RESUMO
Many options now exist for constructing oral vaccines which, in experimental systems, have shown themselves to be able to generate highly effective immunity against infectious diseases. Their suitability for implementation in clinical practice, however, for prevention of outbreaks, particularly in low- and middle-income countries (LMIC), is not always guaranteed, because of factors such as cost, logistics and cultural and environmental conditions. This brief overview provides a summary of the various approaches which can be adopted, and evaluates them from a pharmaceutical point, taking into account potential regulatory issues, expense, manufacturing complexity, etc., all of which can determine whether a vaccine approach will be successful in the late stages of development. Attention is also drawn to problems arising from inadequate diet, which impacts upon success in stimulating effective immunity, and identifies the use of lipid-based carriers as a way to counteract the problem of nutritional deficiencies in vaccination campaigns.
Assuntos
Controle de Doenças Transmissíveis , Doenças Transmissíveis/imunologia , Vacinação , Vacinas/uso terapêutico , Administração Oral , Animais , Doenças Transmissíveis/epidemiologia , Humanos , Vacinas/imunologiaRESUMO
AIM: Randomized, open, single-centre, two-way crossover study comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of subcutaneous (sc) regular human insulin (Actrapid) and oral insulin in a capsule form (Capsulin). METHODS: Sixteen persons (12 males) with type 2 diabetes on oral hypoglycaemic agents (OHAs) participated. Mean (s.d.) age 60.2 (5.5) years, BMI 28.3 (3.4) kg/m(2), haemoglobin A(1c) (HbA(1c)) 7.4% (1.1). Two 6-h isoglycaemic glucose clamp studies were conducted 11 days apart. All subjects received in random order 12U sc Actrapid on one clamp study day and either 150U or 300U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and C-peptide concentrations were determined throughout each 6-h isoglycaemic clamp. Between the clamp study days, all patients received 150U Capsulin twice daily, dropping all their standard OHAs apart from metformin. Self-monitored blood glucose (SMBG) levels were taken four times a day between the clamp study days. RESULTS: Administration of either Actrapid or Capsulin (150 and 300U) increased GIRs reaching a maximum values at approximately 280-330 min. Overall values for maximum GIR values were higher for Actrapid than either dose of Capsulin (p < 0.05). The significantly greater systemic insulin concentrations following Actrapid were reflected in the AUC(0-6 h) (910 +/- 270 vs. 472 +/- 245 pmol h/L; 950 +/- 446 vs. 433 +/- 218 pmol h/L; both p < 0.05 for Actrapid vs. 150U Capsulin and 300U Capsulin respectively). No difference was observed between 150U and 300U Capsulin. During the repeat-dosing period, good safety and tolerability were observed with Capsulin, and SMBG levels remained stable. At the poststudy visit, significant falls in HbA(1c), weight and triglycerides were observed. CONCLUSIONS: Administration of the oral insulin Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h associated with only a small increase in circulating plasma insulin concentrations.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Insulina/farmacocinética , Administração Oral , Glicemia/metabolismo , Cápsulas , Estudos Cross-Over , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Técnica Clamp de Glucose , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Insulina Regular de Porco , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
In this study an in vitro model was developed with the aim of investigating the modulatory effect of cholera toxin (CT) and its counterpart the heat labile toxin of Escherichia coli (LT) on TNF-alpha release induced by murine macrophages and primary human monocytes. Previous studies have demonstrated that the enzymatic activity of CT and LT molecules can inhibit TNF-alpha release by macrophages. The results obtained in this study showed that CT and LT are both, in a dose dependent manner, able either to induce or inhibit TNF-alpha release by murine macrophages and primary human monocytes. The results also showed that recombinant B subunits of CT and LT in the absence of their A subunit induce high levels of TNF-alpha release by macrophages and, in addition, increase the level of TNF-alpha release induced by LPS. The ability of both B subunits (CTB and LTB) in inducing TNF-alpha release by macrophages is not related to the level of LPS contamination, since direct measurements of LPS made in the samples employed in this study showed only traces of LPS (3.4 x 10(-8) EU/ml) which is in our system does not induce TNF-alpha release by macrophages. In contrast to the results obtained with the B subunits, incubation of cells with the A subunit of CT (CTA) inhibit TNF-alpha release induced by native CT, native LT, recombinant LTB and LPS. This inhibitory effect must be related to the activity of the A subunit since viability tests performed in terms of metabolic rate demonstrated that high concentrations of CTA are not toxic to the cells. The data presented herein demonstrate that the A subunits of CT and LT have an inhibitory effect on TNF-alpha release in macrophages, whereas their B subunits have a stimulatory effect on TNF-alpha. The results also suggest that the dose dependent bi-modal effect of native CT and native LT on TNF-alpha release by macrophages is a result of the combined effect of their individual A and B subunits.
