Cisplatin (CDDP) is one of the most active cytotoxic agents commonly used in the treatment of peritoneal carcinomatosis. The disadvantages of its clinical use are systemic side-effects, such as nephrotoxicity and myelotoxicity. Long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP) were developed by our research group aiming to promote the release of CDDP near the tumor as well as decreasing toxicity. The aim of this study was to evaluate the antitumor efficacy and toxicity of SpHL-CDDP after intraperitoneal administration in initial or disseminated tumor-bearing mice, at a dose of 12 mg/kg. The survival was monitored and blood samples were collected for biochemical and hematological analysis. Kidneys, liver and spleen were removed for histopathological examination. Tumor cells were evaluated for cellular viability and cell cycle. The survival of animals treated with SpHL-CDDP was higher than those treated with free CDDP. The cell death caused by treatment with SpHL-CDDP occurred through induction of apoptosis, with a cell cycle arrest at the G0/G1 phase. The treatment of mice presenting initial cancer with both formulations provoked a suppression of granulocytes. Mice treated with free CDDP also showed a decrease in platelet count, which suggests a high myelotoxicity. In an advanced cancer model, SpHL-CDDP treatment allowed an improvement of the immune response. Mice affected by cancer at an early stage and treated with free CDDP or SpHL-CDDP showed a lower urea/creatinine index compared with the saline control group. These findings indicate that both treatments were able to reduce the renal damage caused by peritoneal carcinomatosis. Microscopic analysis of kidneys from mice treated with SpHL-CDDP showed a discrete morphological alteration, while tubular necrosis was observed for free CDDP-treated mice. Concerning hepatotoxicity, no alteration in clinical chemistry parameters was observed. These findings reveal that SpHL-CDDP can improve the antitumor efficacy and decrease renal and bone marrow toxicity.
Arq Bras Endocrinol Metab vol 47 nº 3 Junho 2003 228 RESUMOApesar da dedicação incessante dos pesquisadores no estudo da osteoporose, muito ainda necessita ser elucidado. A deficiência dos esteróides sexuais, principalmente a de estrógeno, é considerada a principal causa de osteoporose, embora existam inúmeros outros fatores envolvidos. O hipertireoidismo, por exemplo, é considerado um dos fatores de risco para indução ou agravamento da osteoporose e tem despertado o interesse para o estudo dos efeitos de T3 e T4 sobre o metabolismo ósseo. Embora o hipotireoidismo e a afuncionalidade das gônadas seja uma associação freqüente na mulher, a hipofunção da tireóide não é considerada fator de risco para a osteoporose da menopausa. Assim, o estudo da inter-relação entre os distúrbios endócrinos, tão comuns na idade avançada, e a osteoporose é fundamental, pois deste conhecimento poderão advir meios de controle e tratamento adequados, bem como a definição da real natureza do distúrbio ósseo. O objetivo desta revisão é apresentar e discutir alguns aspectos da osteoporose e sua inter-relação com os distúrbios endócrinos da tireóide e das gônadas. ABSTRACT Osteoporosis and the Endocrine Disturbances of Thyroid and Gonads.Despite the incessant dedication of the researchers to the study of osteoporosis, a lot still needs to be elucidated. The deficiency of sexual steroids, mainly of estrogen, is considered the main cause of osteoporosis, although a number of other factors are involved. Hyperthyroidism, for instance, is considered a risk factor for induction or aggravation of osteoporosis and has risen the interest in the study of the effects of T3 and T4 on osseous metabolism. Although hypothyroidism and gonadic dysfunction are frequently associated in women, thyroid hypofunction is not considered as a risk factor for postmenopausal osteoporosis. Thus, the study of the inter-relationship between endocrine disturbances, so common in advanced age, and osteoporosis is fundamental. Adequate means of control and treatment may result from this knowledge, as well as a definition of the real nature of the bone disturbance. The aim of this review is to present and discuss some aspects of osteoporosis and its inter-relation with the endocrine dysfunctions of the thyroid and the gonads.
