Pharmacotherapy of ventricular fibrillation. A prospective study in an emergency medical service

This prospective study investigated the effects of standard pharmacotherapy in out-of-hospital ventricular fibrillation (VF) after i.v. or endobronchial (e.b.) administration of epinephrine and lidocaine. METHODS. Only patients presenting with out-of-hospital VF were included in this study, whereby VF of noncardiac origin was excluded. Cardiopulmonary resuscitation (CPR) was performed according to the guidelines of the American Heart Association. Basic life support was initiated by Emergency Medical Service (EMS) technicians. The first step of advanced life support was immediate defibrillation by the EMS physician. Epinephrine was given in doses of 2.5 mg e.b. or 1.0 mg i.v. If indicated, patients received 200-500 mg lidocaine e.b. or 100 mg i.v. The course of CPR was tape-recorded and 2-3 blood samples were taken from each patient for drug monitoring. Plasma levels of epinephrine and lidocaine were measured by high-pressure liquid and gas chromatography, respectively, and then correlated to the course of CPR. RESULTS. Forty-seven patients presented VF on arrival of the EMS physician. Restoration of spontaneous circulation was achieved in 64% (Table 3), and 30% of the patients were discharged from hospital without major neurologic deficits. Immediate defibrillation before initiation of pharmacotherapy produced a success rate of 15.8%, whereas defibrillation after drug therapy was successful in 61.5% of cases. Following e.b. instillation of 2.5 mg epinephrine (Fig. 1), median peak concentrations of epinephrine (40.2, range 4.0-79.8 ng/ml) were reached after 3-4 min and plasma levels greater than or equal to 10 ng/ml were seen for 20 min. After i.v. injection of 1.0 mg epinephrine (Fig. 2) maximum concentrations (71.6, range 4.7-104.2 ng/ml) were measured after 1-2 min and plasma levels decreased below 10 ng/ml after 10 min. Following e.b. instillation of 400-500 mg lidocaine mean lidocaine concentrations within the therapeutic range (2-5 micrograms/ml) were reached after 4-5 min and remained within these limits for 20-30 min. Peak concentrations were obtained after 12 min. Doses of 200-320 mg lidocaine e.b. failed to achieve therapeutic plasma levels (Fig. 3). Regarding the pharmacodynamic aspects of drug therapy, 22.5% of the initial survivors were resuscitated from VF without therapeutic epinephrine, presenting with mean endogenous epinephrine concentrations of 7.1 ng/ml, 51.6% of patients were resuscitated after epinephrine therapy with plasma concentrations greater than 20 ng/ml. In only 1 case could a relationship be demonstrated between the administration of lidocaine and resuscitation success. CONCLUSION. In CPR, the e.b. administration of epinephrine and lidocaine is a reliable alternative to the i.v. injection route of these drugs. Recommended doses are 2.5 mg for epinephrine and 400-500 mg for lidocaine. Resuscitation from VF requires immediate epinephrine therapy if initial defibrillation is not successful. Lidocaine has no effect on resuscitation from VF and therefore should be used specifically for antiarrhythmic therapy after restoration of spontaneous circulation.     

In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.     

SPEECH EVALUATION WITH AND WITHOUT PALATAL OBTURATOR IN PATIENTS SUBMITTED TO MAXILLECTOMY

Most patients who have undergone resection of the maxillae due to benign or malignant tumors in the palatomaxillary region present with speech and swallowing disorders. Coupling of the oral and nasal cavities increases nasal resonance, resulting in hypernasality and unintelligible speech. Prosthodontic rehabilitation of maxillary resections with effective separation of the oral and nasal cavities can improve speech and esthetics, and assist the psychosocial adjustment of the patient as well. The objective of this study was to evaluate the efficacy of the palatal obturator prosthesis on speech intelligibility and resonance of 23 patients with age ranging from 18 to 83 years (Mean = 49.5 years), who had undergone inframedial-structural maxillectomy. The patients were requested to count from 1 to 20, to repeat 21 words and to spontaneously speak for 15 seconds, once with and again without the prosthesis, for tape recording purposes. The resonance and speech intelligibility were judged by 5 speech language pathologists from the tape recordings samples. The results have shown that the majority of patients (82.6%) significantly improved their speech intelligibility, and 16 patients (69.9%) exhibited a significant hypernasality reduction with the obturator in place. The results of this study indicated that maxillary obturator prosthesis was efficient to improve the speech intelligibility and resonance in patients who had undergone maxillectomy.     

