Management of inferior vena cava aneurysm.

AIM: Inferior vena cava (IVC) aneurysm is an infrequent but potentially lethal abnormality. We have seen one such case in our group practice. We have added this case to a review of 53 previously reported cases in order to develop a management algorithm for this entity. METHODS: We conducted a MedLine search of all English-language articles from the first reported case in 1950 through August 2013. Patient demographics, clinical data, management and outcomes were extracted. IVC aneurysms were categorized in 4 types as per Gradman and Steinberg classification. RESULTS: The mean patient age was 27.1 years (range 5-89) and 57.4% were male. A total of 11 (20.3%) had associated vascular anomalies and iliocaval thrombosis was found in 10 (18.5%). There were 23 type I aneurysms, 8 type IIs, 21 type IIIs and 2 type IVs. All but 1 type I was successfully managed conservatively without complications. For type IIs, only 3 patients were managed conservatively with 1 death related to stroke from paradoxical embolus. For type IIIs, resection was the most common management option (14 patients). One patient was treated endovascularly with aneurysm embolization. A total of 6 asymptomatic patients were treated conservatively with 1 death due to thromboembolism. For type IVs, all cases underwent expectant management with 1 death due to aneurysm rupture. CONCLUSION: IVC aneurysms are rare with only 54 cases reported in the literature. Associated vascular anomalies and iliocaval thrombosis should be expected in approximately 20% of cases. Type I aneurysms can be managed expectantly with close surveillance unless symptomatic. For type II-IV, surgical consideration should be given based on high rates of thromboembolic complications and non-negligible risk of rupture.

The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part II.

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined by the WHO. Furthermore, malaria (caused by various Plasmodium species) can be considered a neglected disease in certain countries and with regard to availability and affordability of the antimalarials. Living organisms, especially plants, provide an innumerable number of molecules with potential for the treatment of many serious diseases. The current review attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs. In part I, a general description of the diseases, the current state of therapy and need for new therapeuticals, assay methods and strategies applied in the search for new plant derived natural products against these diseases and an overview on natural products of terpenoid origin with antiprotozoal potential were given. The present part II compiles the current knowledge on natural products with antiprotozoal activity that are derived from the shikimate pathway (lignans, coumarins, caffeic acid derivatives), quinones of various structural classes, compounds formed via the polyketide pathways (flavonoids and related compounds, chromenes and related benzopyrans and benzofurans, xanthones, acetogenins from Annonaceae and polyacetylenes) as well as the diverse classes of alkaloids. In total, both parts compile the literature on almost 900 different plant-derived natural products and their activity data, taken from over 800 references. These data, as the result of enormous efforts of numerous research groups world-wide, illustrate that plant secondary metabolites represent an immensely rich source of chemical diversity with an extremely high potential to yield a wealth of lead structures towards new therapies for NTDs. Only a small percentage, however, of the roughly 200,000 plant species on earth have been studied chemically and only a small percentage of these plants or their constituents has been investigated for antiprotozoal activity. The repository of plant-derived natural products hence deserves to be investigated even more intensely than it has been up to present.

The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part I.

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined as such by WHO due to the neglect of financial investment into research and development of new drugs by a large part of pharmaceutical industry and neglect of public awareness in high income countries. Another major tropical protozoan disease is malaria (caused by various Plasmodium species), which -although not mentioned currently by the WHO as a neglected disease- still represents a major problem, especially to people living under poor circumstances in tropical countries. Malaria causes by far the highest number of deaths of all protozoan infections and is often (as in this review) included in the NTDs. The mentioned diseases threaten many millions of lives world-wide and they are mostly associated with poor socioeconomic and hygienic environment. Existing therapies suffer from various shortcomings, namely, a high degree of toxicity and unwanted effects, lack of availability and/or problematic application under the life conditions of affected populations. Development of new, safe and affordable drugs is therefore an urgent need. Nature has provided an innumerable number of drugs for the treatment of many serious diseases. Among the natural sources for new bioactive chemicals, plants are still predominant. Their secondary metabolism yields an immeasurable wealth of chemical structures which has been and will continue to be a source of new drugs, directly in their native form and after optimization by synthetic medicinal chemistry. The current review, published in two parts, attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs.