Assuntos
Toxinas Bacterianas/farmacologia , Toxina da Cólera/farmacologia , Enterotoxinas/farmacologia , Proteínas de Escherichia coli/farmacologia , Escherichia coli/metabolismo , Macrófagos/efeitos dos fármacos , Subunidades Proteicas/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Células Cultivadas , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/farmacologiaRESUMO
Murine antisera with neutralising activity for the coronavirus causative of Middle East respiratory syndrome (MERS) were induced by immunisation of Balb/c mice with the receptor binding domain (RBD) of the viral Spike protein. The murine antisera induced were fully-neutralising in vitro for two separate clinical strains of the MERS coronavirus (MERS-CoV). To test the neutralising capacity of these antisera in vivo, susceptibility to MERS-CoV was induced in naive recipient Balb/c mice by the administration of an adenovirus vector expressing the human DPP4 receptor (Ad5-hDPP4) for MERS-CoV, prior to the passive transfer of the RBD-specific murine antisera to the transduced mice. Subsequent challenge of the recipient transduced mice by the intra-nasal route with a clinical isolate of the MERS-CoV resulted in a significantly reduced viral load in their lungs, compared with transduced mice receiving a negative control antibody. The murine antisera used were derived from mice which had been primed sub-cutaneously with a recombinant fusion of RBD with a human IgG Fc tag (RBD-Fc), adsorbed to calcium phosphate microcrystals and then boosted by the oral route with the same fusion protein in reverse micelles. The data gained indicate that this dual-route vaccination with novel formulations of the RBD-Fc, induced systemic and mucosal anti-viral immunity with demonstrated in vitro and in vivo neutralisation capacity for clinical strains of MERS-CoV.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Animais , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Modelos Animais de Doenças , Feminino , Imunidade nas Mucosas/fisiologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação/métodos , Carga ViralRESUMO
Here, we report a dual-route vaccination approach for plague, able to induce a rapid response involving systemic and mucosal immunity, whilst also providing ease of use in those resource-poor settings most vulnerable to disease outbreaks. This novel vaccine (VypVaxDuo) comprises the recombinant F1 and V proteins in free association. VypVaxDuo has been designed for administration via a sub-cutaneous priming dose followed by a single oral booster dose and has been demonstrated to induce early onset immunity 14â¯days after the primary immunisation; full protective efficacy against live organism challenge was achieved in Balb/c mice exposed to 2â¯×â¯104 median lethal doses of Yersinia pestis Co92, by the sub-cutaneous route at 25â¯days after the oral booster immunisation. This dual-route vaccination effectively induced serum IgG and serum and faecal IgA, specific for F1 and V, which constitute two key virulence factors in Y. pestis, and is therefore suitable for further development to prevent bubonic plague and for evaluation in models of pneumonic plague. This is an essential requirement for control of disease outbreaks in areas of the world endemic for plague and is supported further by the observed exceptional stability of the primary vaccine formulation in vialled form under thermostressed conditions (40⯰C for 29â¯weeks, and 40⯰C with 75% relative humidity for 6â¯weeks), meaning no cold chain for storage or distribution is needed. In clinical use, the injected priming dose would be administered on simple rehydration of the dry powder by means of a dual barrel syringe, with the subsequent single booster dose being provided in an enteric-coated capsule suitable for oral self-administration.
