Effects of surfactant characteristics on drug availability from suppositories.

The addition of surfactants to suppository formulations is referred to in the scientific literature, but their effects on drug availability remain uncertain. Surfactants are reported to improve drug dispersion into hard fatty excipients, to increase the spreading of the melted suppository on the rectal mucosa leading to a greater contact surface, to reduce the viscosity of the molten mass and to reduce the pathway of drug particles to the interface. In the present study a systematic investigation based on tensiometric and rheological methods was carried out to evaluate the effects of nonionic surfactants with different HLBs (hydrophilic-lipophilic-balance) on drug availability and to clarify the possible mechanisms involved in the release process. The relationship between the melted suppositories and a membrane simulating the rectal barrier were investigated in the course of the in vitro release test by measuring their energy characteristics. At the same time, the potential influences of such interactions on drug release were investigated in suppositories formulated with different kinds and concentrations of surfactant additives. Drug availability was influenced not only by the interaction between the suppository and the rectal membrane but also by the interaction between surfactant, lipophilic excipient and suspended drug particles. Such interactions appear to greatly influence drug release from suppositories, which, in turn, is the main parameter determining drug availability.

Influence of synthesis and processing conditions on the release behavior and stability of sol-gel derived silica xerogels embedded with bioactive compounds.

The influence of processing parameters and synthetic strategies in the properties of sol-gel derived silica matrices intended for the release of bioactive compounds was investigated. The time-evolution of the matrix properties during its aging at room temperature in the dry and wet forms was investigated by measuring some of its physical and drug retaining properties. The results indicate that long term gel aging in the wet form is fundamental for the obtainment of dry matrices that are stable upon storage, a fundamental requirement for any practical application. In the case of hybrid matrices obtained by replacing part of the tetraethoxysilane precursor with mono-methyl trimethoxysilane, the order of addition of the reaction component is also important in determining the properties of the final dry gel, probably by influencing the polymer structural properties. This parameter acts synergistically with the matrix composition in determining the release properties of xerogels embedded with bioactive compounds.

In vitro methods for the evaluation of drug availability from suppositories: comparison between biological and artificial membranes.

Drug availability from suppositories is currently evaluated in vitro by means of a model consisting of a dialysis tube (porous membrane) or isolated biological membrane (animal rectum). We propose a new alternative in vitro method to determine drug availability from suppositories consisting of an artificial membrane soaked with n-octanol, coupled with a filter paper sheet soaked with phosphate buffer. This method provides for an integrated hydro-lipophilic simulation of the biological membrane, including the mucus layer adhering to the rectal mucosa. By simply using the porous membrane, the amount of drug released varied directly according to its solubility for formulations with lipophilic excipients. For formulations with hydrophilic excipients, drugs with low/intermediate solubility in water showed increased availability in comparison to lipophilic excipients. The in vitro rat rectum model provided overall results that were similar to those obtained with the porous membrane method, although the percentage values of AUC were lower. The new model of in vitro simulated absorption produced a degree of drug availability that was lower in comparison to both previous methods. However, the simulated model appeared to give a pattern of drug availability closer to that of the model of in vitro rat rectum. The new in vitro artificial model thus appears to be useful in suppositories preformulation studies, allowing for an estimate of drug availability and the choice of the most adequate excipient.

Uterine artery embolisation for symptomatic adenomyosis with polyzene F-coated hydrogel microspheres: three-year clinical follow-up using UFS-QoL questionnaire.

PURPOSE: This study was designed to assess midterm outcome of uterine artery embolisation (UAE) for women with therapy-resistant adenomyosis using polyzene F-coated hydrogel microspheres. METHODS: Between September 2006 and January 2010, 29 consecutive women with adenomyosis (15 in combination with fibroids) were treated with UAE using polyzene F-coated hydrogel microspheres. Junction zone thickness was assessed with MRI at baseline and 3 months. Women filled out the uterine fibroid symptom and quality of life questionnaire at baseline, 3 months and after a mean clinical follow-up of 37 months (median 35, range 29-64 months). RESULTS: At baseline, symptom severity score of 29 women was mean 67 (median 72, range 23-100). At 3 months, this score decreased to mean 22 (median 15, range 0-66) and mean 15 (median 17, range 0-34) at final follow-up. At final follow-up of mean 37 months (median 35, range 29-64 months), 22 of 29 (76 %) patients were asymptomatic. Of these 22 women, 3 underwent a second UAE at 6, 7, and 14 months. The remaining seven patients clinically improved but still had symptoms; one underwent a hysterectomy. There was no difference in outcome between women with pure adenomyosis and women with additional fibroids. The junction zone of 4 women with additional therapy was significantly thicker compared with the remaining 25 patients. CONCLUSIONS: In women with therapy resistant adenomyosis, UAE using polyzene F-coated hydrogel microspheres resulted in 3 years preservation of the uterus in 28 of 29 (97 %) with good clinical outcome in the vast majority of patients. Initial thickness of the junction zone is related to additional therapy.

