuous interaction between the experimenter and the computer.

Stimulation of endogenous adenosine release by oral administration of quercetin and resveratrol in man.

Epidemiological evidence indicates that moderate alcohol consumption is associated with a significant decrease in the incidence of certain cardiovascular disorders, which can lead to impaired quality of life and to death. However, there are no objective data suggesting a cause-effect relationship and detailed research based on definitive working hypotheses is needed. We tested two flavonoids in man and found that these substances can belong, at least in part, to a wine-dependent mechanism, which leads to increased adenosine plasma levels. If these results could be confirmed by analyzing all the possible influences leading to blood nucleoside increase, a hypothesis of diet-dependent cellular preconditioning could be discussed.

A simple computational approach to model parameter estimation.

The desire to describe biological data using mathematical models has led to the rapid development of various analytical techniques for model identification and parameter estimation. The procedures used may be non-linear and complex, and require long calculation periods. Thus, the aid of a personal computer renders efficient the application of these rather complicated procedures. In this study we developed a simple identification programme for heparan sulfate pharmacodynamics which can be easily and rapidly implemented on a personal computer. The programme is based on an iterative algorithm performing a non-linear regression analysis by the least-square method. This programme was applied to a clinical measured variables with which it was possible to quantify the pharmacodynamic effect of heparan sulfate.

Pharmacokinetics and pharmacodynamics of dermatan sulfate after intravenous and intramuscular administration to healthy volunteers.

The pharmacokinetics and pharmacodynamics of dermatan sulfate (DS) was investigated in healthy volunteers (two groups, namely group A: 6 subjects, group B: 8 subjects). The subjects of group A received 100 mg of DS both i.v. and i.m. and the subjects of group B received 400 mg of DS both i.v. and i.m. in two different days. The resulting anticoagulant activities were assessed by the activated partial thromboplastin time (aPTT) and the pharmacokinetic parameters were calculated from the plasma concentrations of DS measured by a chromogenic assay. The plasma concentrations of DS were fitted by linear and non-linear elimination models (i.e. assuming that the drug elimination follows Michaelis-Menten kinetics). Some evidence of non-linear kinetics was given by the observation that the mean terminal half-life and clearance estimated by the linear model were not independent of the i.v. dose (0.83 +/- 0.1 and 1.74 +/- 0.21 hours and 4.94 +/- 0.64 and 2.67 +/- 0.27 l/h after 100 and 400 mg i.v. respectively. Moreover the mean half-lives estimated after i.m. administrations were much higher than the values estimated after the i.v. dose (2.03 +/- 0.74 and 3.54 +/- 1.3 hours after 100 and 400 mg) and linear models failed to fit simultaneously the DS plasma concentrations after both the administration routes. Using the linear model, the mean drug bioavailability after i.m. administration was estimated to be about 30% and 80% after the 100- and the 400-mg dose respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of pramiracetam in healthy volunteers after oral administration.

The pharmacokinetics of pramiracetam was assessed using an HPLC method after oral administration of two different formulations of 600 mg (a solution and a tablet) of pramiracetam to 11 fasting volunteers. The mean kinetic parameters were: t1 = 4.7 +/- 2.4 - 4.3 +/- 2.2 h, AUC = 57.6 +/- 43.6 - 47.2 +/- 33.9 micrograms h/ml, Cmax = 6.80 +/- 3.2 - 5.80 +/- 3.3 micrograms/ml for the solution and the tablet respectively. The plasma profile of pramiracetam proved to be not highly affected by the formulation, only that the absorption rate was faster after oral administration of the drug in solution than after administration as a tablet. The half-life was very variable between subjects [2-8 hours], but less variable within subjects and it was unaffected by the formulation.

Pharmacodynamics of troxerutine in patients with chronic venous insufficiency: correlations with plasma drug levels.

In a double-blind study the effects of troxerutine were assessed in patients with chronic venous insufficiency. The aim of this clinical pharmacological research was to evaluate, after a single oral dose: haemocoagulative and fibrinolytic balance, haemorheological changes and venous function. Correlation between such changes and simultanously assayed plasma drug levels was evaluated. The data obtained seems to give to troxerutine a more enlarged pharmacological characterization, especially regarding its demonstrated profibrinolytic and rheological activities. The maximal pharmacodynamic effects appeared simultaneous with the plasma drug peak.

Pharmacokinetics and pharmacodynamics of slow-release theophylline during treatment with nimesulide.

The pharmacodynamic and pharmacokinetic interactions were studied between nimesulide, a recently introduced non-steroidal anti-inflammatory drug, and theophylline, another highly protein-bound drug, in patients who were receiving slow-release theophylline for a chronic airflow-obstruction and who also needed anti-inflammatory treatment. A good tolerability was demonstrated of the two drugs association and there was an absence of pharmacodynamic interaction, as shown by lung function parameters, assayed before and after the coinciding nimesulide association. The pharmacokinetics of nimesulide and 4-hydroxy-nimesulide (its active metabolite) were not modified, in agreement with data shown by other authors. On the contrary, there was a slight alteration of theophylline pharmacokinetics, yet neither clinically nor biologically significant, probably due to an enzymatic induction.