Assuntos
Vacina contra a Peste/administração & dosagem , Peste/prevenção & controle , Vacinação/métodos , Administração Oral , Animais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Feminino , Imunidade nas Mucosas , Imunização Secundária , Imunoglobulina A/análise , Imunoglobulina G/sangue , Camundongos Endogâmicos BALB C , Vacina contra a Peste/imunologia , Absorção Subcutânea , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Fatores de Virulência , Yersinia pestisRESUMO
This study compared splenic and hepatic uptake of free and liposome-entrapped sodium antimony gluconate after i.v. administration to mice infected with Leishmania donovani. It was demonstrated that entrapment within liposomes greatly altered the kinetics of uptake of the drug. We were also able to show that liposomes composed of sphingomyelin, stearylamine and cholesterol were marginally better than any other preparation in delivering entrapped drug to liver and spleen. X-ray microanalytical studies on the uptake of liposomes by Kupffer cells infected with L. donovani have indicated that internalised liposomes probably fuse with parasitophorous vacuoles, transferring their contents into the immediate locality of the leishmanial parasites. It is proposed that this is the way in which liposome entrapped antileishmanial agents have an enhanced therapeutic effect over free drug therapy.
Assuntos
Gluconato de Antimônio e Sódio/metabolismo , Gluconatos/metabolismo , Leishmaniose Visceral/metabolismo , Lipossomos/metabolismo , Fagócitos/metabolismo , Animais , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos , Microscopia Eletrônica , Fagócitos/parasitologia , Fagócitos/ultraestrutura , Espectrofotometria Atômica , Baço/metabolismo , Vacúolos/parasitologiaRESUMO
The strain-specific unresponsiveness to H-2 incompatible skin allografts induced by treatment of adult mice with single inoculations of donor strain liver extract and Bordetella pertussis vaccine, as well as three doses of antilymphocyte serum, has been investigated by several in vivo and in vitro methods, with a view to elucidating it mechanism. Lymphoid cells from mice with long surviving skin grafts were found to be reactive in graft-versus-host assays (as measured by splenomegaly or popliteal lymph node enlargement), and mixed lymphocyte culture tests gave positive results. Attempts to cause lethal runting of F1 hybrid mice injected at birth with spleen cells from unresponsive mice gave variable results. However, the injection of F1 hybrid cells into the footpads of unresponsive animals failed to elicit a significant host-versus-graft response. Although lymphoid cells from unresponsive animals did not include detectable numbers of cytotoxic cells, such cells could be generated by previous in vitro mixed lymphocyte culture stimulation or, to some degree, by the injection of the animals with F1 hybrid cells. Attempts to prevent mixed lymphocyte culture stimulation or cytotoxicity with serum from unresponsive mice failed at the serum concentrations used. The data indicate that long-term unresponsiveness in this system is maintained by the production in the hosts of factors that interfere with the cell-mediated response.
Assuntos
Soro Antilinfocitário , Bordetella pertussis/imunologia , Fígado/imunologia , Transplante de Pele , Imunologia de Transplantes , Transplante Homólogo , Animais , Testes Imunológicos de Citotoxicidade , Reação Enxerto-Hospedeiro , Extratos Hepáticos , Linfonodos/citologia , Teste de Cultura Mista de Linfócitos , Linfócitos/imunologia , Linfócitos/efeitos da radiação , Linfoma/imunologia , Masculino , Sarcoma de Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos CBA , Tamanho do Órgão , Efeitos da Radiação , Baço/citologia , Timidina/metabolismo , TrítioRESUMO
Human echinococcosis is highly endemic in north-western China; the main treatment is by surgery. In this paper, we report the results of chemotherapy with albendazole (ABZ), 15-20 mg/kg/d orally, for 30 d with intervals of 10 d between treatments for 3-6 courses. For multi-organ cystic echinococcosis (CE) and alveolar echinococcosis (AE), patients were given 12-18 courses of ABZ. Patients were divided into 4 groups: (i) ABZ surgery group, albendazole with surgery for 21 CE cases: (ii) non-ABZ surgery group, 80 CE cases treated by surgery alone; (iii) ABZ CE group, albendazole treatment alone in 58 CE cases, and (iv) ABZ AE group, 14 AE patients treated by albendazole and surgical intervention and 5 AE patients treated by albendazole alone. Twenty-seven of 34 (79.4%) cysts in group (i) patients showed increased necrotic changes and decreased viability of the cysts compared to group (ii). However, 10 of 84 (11.9%) cysts in group (ii) patients showed spontaneous evidence of necrosis at surgery. In group (iii), ABZ treatment alone was successful in 14 (24.1%), resulted in improvement in 29 (50%) and had no effect in 15 (25.9%) patients. Seven cases in group (iv) improved, with diminished size of lesions which were non-viable. The remaining 7 cases in group (iv) showed evidence of cyst viability at surgery; 2 could not be saved after a further 15 courses of albendazole. Of the five AE patients in group (iv) who received only ABZ, one improved, 2 stabilized, one deteriorated and one died. Albendazole chemotherapy, while not completely effective, has an important role in treatment of both cystic and alveolar echinococcosis.