Opposite hemispheric activations as a result of emotionally threatening and non-threatening words.

Twenty right-handed males participated in a tachistoscopic unilateral letter recognition task with three conditions. In the control condition, each trial consisted of three consonants that were flashed horizontally to the left or to the right visual field. In the threat and non-threat conditions, each lateral three-letter presentation was preceded by an emotionally threatening or non-threatening word presented in central fixation. Across conditions, subjects identified more letters correctly in the right visual field than in the left visual field. The concurrent presentation of threatening words resulted in a selective enhancement of left visual-field performances. The concurrent presentation of non-threatening words resulted in a selective right visual-field enhancement. Our conclusion is that threatening stimuli prime the right hemisphere and can alter predicted laterality patterns.

Protective effect of superoxide dismutase and polyethylene glycol-linked superoxide dismutase against renal warm ischemia/reperfusion injury.

The protective effect of oxygen free radical scavenger superoxide dismutase (SOD) against the warm ischemic damage that occurs in kidneys harvested from non-heart-beating donors is controversial because of its short half-life. In this model, we compared the protective effect of SOD and two longer lasting polyethylene glycol (PEG)-linked forms of SOD in a model of renal ischemia induced by 60 min of arterial clamping in rats. Rats treated with PEG1-SOD and PEG2-SOD had a better renal function than controls, with significantly lower serum creatinine levels throughout the follow-up period and a significantly higher creatinine clearance on postoperative days 1, 2, and 4. In native SOD treated-rats, serum creatinine was lower than in controls, though not significantly so, and creatinine clearance was significantly higher on postoperative day 4. Our results indicate that the protective effect of SOD against renal warm ischemia can be enhanced by prolonging its half-life by binding the enzyme to PEG.

The varying evolution of Friedreich's ataxia cardiomyopathy.

During a mean follow-up period of 8 years, 17% of 66 patients with Friedreich's ataxia developed hypokinetic-dilated cardiomyopathy; most patients originally had a hypertrophic left ventricle. The presence of pathologic Q waves identifies a subgroup of patients with wall motion abnormalities; these patients are more likely to develop a hypokinetic left ventricle, and the prognosis is ostensibly poorer.

Prevalence and prognostic significance of right-sided cardiac mobile thrombi in acute massive pulmonary embolism.

The prevalence of right-sided cardiac mobile thrombi, "in transit" from the systemic venous system, was 18% in a series of 130 patients with massive pulmonary embolism referred to early echocardiography and receiving thrombolytic drugs (56%) or intravenous heparin (40%). The mortality rate was lower than previously reported and seemed to be related more to clinical and hemodynamic impairment than to presence of thromboembolus.

The spectrum of pulmonary embolism. Clinicopathologic correlations.

Pulmonary embolism (PE) is still underdiagnosed even in hospitalized patients. In our recent experience, out of 92 postmortem cases of massive or submassive PE, only 28% were diagnosed before death, whereas the false-positives accounted only for 3% of cases. Similar conclusions have been drawn from large-scale autopsy studies performed in Norway and in the United States. The most important causes of an incorrect diagnosis are failure to suspect PE, and the protean nature of the disease. Remarkable differences actually exist concerning the point of origin and the final localization, as well as the size and age of thromboemboli, the presence or absence of pulmonary infarction, and the underlying pathology. Often a fatal embolus is relatively small but hardly tolerated because of the underlying cardiopulmonary situation. Attention should be called to the frequent autopsy finding of multiple PEs and pulmonary infarctions of apparently different age. This finding is important since it indicates that these patients suffered successive embolizations and the eventual death might have been prevented if an early diagnosis had been made.

Modulation of pulmonary arterial input impedance during transition from inspiration to expiration.