Clinical study on pharmacological interaction between nimesulide and warfarin.

This article describes the pharmacological interaction between nimesulide, a recently introduced non-steroidal anti-inflammatory drug, and warfarin, an indirect anticoagulant. The aim of the study was to demonstrate if nimesulide could potentiate the activity of this anticoagulant drug, as previously shown by some authors. Ten patients, who were taking 5 mg/day of warfarin, were treated with nimesulide 100 mg twice a day, for seven days: the association of the two drugs did not alter, in a statistical way, neither prothrombin time, nor partial thromboplastin time, nor fibrinogenemia, nor bleeding time. The findings showed that, in a short-term treatment, there was no bleeding risk in combining warfarin with nimesulide.

Hemodynamic and hemorheologic effects of i.v. Dilevalol in hypertensive patients.

The authors evaluated the effect of Dilevalol infusion on blood pressure, heart rate, central hemodynamics, and rheologic parameters in hospitalized inpatients affected with mild or moderate hypertension. After a dose-finding phase and a washout period of one week, 10 patients aged fifty to seventy-two-years (median 61.5) were given either a single dose of Dilevalol 60 mg or placebo, and seven days later they underwent the other treatment, according to a single-blind, crossover design. Central hemodynamic measurements were performed by means of M-mode echocardiography, and hemorheologic parameters were evaluated by means of strain-gauge plethysmography. The maximal increase in lower extremity flow at rest had been obtained with the infusion of 60 mg Dilevalol during dose-finding, and so this dose was chosen for the second part of the study. The infusion of Dilevalol significantly increased rest flow and decreased blood viscosity, but the changes in central, parameters were not considered clinically relevant, although statistically significant. Blood pressure decreased without significant changes in heart rate. Thus, the acute administration of Dilevalol reduced blood pressure, without affecting heart rate and central hemodynamics, confirming the vasodilating effect of the drug. A significant improvement was also shown on blood viscosity in these hypertensive patients.

Peripheral neuropathy associated with ischemic vascular disease of the lower limbs.

This paper deals with the possible identification of somatic and autonomic nerve damage in patients with peripheral obliterative arterial disease (POAD) at different stages of the disease, with a well-reproducible technique like electroneurographic evaluation of nerve conduction. In 64 patients with intermittent claudication, 19 patients with pain at rest, and 7 patients with trophic ulcers, electroneurographic evaluation of motor (tibial and peroneal) and sensory (superficial peroneal and sural) nerve conduction was performed. The median nerve (motor and sensory) was used as control. A severe impairment of sural and superficial peroneal nerve velocities was evident in many claudicant patients and in all patients with pain at rest and trophic ulcers, with a progression in the conduction abnormalities in advanced stages of the disease. Motor nerve conduction showed only minor reductions in patients with claudication and pain at rest, although some of them did show very poor velocity values. In 21 patients with intermittent claudication and sensory nerve abnormalities, the autonomic fibers activity, evaluated by the skin sympathetic response (SSR) test, was significantly depressed, thus suggesting an involvement of the local autonomic system in the ischemic disease. A correlation exists between the severity of the somatic nerve damage and the stage of the vascular insufficiency. However, in the group of claudicant patients, the evidence of similar ischemic threshold (claudication distance) may be associated with a marked difference in the amount of somatic nerve damage. The somatic and autonomic nerve alterations may play a relevant role in the progression of the disease toward critical limb ischemia.

Effectiveness and tolerability of nimesulide in the treatment of osteoarthritic elderly patients.

One important point in the treatment of osteoarthritis is to control the pain that accompanies the persistent inflammatory conditions. Because of the chronic nature of the disease, drugs with a good ratio of effectiveness to tolerability must be used. In the following double-blind study the effects of nimesulide, a non-steroidal antiinflammatory drug, were compared with those of placebo in 40 elderly osteoarthritic patients, during and after a treatment cycle of 90 days with two 100-mg tablets a day. The reduction of spontaneous and motion-induced pain and of morning stiffness seen at the various check-ups attested the good effectiveness of nimesulide. Functional status as a whole was improved, and it was found that the concomitant weekly intake of an analgesic (paracetamol) treatment could be decreased during the 3 months of the study. The tolerability of nimesulide was good.

Action of a new non-steroid antiinflammatory drug, nimesulide, on activation of the complement system: an in vitro study.

