[Synthesis of functionalized cyanines. Fluorescence properties following complexation of cations]. / Synthèse de cyanines fonctionnalisées. Etude de leurs propriétés de fluorescence en fonction de la complexation de cations.

The ionophoric properties of podands containing dioxazaphosphocane moieties linked by inactive spacers were studied. To increase the detection sensibility of these compounds we introduced a cyanine as spacer. Fluorescence analysis demonstrated the interest of cyanines as active spacers since the complexation by cations as Ca2+ and Mg2+ gives an enhancement of the emission intensity.

Contribution of dithiol ligands to in vitro and in vivo trypanocidal activities of dithiaarsanes and investigation of ligand exchange in an aqueous solution.

Twelve new dithiaarsanes were evaluated for their in vitro and in vivo trypanocidal properties in regard to their three parent molecules, 4-amino-phenylarsenoxide, melarsenoxide, and 4-dansylamino-phenylarsenoxide. The most potent dithiaarsane, compound 2b, had a minimum effective concentration of 1.5 nM after 48 h of incubation and at a dose of 0.39 micromol/kg of body weight (0.2 mg/kg) administered subcutaneously cured 100% of mice acutely infected with Trypanosoma brucei brucei CMP. With this model, the chemotherapeutic index of compound 2b was 512, compared to 256 for melarsamine dihydrochloride (Cymelarsan) under the same conditions. With a chronic infection produced by T. brucei brucei GVR, compound 2b cured 100% of mice after treatment at a dose of 25 micromol/kg (12.5 mg/kg) for 4 consecutive days, whereas melarsamine dihydrochloride and potassium melarsonyl (Trimelarsan) cured less than 50% mice at this dose. For both acute and late-stage infections, dithiaarsanes having a melaminophenyl ring exhibited the most-potent trypanocidal activity. Compound 2b is thus one of the most active organoarsenicals described in a mouse trypanosomiasis model. Considering that the main intracellular targets of organoarsenicals are thiol groups, we studied the possibility of ligand exchange between Cymelarsan and several dithiols. In aqueous solution, we observed a rapid exchange of cysteamine from melarsamine with free cysteamine and also with various dithiols always in favor of more stable cyclic derivatives. These ligand exchanges suggest the ability of trivalent organoarsenicals to react with targets such as trypanothione and dihydrolipoic acid. Among several ligands, a 1,3-dimercaptopropane moiety appeared the most suitable for trypanocidal activity.

Synthesis and in vitro anthelmintic properties of some new dithiaarsanes.

Fifteen new trivalent organoarsenicals were synthesized and evaluated for anthelmintic properties on three in vitro models, infective larvae of the filaria Molinema dessetae, infective larvae of an intestinal nematode, Nippostrongylus brasiliensis and adults and larvae of Rhabditis pseudoelongata a free living nematode. On the M. dessetae model, the most active compound after a 24 h incubation period had an EC50 of 0.02 mumol/l (compound 3a). Twelve compounds had an EC50 lower than 1 mumol/l whereas potassium melarsonyl exhibited an EC50 of 45.6 mumol/l. After 7 days incubation time, compound 1d had an EC50 of 2 nmol/l. On the N. brasiliensis model, compound 1d was also the most efficient after a 4 day incubation period (EC50 of 1 mumol/l). This compound was 100 times more active than potassium melarsonyl used as a reference compound. Nevertheless, no compound had an EC50 less than 100 mumol/l on Rhabditis pseudoelongata. Concerning the effect of dithiol ligands on the anthelmintic activity of these trivalent organoarsenicals on M. dessetae and N. brasiliensis, 2,2'-dimercaptodiethyloxide was more efficient as dithiol ligand than 1,3-dimercaptopropane which was more efficient than 1,2-dimercaptoethane. Moreover, the para-amino haptophore was more efficient than the melaminyl haptophore. These results showed that the use of new dithiol ligands for trivalent arsenicals enhanced greatly the anthelmintic activity compared with potassium melarsonyl.

Musculoskeletal pain in cardiac ultrasonographers: results of a random survey.