We investigated whether respiration influences pulmonary arterial input impedance during transition from inspiration to expiration in five anesthetized, spontaneously breathing dogs. Impedance (Z) was separately assessed for heart beats occurring in inspiration, in expiration, and during the transition from inspiration to expiration (transitional beat). Transitional beats were scored by the ratio between the fraction of beat falling in expiration and the total beat duration [expiratory fraction (Efr)] to quantify their position within the transition. In transitional beats, input resistance linearly increased with Efr; Z modulus at the heart-rate frequency (fHR) decreased up to -50% for Efr = 50%. Z phase at fHR was greater than in inspiration for Efr <40% and lower for Efr >50%. Unlike blood flow velocity, mean value and first harmonic of pulmonary arterial pressure were correlated to Efr and paralleled the changes of input resistance and Z at fHR. This indicates that respiration influences Z through modifications in arterial pressure. The evidence of important respiratory influences on Z function may help the pathophysiological interpretation of dysfunctions of the right heart pumping action, such as the so-called cor pulmonale.

Factors influencing the clinical diagnosis of pulmonary embolism: analysis of 229 postmortem cases.

Although appreciable advances have been made in understanding epidemiology, diagnosis and treatment, acute pulmonary embolism (PE) is still largely undetected and untreated. The aim of our study was to ascertain whether the rate of correct clinical diagnosis of acute PE has changed in recent years (from 1989 to 1995) and, possibly, to identify factors that might contribute to the underdiagnosis of the disease.

N-hydroxysuccinimide carbonates and carbamates are useful reactive reagents for coupling ligands to lysines on proteins.

Ligands containing amino or hydroxyl groups were converted to their corresponding activated N-hydroxysuccinimidyl carbamate and carbonate by reaction with disuccinimidyl carbonate (DSC). The latter reagents can be used for the group-specific modification of primary amines as an alternative to the widespread usage of N-hydroxysuccinimide esters. Biotin and 2,4-dinitrophenyl (DNP) derivatives were used as examples to demonstrate the approach. Biotin and DNP were each extended by attaching two different spacer arms, carrying either a hydroxyl group or a primary amine as terminal functions. The latter were then activated via their conversion to N-hydroxysuccinimide carbonates and carbamates, respectively. The usefulness of these reagents for protein modification was investigated. The modified proteins obtained exhibited similar stability and activity characteristics compared to those modified with active N-hydroxysuccinimdyl esters. The activation of hydroxy- or amino-terminating compounds with DSC represents a general method that can be applied to any ligand which contains these functional groups for its covalent coupling to amines.

Role of echo/Doppler in the diagnosis of pulmonary embolism.

Echocardiography supplemented with pulsed and continuous wave Doppler facilities is a potent diagnostic tool in many cardiovascular disorders. Its potential role in the management of patients with suspected pulmonary embolism, though less extensively studied, deserves attention. Benefits of echo/Doppler in these patients are as follows: (1) Echo/Doppler is a noninvasive, relatively inexpensive technique, readily available and repeatable in critically ill patients at the bedside. (2) Echo/Doppler provides a number of independent parameters related to the pulmonary hemodynamics. These parameters include: (a) characteristics of blood flow velocity curves across the right heart valves as well as systolic and diastolic time intervals of the right ventricle (b) motion pattern of the interventricular septum (c) dimensions of the heart chambers and inferior vena cava (d) thickness of the right ventricular free wall (3) Echocardiography allows detection of thrombi within right heart chambers or in major branches of the pulmonary artery in some patients. (4) Echo/Doppler may disclose alternative abnormalities explaining symptoms found in a patient with suspected pulmonary embolism such as pericardial disease, myocardial infarction, aortic dissection, hypovolemic shock, etc.

Recording eye movements in mice: a new approach to investigate the molecular basis of cerebellar control of motor learning and motor timing.

The vestibulocerebellum is involved in the control of compensatory eye movements. To investigate its role in learning and timing of motor behavior, we investigated compensatory eye movements in mice with the use of search coils. Wild-type mice showed the ability to increase the gain of their vestibulo-ocular reflex by visuovestibular training. This adaptation did not occur in lurcher mice, a natural mouse mutant that completely lacks Purkinje cells. During the optokinetic reflex the phase of the eye movements of lurcher mice in reference to the stimulus lagged behind that of wild-type littermates, whereas during the vestibulo-ocular reflex it led that of the wild-type mice. During combined optokinetic and vestibular stimulation, the phase of the lurcher mice lagged behind that of the wild-type mice at the low stimulus frequencies, whereas it led the phase of the wild-type mice at the high frequencies. In addition, the optokinetic response of the lurcher mice showed a significantly longer latency during constant-velocity step stimulation than that of the wild-type mice. We conclude that Purkinje cells are necessary for both learning and timing of compensatory eye movements in mice. The present description of gain adaptation and phase dynamics provides the basis for studies in which the molecular mechanisms of cerebellar control of compensatory eye movements are investigated with the use of genetically manipulated mice.