The complement system has a pivotal role in the antiinflammatory reaction. Furthermore it has been shown that the sequential activation of the complement system may be inhibited at various levels by pharmacological agents such as non-steroidal antiinflammatory drugs. Therefore the eventual anticomplementary action of Nimesulide was assessed in vitro in various experimental models. It was found that it blocks immunohaemolysis in vitro and has a direct effect on serum complement activity. Nimesulide blocks the activation of third complement and this explains why the drug is also inhibitory on the inulin-induced haemolytic reaction.

[Pharmacogenetics: pharmacokinetics and clinical implications]. / Farmacogenetica: farmacocinetica ed implicazioni cliniche.

In the last years, pharmacogenetic studies tried to identify the hereditary bases characterizing different individual response to drugs. Human organism tries to remove drugs by activating enzyme systems. Metabolization reaction rate shows wide interindividual variations, being characterized by different factors, such as physiologic (age, sex), pathologic (liver and kidney diseases), and genetic characteristics. Inborn errors may lead to some alterations in functional enzyme activities. These alterations led to divide the whole population into two groups: slow metabolizers PM (having a slow metabolism), and fast metabolizers EM (having a normal metabolism). Such a different behaviour may lead to changes in pharmacokinetic parameters which may also influence pharmacodynamic characteristics of the drug, thus leading to: 1) an excessive therapeutic effect, 2) a decreased therapeutic effect, 3) an increased toxicity of the drug not undergoing its transformation, 4) toxicity of a metabolic byproduct formed by a pathway different from the main one.

[Meta-analysis of antiaggregant therapy trials. Proposal of an additional reading key]. / La metanalisi dei trial di terapia antiaggregante. Proposta di una chiave aggiuntiva di lettura.

The efficacy of drug treatment is conventionally assessed by clinical trials. In these studies, experimental design, data analysis and interpretation of results are based on statistical methods. It is difficult to relate to a specific patient the data obtained from statistically analysed studies of population. In our opinion the statistical parameter NNT (Number of patients Needed to Treat) indicates the effectiveness of a treatment taking into consideration the basal risk as well as the risk reduction after therapy. We applied the NNT parameter to data taken from the metaanalysis Antiplatelet Trialists' Collaboration concerning secondary prevention of adverse vascular events with antiplatelet drugs. We focused on the long-term effect of antiplatelet therapy on the adverse events reduction; in the first year of treatment we observed a NNT value of 37, in the second year a NNT value of 59 and in the third year a NNT value of 200; in the fourth year we found absence of effect. The NNT parameter allows us to evaluate immediately the economic consequences of therapeutic strategies and the clinical impact of a long-term treatment.

[Effects of 2 single oral doses of mesoglycan on the coagulation-fibrinolysis system in man. A pharmacodynamic study]. / Azione di due dosi orali singole di mesoglicano sul sistema coagulativo-fibrinolitico dell'uomo. Studio farmacodinamico.

In this study the profibrinolytic activity of two single oral doses of mesoglycan was evaluated. Furthermore, a mathematical model describing the patterns of the resulting phenomena was applied. Ten patients with impaired fibrinolytic system (euglobulin lysis time > 180 min) were enrolled in the study. In the morning following a 24 hour fast period, the patients were given orally a single dose (100 and 50 mg) of mesoglycan and placebo, with an interval of 48 hours between each treatment. The following parameters were evaluated at the time 0 and after 2, 4, 6, 8, 10 and 12 hours from each administration: tissue plasminogen activator (t-PA) and its inhibitor PAI-1, euglobulin lysis time, plasminogen and alfa-2-antiplasmin as indexes of the fibrinolytic system; aPTT, TT, fibrinogen as indexes of the hemostatic-coagulative system. Mesoglycan showed a dose-dependent profibrinolytic activity, that was also present after placebo but in a less entity. The mathematical study confirms the experimental observations and thus may allow to describe, with a high degree of approximation, the in vivo pharmacology of mesoglycan through the use of the mathematical function.

[Effects on the coagulation-fibrinolysis system of a single oral dose of mesoglycan at the beginning and at the end of a prolonged treatment in man]. / Effetti sul sistema coagulativo-fibrinolitico dell'uomo indotti da una dose orale singola di mesoglicano all'inizio ed alla fine di un trattamento prolungato.

We evaluated the mesoglycan effects on the coagulative-fibrinolytic system in 10 patients with euglobulin lysis time (ELT) over 180 minutes. A mathematical model was used to analyze such phenomena. 100 mg of mesoglycan was administered to 10 patients for 14 days. The following parameters were evaluated: tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), euglobulin lysis time (ELT), plasminogen, alpha 2 antiplasmin, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin clotting time (TCT), and fibrinogen. Those parameters were evaluated on the first and on the last day of the mesoglycan treatment at the following times: 0 (basal), 2, 4, 6, 8, 10 and 12 hours. Our results suggest that the mesoglycan is able to reduce a profibrinolytic activity without any influence on the coagulative-fibrinolytic system, at the baseline conditions and after chronic administration. The pharmacodynamic study and the statistical analysis using our mathematic model resulted to be statistically significant.