The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part I

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined as such by WHO due to the neglect of financial investment into research and development of new drugs by a large part of pharmaceutical industry and neglect of public awareness in high income countries. Another major tropical protozoan disease is malaria (caused by various Plasmodium species), which -although not mentioned currently by the WHO as a neglected disease- still represents a major problem, especially to people living under poor circumstances in tropical countries. Malaria causes by far the highest number of deaths of all protozoan infections and is often (as in this review) included in the NTDs. The mentioned diseases threaten many millions of lives world-wide and they are mostly associated with poor socioeconomic and hygienic environment. Existing therapies suffer from various shortcomings, namely, a high degree of toxicity and unwanted effects, lack of availability and/or problematic application under the life conditions of affected populations. Development of new, safe and affordable drugs is therefore an urgent need. Nature has provided an innumerable number of drugs for the treatment of many serious diseases. Among the natural sources for new bioactive chemicals, plants are still predominant. Their secondary metabolism yields an immeasurable wealth of chemical structures which has been and will continue to be a source of new drugs, directly in their native form and after optimization by synthetic medicinal chemistry. The current review, published in two parts, attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs.

Prevalence of leptospirosis in dairy cattle from small rural production units in Toluca Valley, State of Mexico.

In order to know the seroprevalence of Leptospira spp. in stabled dairy cattle, a study was conducted from 2004 to 2006 in which 416 sera were tested using a microscopic agglutination test conducted on microplates. A collection of culture reference antigens, each representing a serogroup, was used for these tests. Results showed that 10.33% (43) of the animals had antibody titers ranging from 1:100 to 1:1600. The main serovars detected in these tests were L. interrogans serovar hardjo and L. interrogans serovar canicola. It is important to note that these serovars represent a high risk for transmission to other susceptible animal species, between individuals, and to human health. This serological survey provides useful information establishing the presence or absence of these serovars in this type of herd. The range of antigens used in this study included serovars representative of all common serogroups.

Antileishmanial activity of indole alkaloids from Aspidosperma ramiflorum.

The present study was designated to evaluate the antileishmanial activity of acid and basic fractions that were obtained after acid-basic extraction, from ethanolic 70% crude extract and pure compounds from the stem bark of Aspidosperma ramiflorum. The basic alkaloidal fraction presented a good activity against the extracellular form (promastigotes) of Leishmania (L.) amazonensis (LD(50) value<47 microg/ml). Based on these findings, the basic fraction was fractionated on silica gel column chromatography in a bioassay-guided fractionation affording individual purified ramiflorines A and B. Both ramiflorines A and B showed significant activity against Leishmania (L.) amazonensis (LD(50) values of 16.3+/-1.6 microg/ml and 4.9+/-0.9 microg/ml, respectively). Our results are promising, showing that these compounds are biologically active against Gram-positive bacteria.

Amidine derivatives and Leishmania amazonensis: an evaluation of the effect of nitric oxide (NO) production on the parasite-macrophage interaction.

Previous work has demonstrated that N-N'-diphenyl-R-benzamidine was highly effective against Leishmania amazonensis promastigotes/axenic amastigotes and Trypanosoma evansi trypomastigotes and the compound with a methoxy substituent, was the most effective derivative in the parasite-macrophage interaction. Comparative analysis of the nitric oxide (NO) released from the culture infection's supernatant showed the amidine to be less effective than pentamidine Isethionate as a reference drug. Additionally, in order to verify if the methoxylated derivative interferes with NO production by L. amazonensis, the effect of the amidine on the constitutive nitric oxide synthase (cNOS) purified from parasites, was examined, but demonstrated less activity in comparison with the reference drug. This data contributes to studies concerning the metabolic targets present in Leishmania parasites for leishmanicidal drugs.

2-propen-1-amine derivatives and their synthetic intermediates: activity against pathogenic trypanosomatids.

The potential activity of three new derivatives of 3-(4'-Y-[1,1'-biphenyl]-4-yl)-3-(4-X-phenyl)-N,N-dimethyl-2-propen-1-amine (2-PAMs) was assayed against Trypanosoma cruzi and Leishmania amazonensis. They showed higher activity against trypomastigotes and epimastigotes of T. cruzi than the standard drugs, crystal violet and nifurtimox. Besides these derivatives, a series of eleven 2-PAMs derivatives and the corresponding intermediates, biphenyl methanones (BPMs) were assayed against promastigotes of L. amazonensis, showing that the 2-PAMs were remarkably more active than the BPMs. The PAMs 2c, 2e and 2j were about 2-fold more active that pentamidine isothionate and between 27.2- and 46.4-fold less toxic to V79 mammalian cells. The present results encourage further studies, especially against intracellular parasites and in experimental animals.

Cyclic 3'-5' guanosine monophosphate-dependent activity in Leishmania amazonensis.

Although there are some data concerning the nitric oxide and the cyclic 3'-5'guanosine monophosphate (cGMP) signaling pathway in trypanosomatids, there is no report about the cGMP-dependent enzymatic activity identification. In this sense, a cGMP dependent activity was detected on soluble fraction from Leishmania amazonensis promastigotes with a high metacyclic level. This information is valuable in order to explore the metabolic pathway of G kinase protein in this parasite.

Biological activities of Curcuma longa L.