Can pulmonary artery pressure be predicted without right heart catheterization in chronic obstructive lung disease?

We have investigated the dependance of observed pulmonary artery mean pressure (PAP) on body surface, age, PaO2, pH, PaCO2, hematocrit, and spirometric data (VC, FEV1/VC, RV/TLC) in 70 patients with chronic obstructive lung disease (COLD). After elimination of all variables that failed to correlate with PAP, multifactorial analysis showed that only two of nine independent variables, namely PaO2 and body surface, correlated significantly with PAP. According to our calculations, 28.9% of total PAP is predictable by PaO2, 1.5% by H+ concentration, 2.8% by RV/TLC, and 2.5% by body surface. Fully 64.2% of total variability was not accounted for by our regression analysis; thus the error of predicted PAP was so great (+/- 17 mm Hg for P = 0.05) as to invalidate the method. We also recalculated our subjects' PAP values by applying Enson's and Grassi's equations to our own lung function and biochemical data, and compared the predicted PAP values thus obtained with those measured directly in our subjects. Both equations proved imprecise and/or inaccurate in the individual case. From this we conclude that whereas available equations may be suitable for predicting the mean PAP value of a large population sample, the same equations cannot give a reliable prediction in individual cases.

Covalent modification of mushroom tyrosinase with different amphiphic polymers for pharmaceutical and biocatalysis applications.

Two different poly(ethylene glycol) derivatives (linear, mol wt 5000 and a branched form, mol wt 10000) and a new polymer (poly-[acryloylmorfoline], mol wt 5500) were covalently bound to the enzyme tyrosinase. The polymer-protein conjugates were studied with a view to their potential pharmaceutical application and to their use for the bioconversion of phenolic substrates in organic solvents. Vmax and Km for the dopa-dopaquinone conversion, thermostability, stability toward inactivation by dopa oxidation products, half-life in blood circulation, and behavior in organic solvents for the different adducts were investigated. Arrhenius plots for the dopa-dopaquinone conversion were also obtained in order to study the effects of temperature on the different enzyme forms. Covalent attachment of the polymers increased enzyme stability in aqueous solution and the solubility in organic solvents. However, organic solvent solubilization brought about loss of enzyme conformation as assessed by CD measurements, which is accompanied by a nonreversible loss of catalytic activity.

[Contribution of the mechanocardiography to the study of obstructive chronic bronchopneumopathy]. / L'apporto della meccanocardiografia allo studio delle broncopneumopatie croniche ostruttive

Kinetocardiography, ECG and radiography, were compared as ways of obtaining early diagnosis of chronic cor pulmonale in two series of patients (81 in all) with chronic obstructive bronchopneumopathy. Kinetocardiography proved markedly superior in this respect. It revealed right ventricular pressure overload in a higher percentage of cases and at an earlier stage, i.e. when PAP values were little above normal resting values, of even when their increase appeared only during physical effort.

Bioconjugation in pharmaceutical chemistry.

Polymer conjugation is of increasing interest in pharmaceutical chemistry for delivering drugs of simple structure or complex compounds such peptides, enzymes and oligonucleotides. For long time drugs, mainly with antitumoral activity, have been coupled to natural or synthetic polymers with the purpose of increasing their blood permanence time, taking advantage of the increased mass that reduces kidney ultrafiltration. However only recently complex constructs were devised that exploit the 'enhanced permeability and retention' (EPR) effect for an efficient tumor targeting, the high molecular weight for adsorption or receptor mediated endocytosis and finally a lysosomotropic targeting, taking advantage of acid labile bonds or cathepsin susceptible polypeptide spacers between polymer and drug. New original, very active conjugates of this type, as those based on poly(hydroxyacrylate) polymers, are already in advanced state of development. Labile oligonucleotides, including antisense drugs, were also successfully coupled to polymers in view of an increased cell penetration and stabilization towards nucleases. However, the most active research activity resides in the field of polypeptides and proteins delivery, mainly for the two following reasons: first of all because a great number of therapeutically interesting compounds are now being produced by genetic engineering in large quantity and, secondly, because these products are difficult to administer to patients for several inherent drawbacks. Proteins are in fact easily digested by many endo- and exo-peptidases present in blood or in other body districts; most of them are immunogenic to some extent and, finally, they are rapidly excreted by kidney ultrafiltration. Covalent polymer conjugation at protein surface was demonstrated to reduce or eliminate these problems, since the bound polymer behaves like a shield hindering the approach of proteolytic enzymes, antibodies, or antigen processing cell. Furthermore, the increase of the molecular weight of the conjugate allows to overcome the kidney elimination threshold. Many successful results were already obtained in peptides and proteins, conjugated mainly to water soluble or amphiphilic polymers like poly(ethylene glycol) (PEG), dextrans, or styrenemaleic acid anhydride. Among the most successful are the conjugates of asparaginase, interleukin-2 or -6 and neocarcinostatin, to remind some antitumor agents, adenosine deaminase employed in a genetic desease treatment, superoxide dismutase as scavenger of toxic radicals, hemoglobin as oxygen carrier and urokinase and streptokinase as proteins with antithrombotic activity. In pharmaceutical chemistry the conjugation with polymers is also of great importance for synthetic applications since many enzymes without loss of catalytic activity become soluble in organic solvents where many drug precursors are. The various and often difficult chemical problems encountered in conjugation of so many different products prompted the development of many synthetic procedures, all characterized by high specificity and mild condition of reaction, now known as 'bioconjugation chemistry'. Bioconjugation developed also the design of new tailor-made polymers with the wanted molecular weight, shape, structure and with the functional groups needed for coupling at the wanted positions in the chain.