Myalgias and arthralgias are common among workers whose jobs require repetitive isometric maneuvers or malalignment of body position. However, few systematic studies have been performed to evaluate the frequency of these complaints among cardiac ultrasonographers. Therefore the purpose of this study was to determine the prevalence of musculoskeletal pain (MSP) among ultrasonographers and to identify risk factors related to their occurrence. Two hundred twenty ultrasonographers randomly chosen from a list of more than 1600 active members of the American Society of Echocardiography were mailed surveys consisting of 22 questions. Included were questions regarding height, age, years of experience, frequency and type of physical exercise, and job-related parameters such as a number of scans per day, scanning from right or left side of bed, number of hours, bed type, type of equipment, and manual or self-propelled machines. Respondents were asked whether they had had back, neck, or shoulder pain related to their profession and to describe treatment rendered and its effectiveness. One hundred thirteen (51%) of 220 ultrasonographers responded to the survey. Ninety (80%) of 113 respondents reported new pain that was not present before they began scanning, with 42 of this group (46%) requiring either physiotherapy (n = 17) or medication (n = 23). Treatment was believed to be helpful in 63% of cases. Factors found to have a positive relationship to MSP included ultrasonographer height less than 63 inches, performing 100 or more scans per month, average scan time of 25 minutes or more per patient, and use of manually propelled machines (each p < 0.05). Factors found to have no relationship to MSP included age, type of equipment, right or left scan position, physical conditioning, bed type, and time between patients. Musculoskeletal pain is prevalent among cardiac ultrasonographers, and may have specific work-related factors for its occurrence.

Synthesis of catecholamide spiroarsoranes and their in vitro anthelmintic properties against Molinema dessetae and Nippostrongylus brasiliensis infective larvae.

Catecholamide spiroarsoranes were synthesized and evaluated for anthelmintic properties on two in vitro models, infective larvae of the filaria Molinema dessetae and infective larvae of an intestinal nematode. Nippostrongylus brasiliensis. On the N dessetae model, the most active compound after 24 h incubation time had an EC50 of 0.1 mumol/l. Eleven compounds had EC50 's in a range from 2 to 200 mumol/l. After 7 days incubation time, the two most active compounds had EC50 's of 0.03 and 0.07 mumol/l, respectively. On the N brasiliensis model, only three compounds were slightly active after 4 days incubation time. The ligands used for the spiroarsoranes synthesis were also evaluated for anthelmintic activity in order to know the contribution of these structures in the spiroarsoranes activity. Spiroarsoranes as prodrugs of arsonic acids were very active on the filaria, nematode having predominantly transcuticular uptake of nutrients while the activity on the intestinal nematode having both the types, transcuticular and intestinal uptake was low. The high sensitivity of filarial infective larvae is probably in relation to their location in the mosquito whereas N. brasiliensis infective larvae are telluric and should be more unsensitive to survive in a variable environment.

The effect of spiroarsoranes on Trypanosoma brucei brucei and T. b. rhodesiense.

Topical application and intraperitoneal administration of spiroarsoranes were carried out to cure central nervous system (CNS) trypanosomiasis in the chronic Trypanosoma brucei GVR 35 mouse model. Topical application appeared more efficient than intraperitoneal injection. The periods of aparasitaemia after treatment were longer but none of the mice was permanently cured. Combination treatment with eflornithine (DFMO) and the spiroarsoranes failed to show any synergistic effect. In addition, spiroarsorane I was evaluated against the T. b. rhodesiense KETRI 2634 strain, whereby 60-mg/kg treatment produced a noticeable prolongation of the life span of trypanosome-positive animals. These in vivo results suggests that the spiroarsoranes have difficulty in crossing the blood-brain barrier (BBB) and clearing the parasites from the CNS or, alternatively, that these strains are less sensitive to pentavalent arsenicals than the T. b. brucei CMP fast strain, which in the present study was more sensitive to spiroarsoranes whose lipophilicity corresponded to a log-P value ranging from 2.5 to 3.7.

Selection of appropriate support surfaces.

Many claims are made regarding the appropriate selection of support surfaces. ET nurses do not need to "reinvent the wheel" when they decide which system is best for their patients, but they do need to be aware of the most current scientific and expert recommendations. The WOCN and the Agency for Health Care Policy and Research have published guidelines that list concrete suggestions about the prediction and prevention of pressure ulcers in adults. I developed an algorithm that incorporates the two groups' recommendations and the most recent scientific research. This algorithm can be used in multiple nursing settings.

Design, synthesis and biological study of new antiparasitic spiroarsoranes.

Thirty-eight new spiroarsoranes were synthesized after structure-activity relationship studies from the first series. These compounds were predicted to cross more easily the membrane of protozoae or the cuticle of Nematodes and to reach their biological target with efficiency. The spiroarsoranes were evaluated for their antiparasitic properties, on helminths and protozoa models in regard of their parent arsonic acids. The following parasite models were used: Entamoeba histolytica and Trichomonas vaginalis in vitro; Molinema dessetae infective larvae in vitro, adults and microfilariae in vivo; Nippostrongylus brasiliensis infective larvae in vitro. The results obtained on these models indicated that the "spiranization" of arsonic acids produced new compounds with a biological activity 10-fold superior to those of arsonic acids. Nevertheless, each parasite had its own sensitivity to spiroarsoranes. Moreover, in vivo results showed that the lipophilicity of the molecules should be optimal to avoid high toxicity in host such as arsenical encephalopathy.

Spiroarsoranes of second generation: evaluation of trypanocidal properties against Trypanosoma brucei brucei.