Functional Anatomy of Visuomotor Skill Learning in Human Subjects Examined with Positron Emission Tomography

The present study was designed to examine patterns of regional cerebral blood flow (CBF) associated with the learning of a repeated visuomotor sequence both in the early and late phases of the acquisition process. In addition, changes in blood flow related to the implicit versus explicit aspects of learning such a skill were investigated. Fourteen normal control subjects were scanned while performing the task (i) in both early and advanced learning stages of the visuomotor sequence; (ii) after having acquired explicit knowledge of the sequences; and (iii) in two control conditions (perceptual and random sequence). Subtraction of the random condition from the highly learned condition revealed specific areas of activity in the right ventral striatum and dentate nucleus of the cerebellum. Blood flow changes in the right hemisphere were also seen in the medial posterior parietal and prestriate regions, as well as in the anterior cingulate cortex. Finally, once the subjects had acquired explicit knowledge of the embedded sequence that was presented in the highly learned condition, increased CBF activity was observed only in the mid-ventrolateral frontal area in the right hemisphere. These findings confirm that both the striatum and the cerebellum are involved in the implicit acquisition of a visuomotor skill, especially in the advanced stages of the learning process, and furthermore that the ventrolateral prefrontal cortex contributes preferentially to the declarative aspect of this task.     

Systemic amyloidosis: diagnosis before treatment.

Familial amyloidotic polyneuropathy is a systemic amyloidosis with a dismal prognosis for which a surgical treatment exists. Awareness of the clinical characteristics of the disease is critical for early genetic diagnosis and timely referral for liver transplantation. In this report we describe the history of a 49-year-old man in whom non-AA amyloidotic infiltration of the heart and the intestinal tract was diagnosed. Initially, inappropriate identification of the etiology of the disease led to maltreatment.     

Antiinflammatory effects of second-generation leukotriene B4 receptor antagonist,SC-53228: Impact upon Leukotriene B4- and 12(R)-HETE- mediated events

Leukotriene B₄ (LTB₄) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB₄ and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 {7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid}, a first-generation LTB₄ receptor antagonist, inhibited the chemotactic actions of LTB₄ when given orally with an ED₅₀ value of 1.7 mg/kg. The second-generation LTB₄ receptor antagonist, SC-53228 [(+)-(S)-7-(3-{2-(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy} propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid], inhibited LTB₄-induced chemotaxis when given intragastrically with an ED₅₀ value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12(R)-HETE-induced granulocyte chemotaxis with an oral ED₅₀ value of 5.8 mg/kg. When dosed orally over a range of 0.03–100 mg/kg, SC-53228 gaveC _max plasma concentrations of 0.015–41.1g/ml. SC-53228 inhibited LTB₄-primed membrane depolarization of human neutrophils with an IC₅₀ value of 34 nM. As a potent LTB₄ receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB₄ and/or 12(R)-HETE are implicated as inflammatory mediators.     

Lutzomyia longipalpis salivary gland homogenate impairs cytokine production and costimulatory molecule expression on human monocytes and dendritic cells

In this report, we describe an investigation of the effects of Lutzomyia longipalpis sand fly salivary gland homogenates (SGH) on cytokine production and expression of costimulatory molecules on human monocytes, macrophages (Ms), and dendritic cells (DCs). SGH of L. longipalpis induced an increase in interleukin-6 (IL-6), IL-8 and IL-12p40 production but a decrease in tumor necrosis factor alpha and IL-10 production by lipopolysaccharida (LPS)-stimulated monocytes. We also examined the expression of costimulatory molecules on the surface of monocytes, Ms, and DCs. Whereas SGH affected the expression of these molecules on monocytes and Ms, it had little effect on these molecules on DCs. However, when DCs were generated from human monocytes in the presence of SGH, SGH inhibited the expression of costimulatory molecules. In addition, a decrease in the maturation of DCs induced by CD40L was observed in the presence of SGH. Finally, preincubating SGH with human sera containing anti-SGH-specific antibodies abolished the effects of SGH on cytokine production by LPS-stimulated monocytes.