RESUMOO efeito do hipotireoidismo sobre o metabolismo ósseo e as paratireóides na deficiência ou suficiência dos esteróides ovarianos foi estudado em 32 ratas Wistar, com 2 meses de idade, distribuídas em 4 grupos de 8: eutireóideo não castrado (ENC), eutireóideo castrado (EC), hipotireóideo não castrado (HNC) e hipotireóideo castrado (HC). Após 120 dias de tratamento, as ratas foram sacrificadas e o plasma colhido para dosagem de T4 livre. Foi evidenciada hipertrofia das paratireóides somente no grupo HNC. As ratas do grupo HNC apresentaram osteopenia de maior extensão e intensidade, decorrente do menor crescimento, da inibição da aposição e do aumento da reabsorção ósseas. Nas ratas EC, a osteopenia foi causada por menor aposição e aumento da reabsorção ósseas. Embora a osteopenia na associação hipotireoidismo-castração tenha sido quase sempre mais intensa em relação à das ratas EC, sua intensidade, quando comparada à osteopenia dos animais HNC, foi variável e dependente do sítio ósseo estudado. Apesar de causar necrose dos ossos de maior metabolismo, a associação hipotireoidismo-castração não potencializou a osteopenia decorrente da ação isolada do hipotireoidismo até os 120 dias de tratamento. The effect of hypothyroidism on bone metabolism and the parathyroids in states of deficiency or sufficiency of sex steroids was studied in 32 two-months-old female Wistar rats distributed in 4 groups of 8 animals each: intact euthyroid (IE), castrated euthyroid (CE), intact hypothyroid (IH) and castrated hypothyroid (CH). After 120 days of treatment, animals were sacrificed and plasma taken to assess free T4. Hyperplasia or hypertrophy of all parathyroids were evident only in IH and CE groups. Of all groups, IH rats presented the most extensive osteopenia, reaching lumbar vertebrae, dental alveolae (jaw and mandible) and long bones. In this group osteopenia resulted from the reduced bone growth, inhibition of bone apposition and return of bone resorption. Although osteopenia in the CH group was almost always more intense in relation to osteopenia presented by CE rats, its intensity was variable when compared to IH rats and dependent on the region studied. Even though it also caused necrosis of higher metabolism bones, the association hypothyroidism-castration did not potentialize the resultant osteopenia of the isolated action of hypothyroidism or castration until 120 days of treatment.
Background: Scorpionism is a worldwide medical issue, especially relevant in the tropical and subtropical countries. Tityus serrulatus is the species responsible for most cases in Brazil. Antivenom administration to victims is the sole specific therapy obtained from donor animals. Most of these donors suffer with symptoms of the poisoning, debilitating their health and reducing their life expectancy. The aim of the present research was to evaluate whether the immunogens prepared from the crude and detoxified venom of T. serrulatus promoted different changes in fractionated sheep plasma proteins, during a scorpion antivenom serum production.Materials, Methods & Results: Twelve sheep, healthy, mean weight of 30 kg, were distributed into 3 groups (n = 4): G1 (control), G2 (crude venom) and G3 (detoxified venom). The adopted immunization protocol (first cycle) had 6 doses, 3 using Freund's adjuvant, with a 21-day interval between each one (day 0, 22 and 43), and 3 doses with no adjuvant (booster) and 0.2 mg of antigen (reinforcement), spaced 3 days between each other (day 50, 53 and 56). Group control (G1) received 6 immunizations with phosphate buffered saline (PBS) associated with Freund's adjuvant (1:1), while the other 2 groups received 0.5 mg of venom (G2) and detoxified venom (G3), respectively, diluted in PBS, associated with the Freund adjuvant. The boosters were 1/3 of the initial dose, diluted only PBS. At baseline (T0) and at 24 and 48 h after immunization, all animals underwent clinical examinations. Blood samples were collected at day 0, 22, 43, 53 and 56 for proteinogram analysis. Total protein, albumin and globulins fractions were measured. Plasma albumin concentration at T0 ranged from 3.41-4.86 g/dL, with a mean value of 4.12 g/dL. There was no statistical difference between the 3 experimental groups. The normal values determined for α-globulin range from 0.14 to 0.54 g/dL, with a mean of 0.31 g/dL (T0). There was a significant increase in the 3rd immunization and its respective interval (24-48 h), with values above normal in all groups: G1 (0.66 g/dL), G2 (0.62 g/dL) and G3 (0.65g/dL). The β-globulin was subdivided into β1 and β2 globulin. At T0, the normal values of β1 ranged from 0.45 to 1.05 g/dL, with a mean of 0.664 g/dL, and no significant change was observed in this classification. On the other hand, there was an abrupt increase in β2 in all groups after the first immunization, compared to the baseline value in T0 (0.37 g/dL mean value). From the third to the 6th immunization, there was an important reduction in β2 fraction when compared with baseline value. The γ-globulins fraction ranged from 0.80 g/dL to 76 g/dL. In the 6th immunization, there was a significant difference between G1 and the groups that received venom (G2 and G3). Therefore, all animals presented an acute inflammatory response, evidenced by the significant reduction of plasma albumin and an increase in α-globulin and β2-globulin. It is important to point out that T. serrulatus detoxified venom did not cause alterations in ovine proteinogram during the first cycle of immunization.Discussion: The fact that both groups (G2 and G3) presented acute inflammatory response, indicates that this alteration is caused by the adjuvant present in the immunization protocol. Tityus serrulatus venom detoxified with glutaraldehyde did not ~cause significant alterations in ovine proteinogram in the early stages, suggesting that itmay be used as an alternative antigen for the production of antivenom, improving clinical conditions of donor animals.Keywords: scorpion, clinical pathology, ruminants, inflammation, antiserum.Título: Proteinograma de ovelhas imunizadas com veneno detoxificado do escorpião Tityus serrulatusDescritores: escorpião, patologia clínica, ruminantes, inflamação, antisoro.
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