[Cardiologic aspects of Friedreich type heredoataxia]. / Aspects cardiologiques de l'hérédoataxie du type Friedreich.

The authors performed ambulatory electro-vectorcardiography polycardiography and echocardiography in 18 patients with typical Friedreich's disease, and 6 patients with atypical forms of hereditary spino-cerebellar ataxia classified on e basis of the degree of neurological involvement, without clinical signs of cardiocirculatory failure. The ECG and VCG recording commonly showed appearances suggestive of myocardial "necrosis" and were of little value in the differential diagnosis between typical and atypical forms of Friedreich's ataxia. This limitation also applied to the kinetocardiogramme which was sometimes pathological confirming the echocardiographic diagnosis of symmetric LV hypertrophy and of septal hypokinesia despite normal ECG and VCG. The systolic time intervals and echocardiographic parameters of the interventricular septum were more helpful in the differential diagnosis. Hypertrophic cardiomyopathy, usually symmetric, was observed in about 70 p. 100 of typical and only rarely in atypical forms of Friedreich's disease. The symmetric or asymmetric hypertrophy was associated with reduced left ventricular performance in less than 20 p. 100 of typical Friedreich's disease, systolic anterior motion of the mitral valve and other signs of dynamic left ventricular outflow tract obstruction were not observed in any of these patients. The correlations between the degree of neurological disability and the cardiac abnormalities, were, in general, disappointing compared with other reported series. The cardiac investigation of patients with Friedreich's disease remains valuable from the point of view of recent pathological hypotheses of a metabolic abnormality with eventual therapeutic implications.

[Electromechanical dissociation in myocardial infarction. Anatomical-clincal study of 82 cases]. / Dissociazione elettromeccanica nell'infarto miocardico. Studio anatomo-clinico di 82 casi.

UNLABELLED: In our experience electromechanical dissociation (EMD) is the most common mechanism of fatal cardiac arrest in patients with acute myocardial infarction (AMI). METHODS: We reviewed retrospectively 82 autopsy cases of AMI in whom the medical record documented EMD as terminal cardiac arrest in order to outline the clinical and pathologic features of different subgroups: 26 cases with external cardiac rupture (CR) were compared with 56 cases without CR. In turn, inside the latter series, 16 cases of sudden EMD were compared with 40 cases of EMD occurring in the terminal phase of cardiac shock. RESULTS: In comparison with those without CR, patients with CR showed at multiple regression analysis less evidence of left ventricular failure (p < 0.05); less extended infarct areas (p < 0.01); more frequent sudden EMD (p < 0.05). Most patients with CR had massive pericardial effusion; cardiac rhythm at the onset of EMD was seldom slow in those cases. In the group without CR no discriminant characteristics were found in cases of sudden EMD vs cases preceded by cardiac shock. CONCLUSIONS: In case of CR EMD occurs in less extensively damaged hearts and is generally sudden; in AMI without CR EMD may affect patients with severe depression of pump performance, but not necessarily in shock. EMD after an AMI may result from several factors: cardiac tamponade is prevalent in the presence of CR; in cases without CR our data don't permit to conjecture a distinct pathogenesis for sudden EMD in comparison with cases preceded by shock.