There are several data in the literature indicating a great variety of pharmacological activities of Curcuma longa L. (Zingiberaceae), which exhibit anti-inflammatory, anti-human immunodeficiency virus, anti-bacteria, antioxidant effects and nematocidal activities. Curcumin is a major component in Curcuma longa L., being responsible for its biological actions. Other extracts of this plant has been showing potency too. In vitro, curcumin exhibits anti-parasitic, antispasmodic, anti-inflammatory and gastrointestinal effects; and also inhibits carcinogenesis and cancer growth. In vivo, there are experiments showing the anti-parasitic, anti-inflammatory potency of curcumin and extracts of C. longa L. by parenteral and oral application in animal models. In this present work we make an overview of the pharmacological activities of C. longa L., showing its importance.

Biological activities of Curcuma longa L

There are several data in the literature indicating a great variety of pharmacological activities of Curcuma longa L. (Zingiberaceae), which exhibit anti-inflammatory, anti-human immunodeficiency virus, anti-bacteria, antioxidant effects and nematocidal activities. Curcumin is a major component in Curcuma longa L., being responsible for its biological actions. Other extracts of this plant has been showing potency too. In vitro, curcumin exhibits anti-parasitic, antispasmodic, anti-inflammatory and gastrointestinal effects; and also inhibits carcinogenesis and cancer growth. In vivo, there are experiments showing the anti-parasitic, anti-inflammatory potency of curcumin and extracts of C. longa L. by parenteral and oral application in animal models. In this present work we make an overview of the pharmacological activities of C. longa L., showing its importance

Protein kinase A of Leishmania amazonensis as a potential target for methoxy-amidine.

Cyclic 3',5'-adenosine monophosphate (cAMP) is one of the most important signaling molecules for cell growth and differentiation in several systems including protozoal parasites such as Trypanosoma cruzi and Leishmania species. The most important event during Leishmania developmental cycle is the differentiation of procyclic into metacyclic promastigotes, which is associated with the appearance of pathogenicity. As previously demonstrated Leishmania amazonensis metacyclogenesis is associated with an increase of a protein kinase A activity, and therefore further studies on the activity of this phosphorylating enzyme as a target for chemotherapy were performed. Among several amidine derivatives tested by the authors against trypanosomatids (T. cruzi, T. evansi and L. amazonensis) the most effective compounds was defined as that with a methoxy group as substituent. In this work the inhibitory effect of this derivative on the phosphorylating activity of cAMP-dependent protein kinase (PKA) of promastigotes (containing high amounts of metacyclic forms) and axenic amastigotes of L. amazonensis is demonstrated. Soluble fractions (SF) and enriched membrane fractions (MF) were submitted to anion exchange chromatography in a DEAE-cellulose column and the collected fractions used to evaluate the phosphorylating activity associated with cAMP, in the presence/absence of methoxy-amidine and pentamidine (CAS 100-33-4), the latter being used as reference drug.

Studies on the effectiveness of diarylheptanoids derivatives against Leishmania amazonensis.

In a previous work we demonstrated that diarylheptanoids extracted from Centrolobium sclerophyllum are very active against Leishmania amazonensis promastigotes. In order to continue our studies with these class of compounds, we decided to evaluate the activity of several diarylheptanoids derived from curcumin (diferuloyl methane) against the extracellular form (promastigotes) of L. amazonensis. Furthermore, an experiment against the intracellular form of the parasite (amastigotes) was carried out, comparing the most active compound among the curcumin derivatives (the methylcurcumin) with des-O-methylcentrolobine, the most active diarylheptanoid derived from C. sclerophyllum.

Humoral immune response kinetics in Philander opossum and Didelphis marsupialis infected and immunized by Trypanosoma cruzi employing an immunofluorescence antibody test.

Philander opossum and Didelphis marsupialis considered the most ancient mammals and an evolutionary success, maintain parasitism by Trypanosoma cruzi without developing any apparent disease or important tissue lesion. In order to elucidate this well-balanced interaction, we decided to compare the humoral immune response kinetics of the two didelphids naturally and experimentally infected with T. cruzi and immunized by different schedules of parasite antigens, employing an indirect fluorescence antibody test (IFAT). Both didelphids responded with high serological titers to different immunization routes, while the earliest response occurred with the intradermic route. Serological titers of naturally infected P. opossum showed a significant individual variation, while those of D. marsupialis remained stable during the entire follow-up period. The serological titers of the experimentally infected animals varied according to the inoculated strain. Our data suggest that (1) IFAT was sensitive for follow-up of P. opossum in natural and experimental T. cruzi infections; (2) both P. opossum and D. marsupialis are able to mount an efficient humoral immune response as compared to placental mammals; (3) experimentally infected P. opossum and D. marsupialis present distinct patterns of infection, depending on the subpopulation of T. cruzi, (4) the differences observed in the humoral immune responses between P. opossum and D. marsupialis, probably, reflect distinct strategies selected by these animals during their coevolution with T. cruzi.