Assuntos
Albendazol/uso terapêutico , Equinococose/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Albendazol/administração & dosagem , Albendazol/efeitos adversos , Criança , China , Terapia Combinada , Esquema de Medicação , Equinococose/cirurgia , Equinococose Hepática/tratamento farmacológico , Equinococose Hepática/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Nigerian Echis carinatus venom incorporated into sphingomyelin-cholesterol liposomes stabilized with osmium tetroxide produced a rapid, sustained and protective immune response when injected i.v. into sheep. The response was similar to that reported earlier in mice. The implications of the findings are discussed in relation to the production of cheaper and more effective antivenoms. The possible use of immunostimulants for increasing the protective effect of antisera raised using this method are also considered.
Assuntos
Imunização , Lipossomos/imunologia , Mordeduras de Serpentes/imunologia , Venenos de Víboras/imunologia , Animais , Anticorpos/análise , Ensaio de Imunoadsorção Enzimática , Imunoglobulina G/análise , Camundongos , Ovinos , Fatores de TempoRESUMO
A method is described which produces a high, permanent antibody response following a single injection of venom. Animals (mice, rabbits, sheep) were given intravenous, subcutaneous or orally administered Nigerian Echis carinatus (carpet viper) venom which had been incorporated into sphingomyelin-cholesterol liposomes whose membranes had been stabilized by cross-linking adjacent molecules of sphingomyelin using osmium tetroxide. Before use the preparations were thoroughly dialysed to remove any unbound osmium tetroxide. Antibody levels were estimated using enzyme immunoassay. Venom treated in this way and administered i.v. or s.c. produced a powerful, sustained and protective antibody response lasting for the lifetime of a mouse. We also report the development of significant antibody responses after oral administration of liposome-entrapped but not free venom.
Assuntos
Lipossomos/administração & dosagem , Mordeduras de Serpentes/imunologia , Venenos de Víboras/imunologia , Animais , Anticorpos/análise , Colesterol , Ensaio de Imunoadsorção Enzimática , Imunização , Camundongos , Tetróxido de Ósmio , Coelhos , Ovinos/imunologia , Fatores de TempoRESUMO
Crotalus durissus venom has been described as a weak antigen when injected in combination with Freund's complete adjuvant during the course of traditional methods of equine immunisation. Antibody production is slow and unpredictable, with a wide variation in individual responses. In this experimental study, C. durissus venom was incorporated into stabilised sphingomyelin-cholesterol liposomes both in the presence and absence of lipopolysaccharide immunostimulant and injected by both i.v. and s.c. routes into mice and rabbits. A rapid, sustained and protective immune response was obtained following a single injection of these preparations in mice. Antibody levels were estimated using enzyme-linked immunosorbent assay (ELISA), and the protective effect was evaluated by subsequent challenge with a subcutaneous minimum lethal dose of the venom. Results indicated that the immune response was significantly potentiated by the presence of immunostimulant in the venom liposomes. The use of C. durissus venom liposomes should be a useful tool for the immunisation of animals both in experimental and commercial procedures.