The spiroarsoranes are a series of pentavalent arsenicals having interesting trypanocidal properties. They are less toxic than trivalent arsenicals but their activity appear at higher doses and concentrations. The structure-activity relationships study from the first series led to a new generation of spiroarsoranes which has been synthesized and evaluated in vitro and in vivo against Trypanosoma brucei brucei bloodstream forms. Among 40 compounds, 5 were active in vitro at concentrations less than 10 mumol/l and 7 were active in vivo. The most interesting compound of this series (compound I e 2) showed an in vitro activity at 125 mumol/l after 24 hours incubation time and in vivo all the mice were cured after a subcutaneous treatment at 600 mumol/kg in one single dose. The spiranization and the substitution of para-arsanilic acid allowed to obtain a better mean survival time at 300 mumol/kg comparatively to para-arsanilic acid itself used as reference compound. Nevertheless, this second generation of compounds was less active than the selected compound of the first series which was efficient at 150 mumol/kg in subcutaneously one single dose.

[Plasma kinetics of a spiroarsorane trypanocidal agent in sheep trypanosomiasis]. / Cinétique plasmatique d'un spiroarsorane trypanocide chez le mouton parasité.

In a previous study, spiroarsoranes were very effective against both the two pathogenic phases of the experimental sheep trypanosomiasis. In this paper, the authors had studied the plasmatic pharmacokinetics of these compounds. Data had shown one peak 10 min after injection of a 3 months inoculated sheep, and 90 min for the control sheep. Spiroarsorane had a good diffusion into the central nervous system, but the trypanocidal activity, during the second phase of the disease, was effective only after repeated treatment. The spiroarsorane low toxicity could allow its direction against nervous trypanosomiasis.

Pharmacokinetics of two spiroarsoranes administered intravenously or orally to rabbits.

The pharmacokinetics of two spiroarsorane molecules (1,2) were investigated after both intravenous bolus and an oral administration in rabbits. After iv administration of a 15-mg/kg dose, for the two substances, the plasma concentration-time curves were well described by an open two-compartmental model. The half-lives of the first phase were 0.47 +/- 0.12 and 0.27 +/- 0.02 h for 1 and 2, respectively. The half-lives of the terminal phase were of the same order of magnitude for the two substances: 4.38 +/- 0.24 and 6.03 +/- 1.14 h, respectively. Total plasma clearances were 2.47 +/- 0.44 and 0.81 +/- 0.04 L/h, respectively, and the steady-state volume of distribution of 2 (14.99 +/- 2.57 L) was larger than that of 1 (4.27 +/- 0.28 L). After oral administration, spiroarsorane 2 was not absorbed. The availability of the suspension of 1 was 18%. The rate of the absorption phase of 1 showed a saturation process, probably due to the solubility of the molecule. When increasing oral doses of 1 (15, 30, and 60 mg/kg) were administered, the plasma concentrations did not increase to the same extent.

Trypanocidal activity of a new series of arsenical compounds the spiroarsorans.

The trypanocidal activity of a new class of arsenical compounds, the spiroarsorans, was investigated against Trypanosoma brucei brucei. The most active compound was found to be effective at a dose of 30 mg.kg-1 and had low toxicity.

[A new series of antiparasitic organic arsenicals: the spiroarsoranes. Experimental trypanocidal activity]. / Une nouvelle série d'organoarséniés antiparasitaires: les spiroarsoranes. Activité trypanocide expérimentale.

Arsenical compounds are the main therapeutic way, effective in the neurological phase of trypanosomiasis. Unfortunately, their important toxicity prevents their easy administration. Structural cyclization of arsonic acid derivatives has led to a class of non-toxic compounds: spiroarsoranes. A 47 compound primary screening on an in vivo murine model of Trypanosoma brucei brucei resulted in the isolation of a very effective derivative after a single subcutaneous injection of 30 mg.kg-1 body weight (Chemotherapeutic Index = 21). In this study, trypanocidal activity of this compound was evaluated on an in vivo sheep model of trypanosomiasis by T. brucei brucei, according to experimental model of the Institute of Neurological Epidemiology and Tropical Neurology of Limoges (France). A single subcutaneous injection of 30 and 100 mg.kg-1 b.w., and 30 and 60 mg.kg-1 b.w. was given respectively during first and second phase of trypanosomiasis. Ovine pharmacokinetics of this compound will be evaluated in a further study.

Day hospital treatment of borderline patients: a clinical perspective.

The authors suggest that day hospitalization can provide a useful therapeutic framework for patients with borderline personality organization without creating the ego regression often seen in such patients during 24-hour hospitalization. The lack of room and board facilities and of contact with patients who need 24-hour hospitalization plus the maintenance of contact with the people in the patient's nonhospital life facilitate treatment in this setting.