Amidine derivatives are highly effective against Trypanosoma evansi trypomastigotes.

The in vitro effect of N,N'-diphenyl-4-R-benzamidine (where R = H, CN, Br, Cl, CH3, OCH3 and NO2) in three isolates of Trypanosoma evansi was studied. The compounds were solubilized in dimethysulphoxide (DMSO) and tested in a concentration range of 5 to 160 micrograms/ml. The parasites were isolated from a horse, a dog and a coati. They were maintained in immunosuppressed rats, since they could not be cultured in vitro, and further purified through a diethylaminoethanol (DEAE) column. The trypomastigotes obtained were mixed with different concentrations of the drugs and after incubation at 26 degrees C for 24 h, the remaining parasites were counted in a Neubauer chamber. The percentage of inhibition was evaluated compared with the control, without the drugs. Most of the amidine derivatives showed high activity against the three T. evansi isolates, but different patterns of sensitivity to the tested compounds were observed. At least four compounds with Br, Cl, OCH3 and NO2 as substituents, were much more effective than Berenil [4,4'-(diazoamine)-dibenzamidine aceturate], the reference drug used, which is included in the same chemical class of amidines.

Leishmania amazonensis: long-term cultivation of axenic amastigotes is associated to metacyclogenesis of promastigotes.

Axenic Leishmania amazonensis cultures were obtained (with 2 years of follow-up) in Schneider's medium at pH 5.5 and a temperature of 32 degrees C. Differentiation of promastigotes into amastigotes is directly associated with the metacyclogenesis rate of the original promastigotes. Promastigote cultures containing different percentages of metacyclic forms, as evaluated by the complement lysis test, resulted in axenic amastigote cultures containing a variable amount of undifferentiated forms. We observed that a culture originally containing a large amount of metacyclic forms (73%) underwent a complete differentiation process, resulting in a 100% amastigote culture with no promastigote forms. All other cultures (with a decreasing amount of metacyclic forms: 50% and fewer) failed to differentiate completely, resulting in cultures with increasing percentages of promastigote contamination. The amastigote/promastigote rate in these cultures has been maintained at the same level thus far. The axenic Leishmania amazonensis amastigotes were cryopreserved, thawed as such, and successfully cultivated under appropriately defined growth conditions.

The potential effects of new synthetic drugs against Leishmania amazonensis and Trypanosoma cruzi.

Amidine derivatives, never used before on trypanosomatids, were tested against Leishmania amazonensis and Trypanosoma cruzi. These drugs in doses up to 500 mg/kg inoculated into Swiss mice did not show any toxic effect (Santos, 1993). The in vitro effect of N,N'-diphenyl-4-R- benzamidine was evaluated. L. amazonensis promastigotes, epimastigotes and blood forms of T. cruzi, were assayed with/without the drugs in axenic media, using pentamidine isethionate and benznidazole, as reference drugs. The results were very promising for L. amazonensis, showing that the most active compounds were the metoxy and Br-derivatives, with LD50 of 20 microM and 22 microM, respectively. In general the amidines showed lower activity against T. cruzi than L. amazonensis. The most active compounds against blood trypomastigotes were the same metoxy and Br-derivatives, but in much higher concentrations, e.g. as LD50 of 59 nM and 251 nM, respectively. All amidines had a very low activity against epimastigotes, and the only active compounds were the halogen-derivatives with LD50 = 424 nM for the Br-derivative and LD50 of 474 nM for the C1-derivative.

Effects of temperature on promastigotes of several species of Leishmania.

Six Leishmania species were studied comparatively, in order to determine the influence of temperature "in vitro" on differentiation, infectivity and protein synthesis. Differentiation occurred in a heterogeneous manner, even in species that produce similar clinical manifestations. Thus, no association could be found between thermosensitivity and disease. The association between expression of proteins and increasing temperatures was analyzed at 34 degrees C by polyacrylamide gel electrophoresis with sodium dodecyl sulphate (SDS-PAGE), using different incubation times, and employing a technique involving metabolic incorporation of [35S]-methionine. Protein synthesis was very similar in all the New World species apart from L. amazonensis, which expressed a protein of approximately 80 kDa when incubated at 34 degrees C for 2 hours. All the tested species had in common the expression of a 70 kDa protein. Differences, however, were observed in relation to the time interval for protein expression. In L. chagasi, synthesis was detected after 30 minutes of incubation at 34 degrees C, while L. braziliensis required 1 hour at the same temperature. The "in vivo" and "in vitro" infectivity of the differentiated forms was also analyzed, but no significant differences were observed.