Assuntos
Venenos de Crotalídeos/imunologia , Lipossomos , Animais , Formação de Anticorpos , Ensaio de Imunoadsorção Enzimática , Imunização , Lipopolissacarídeos/análise , Lipossomos/análise , Masculino , Camundongos , CoelhosRESUMO
It is well known that Loxosceles venom induces local dermonecrosis in rabbits, guinea pigs and humans but not in mice, although, depending on the dose, Loxosceles venom can be lethal to mice. In this work we demonstrate that mice injected intradermally in the dorsal area of the back can survive a lethal dose of Loxosceles gaucho venom and also develop an inflammatory reaction (with infiltration of leukocytes shown by histological analysis) at the local injection site when the venom is co-administered with sphingomyelin. It was observed that more venom was retained for a longer period of time at the local injection site when venom was co-administered with sphingomyelin. The presence of exogenous sphingomyelin did not influence significantly the release of TNF-alpha induced by L. gaucho venom. These results suggest that the action of venom on sphingomyelin, producing ceramide phosphate, causes the development of an inflammatory reaction, which in turn traps the venom in the local area for a long period of time and does not allow it to disperse systemically in a dose sufficient to cause death. Our findings also indicate that the size and availability of the local sphingomyelin pool may be important in determining the outcome of Loxosceles envenoming in different mammalian species.
Assuntos
Inflamação/induzido quimicamente , Diester Fosfórico Hidrolases/toxicidade , Esfingomielinas/metabolismo , Venenos de Aranha/toxicidade , Fator de Necrose Tumoral alfa/metabolismo , Animais , Ceramidas/administração & dosagem , Ceramidas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Injeções Intradérmicas , Injeções Subcutâneas , Dose Letal Mediana , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Diester Fosfórico Hidrolases/administração & dosagem , Diester Fosfórico Hidrolases/imunologia , Esfingomielinas/administração & dosagem , Venenos de Aranha/administração & dosagem , Venenos de Aranha/imunologia , Aranhas/metabolismo , Fatores de TempoRESUMO
This study was performed to investigate whether the toxic effects of Loxosceles gaucho venom on cells might be exerted via stimulators of TNF-alpha release generated by sphingomyelinase D--a major component of the venom. It was demonstrated that L. gaucho venom alone is unable to induce TNF-alpha release by J774A.1 cells, while in the presence of exogenous sphingomyelin it induces a high level of TNF-alpha release which is significantly increased by incubation with non-inactivated serum. Ceramide phosphate also induces TNF-alpha release in J774A.1 cells, but (unlike sphingomyelin/sphingomyelinase) the level of release is not influenced by the presence or otherwise of non-inactivated serum. L. gaucho venom does not induce proliferation of J774A.1 cells and even at high concentrations it does not affect their viability. J774A.1 cells, which prior to venom treatment were elongated and clumped, round up after venom treatment, but, revert to their original morphology after incubation with fresh medium. TNF-alpha resistant MRC-5 cells and TNF-alpha sensitive MCF-7 cells are susceptible to the toxic effect of both L. gaucho venom and ceramide phosphate. The results obtained in this study demonstrate that exogenous sphingomyelin can modulate, in vitro, the release of TNF-alpha induced by L. gaucho venom in mouse macrophages. In addition, the results also indicate that ceramide phosphate and L. gaucho venom are toxic to several different cell types, via a variety of mechanisms, some, but not all, of which may involve TNF-alpha as an intermediary.
Assuntos
Ceramidas/metabolismo , Macrófagos/efeitos dos fármacos , Diester Fosfórico Hidrolases/toxicidade , Esfingomielinas/metabolismo , Venenos de Aranha/toxicidade , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacosAssuntos
Doxorrubicina/efeitos adversos , Lipossomos/administração & dosagem , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Neoplasias do Colo/tratamento farmacológico , Doxorrubicina/uso terapêutico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Segmented polyurethane ureas with different hard segment content and composition were synthesized using 4,4'-diphenylmethane diisocyanate and polytetramethylene glycols. Using polyols with different molecular weights, it was possible to synthesize polyurethane ureas with either: (i) a constant ratio of urethane to urea bonds; (ii) a constant urethane content; or (iii) a constant urea content. Bulk properties were assessed by dynamic mechanical analysis. Surface properties were estimated by contact angle measurements and streaming potential measurements. Haemocompatibility was evaluated in vitro by measuring the adsorption of human serum albumin (HSA) and fibrinogen (Fg), the adhesion of human peripheral blood lymphocytes (PBL), and the presence of activated platelets on the biomaterial surfaces. Enzyme immuno assays (EIA) have been specially developed for this purpose for the detection of antibody-recognizable plasma proteins and platelet surface membrane proteins. No simple correlation between chemical structure of the polymers and surface properties was found. Parameters of haemocompatibility correlated more closely with hard segment content and chemical composition than with the surface characteristics of the polymers. Adsorption of plasma proteins, adhesion of lymphocytes and the adhesion/activation of platelets were found to increase with increasing hard segment content of the polyurethane ureas. However, the monoclonal-antibody recognisable fibrinogen and the platelet activation were nearly constant with increasing hard segment content, if the urea content was kept constant.
Assuntos
Proteínas Sanguíneas/metabolismo , Linfócitos/citologia , Ativação Plaquetária/fisiologia , Adesividade Plaquetária/fisiologia , Poliuretanos/química , Ureia/química , Adsorção , Fenômenos Biomecânicos , Adesão Celular/fisiologia , Fenômenos Químicos , Físico-Química , Humanos , Teste de Materiais , Propriedades de SuperfícieRESUMO
Liposome-entrapped doxorubicin (Lip-Dox) was evaluated in two phase I clinical trials in patients with hepatic malignancy. Patients with metastases from primary gastric or colonic tumours and patients with hepatoma were eligible. Lip-Dox was extremely well tolerated and acute toxicities such as nausea and vomiting were totally eliminated; no antiemetics were used even at doses of 80 mg/m2. Toxicities such as alopecia and myelosuppression were also ameliorated. There were tumor regressions and reductions in hepatomegaly in patients treated on both the weekly and 21-day studies. The maximum tolerated dose (MTD) in the weekly study was 22.5 mg/m2/week and in the 21-day trial the MTD was 70 mg/m2.
Assuntos
Doxorrubicina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Portadores de Fármacos , Avaliação de Medicamentos , Feminino , Humanos , Lipossomos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-IdadeRESUMO
Concentrations of albendazole were measured, by high-pressure liquid chromatography, in 19 patients being treated for cystic echinococcosis. All of the patients were given three 4-week courses of albendazole (20 mg/kg/day), separated by 10-day-long drug-free intervals. Seven patients also received three courses of cimetidine (10 mg/kg/day). Concentrations of albendazole sulphoxide (ABZSX) were significantly higher in samples of bile and hydatid cyst fluid from the patients receiving albendazole and cimetidine than in those from patients receiving albendazole alone (P < 0.05). The therapeutic benefit of the combined drug treatment, which was well-tolerated, was more than that with albendazole alone.
Assuntos
Albendazol/uso terapêutico , Cimetidina/uso terapêutico , Equinococose/tratamento farmacológico , Albendazol/análogos & derivados , Albendazol/metabolismo , Albendazol/farmacocinética , Anti-Helmínticos/metabolismo , Bile/química , Cromatografia Líquida de Alta Pressão , Quimioterapia Combinada , Equinococose/metabolismo , HumanosRESUMO
Encapsulation of the benzimidazole albendazole in multilamellar liposomes results in a preparation in which this normally insoluble anti-hydatid drug is well solublilized in aqueous media. The high entrapment efficiency observed (75-87%) and the stability of the formulation make this a promising delivery vehicle for improved chemotherapy with albendazole. In particular, the high degree of association with phospholipid may give rise to increased oral bioavailability. Oral administration of albendazole in liposomes led to increased concentration and/or altered metabolism of albendazole sulphoxide (ABZSX) in liver and/or plasma in non-infected Wistar rats. Results from experiments using cotton rats (Sigmodon hispidus) infected with metacestodes of Echinococcus multilocularis show that entrapment within liposomes clearly increases the uptake of albendazole via the oral route. This was reflected by increased levels of albendazole and the two major metabolites in plasma, liver and cyst homogenate when a dose of liposomal albendazole (35 mg/kg) was given orally compared to free albendazole at 50 mg/kg. There was a 75-94% reduction in biomass of the metacestode and a significant increase in survival time for the animals treated with liposome entrapped albendazole. A clear difference in distribution of albendazole and its metabolites in the liver and the metacestode tissues in the presence of cimetidine indicated that the latter has a profound effect on the metabolism of albendazole. There appeared to be a synergistic interaction between albendazole and cimetidine, since the metabolism of albendazole was markedly altered in the combined cimetidine/ liposome-albendazole group, and higher therapeutic effect was observed. These findings indicate potential both for improvement of treatment of larval E. multilocularis infection and for reduction of albendazole dose levels.