Aspects of the pharmacology of a new anthelmintic: Pyrantel

1. The pharmacological properties of an anthelmintic, pyrantel, and some of its analogues have been described and compared with piperazine in a variety of vertebrate and helminth preparations.2. Pyrantel and its analogues in common with nicotine and decamethonium cause spastic paralysis in chicks and contracture of the chick semispinalis and toad rectus abdominis muscles.3. In the soleus and anterior tibialis muscles of the cat, pyrantel in large amounts caused a short-lived neuromuscular block that was preceded by initial depolarization.4. In preparations from cat and rat, pyrantel showed properties common to both competitive and depolarizing neuromuscular blocking drugs.5. Pyrantel blocked the contracture evoked by transmural stimulation and caused a marked contracture of the worm. Piperazine caused a gradually developing reduction in the responses to transmural stimulation and no contracture.6. Pyrantel and its analogues caused a slowly developing contracture of strip preparations of Ascaris, being more than 100 times more active than acetylcholine in this respect. Piperazine caused a relaxation of Ascaris strip preparations and in common with (+)-tubocurarine blocked the responses to acetylcholine and pyrantel analogues on this preparation.7. Pyrantel caused depolarization and increased spike discharge frequency in single muscle cells of Ascaris, these changes being accompanied by increase in tension. Piperazine, on the other hand, caused hyperpolarization and reduction in spike discharge frequency and relaxation, and antagonized the effects of pyrantel.     

Preoperative blood volume deficit influences blood transfusion requirements in females and males undergoing coronary bypass graft surgery

STUDY OBJECTIVE: To evaluate whether preoperative blood volume and postoperative blood loss influence blood transfusion in females and males undergoing coronary artery bypass graft (CABG) surgery. DESIGN: Prospective study. SETTING: Anesthesiology department of a teaching hospital. PATIENTS: 57 CABG patients (21 females and 36 males). MEASUREMENTS: Blood volume was determined using the radioactivity dilution method. Preoperatively, each patient received intravenous (IV) injection of 1 mL Albumin I(131) tracer having 25 microcuries of radioactivity. Five-milliliter blood samples were collected at different intervals. From these samples, hematocrit (Hct) value, preoperative total blood volume, red blood cell (RBC) volume, and plasma volume were determined. Postoperatively, some consenting patients received another 1 mL dose of the tracer, and the postoperative blood volumes were determined. If a patient received a blood transfusion, the units of packed red blood cells (PRBCs), platelets, or fresh frozen plasma (FFP) transfused were recorded. For each patient we recorded the gender, age, weight, height, body surface area (BSA), preoperative Hct, duration of surgery, and discharge Hct. RESULTS: Preoperatively, the mean total blood volume, RBC volume, and plasma volume, respectively, were 2095 mL/m(2), 631 mL/m(2), and 1,465 mL/m(2) in females; and 2,580 mL/m(2), 878 mL/m(2), and 1,702 mL/m(2) in males. The preoperative blood volumes were significantly lower (p < 0.01) in females than in males. There was no significant difference between males and females in the extent of blood loss during CABG. Intraoperatively, females received PRBC transfusion of 1.38 units, significantly more (p < 0.01) than the 0.39 units received by males. During the entire hospital stay, females received 4.33 units of PRBC, significantly more than (p < 0.02) the 1.33 units received by males. Significantly more (p < 0.01) females (12 of 21) received intraoperative PRBC transfusion than did males (6 of 36). Multiple logistic regression analysis of the data showed that PRBC transfusion was significantly correlated with the preoperative total blood volume and RBC volume. CONCLUSION: The greater need for blood transfusion in females than in males during CABG is primarily attributable to significantly lower preoperative total blood volume and RBC volume in females.     

Immune functions, clinical parameters and hormone receptor status in breast cancer patients

We have carried out a detailed analysis of the cellular immune functions of breast cancer patients in comparison with healthy controls. A possible correlation between immune and clinical parameters was analysed in 50 breast cancer patients. Immune parameters, natural killer cell and T lymphocyte functions and the numbers of circulating T lymphocytes were analysed against the clinical parameters comprising the tumour burden, the stage of the disease and the expression of hormone receptors on the tumour. In order to analyse the immune function data effectively, low responders were identified with stringent cut-off values. Considerably higher proportions of low responders were found among the patient population. Elevated numbers of circulating T lymphocytes and CD3-directed cytolysis correlated with the expression of oestrogen receptors independently of the clinical/histological parameters. Received: 11 September 1998 / Accepted: 7 December 1998     

Metastasis suppressor pathways--an evolving paradigm

A greater understanding of the processes of tumor invasion and metastasis, the principal cause of death in cancer patients, is essential to determine newer therapeutic targets. Metastasis suppressor genes, by definition, suppress metastasis without affecting tumorigenicity and, hence, present attractive targets as prognostic or therapeutic markers. This short review focuses on those twelve metastasis suppressor genes for which functional data exist. We also outline newly identified genes that bear promising traits of having metastasis suppressor activity, but for which functional data have not been completed. We also summarize the biochemical mechanism(s) of action (where known), and present a working model assembling potential metastasis suppression pathways.     

IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor gamma 1

IL-4 is a pleiotropic immune cytokine secreted by activated T(H)2 cells that inhibits bone resorption both in vitro and in vivo. The cellular targets of IL-4 action as well as its intracellular mechanism of action remain to be determined. We show here that IL-4 inhibits receptor activator of NF-kappaB ligand-induced osteoclast differentiation through an action on osteoclast precursors that is independent of stromal cells. Interestingly, this inhibitory effect can be mimicked by both natural as well as synthetic peroxisome proliferator-activated receptor gamma1 (PPARgamma1) ligands and can be blocked by the irreversible PPARgamma antagonist GW 9662. These findings suggest that the actions of IL-4 on osteoclast differentiation are mediated by PPARgamma1, an interpretation strengthened by the observation that IL-4 can activate a PPARgamma1-sensitive luciferase reporter gene in RAW264.7 cells. We also show that inhibitors of enzymes such as 12/15-lipoxygenase and the cyclooxygenases that produce known PPARgamma1 ligands do not abrogate the IL-4 effect. These findings, together with the observation that bone marrow cells from 12/15-lipoxygenase-deficient mice retain sensitivity to IL-4, suggest that the cytokine may induce novel PPARgamma1 ligands. Our results reveal that PPARgamma1 plays an important role in the suppression of osteoclast formation by IL-4 and may explain the beneficial effects of the thiazolidinedione class of PPARgamma1 ligands on bone loss in diabetic patients.     

Dickkopf1: A tumor suppressor or metastasis promoter?

Dickkopf1 (DKK1), a secreted inhibitor of the Wnt/β‐catenin pathway, is a negative regulator of bone formation. DKK1 acts as a switch that transitions prostate cancer bone metastases from osteolytic to osteoblastic and also is an active indicator of poor outcome for multiple myeloma. However, in other tumor types, DKK1 upregulation or overexpression suppresses tumor growth. Thus, the role of DKK1 in cancer appears to be diverse. This raises a question: Could the increased levels of DKK1 still be tumor protective when observed in high levels in the serum of patients? Here, we summarize the diverse, seemingly contradicting roles of DKK1 and attempt to explain the apparent dichotomy in its activity. We propose that DKK1 is a critical secreted factor that modulates microenvironment. Based on the location and components of the microenvironment DKK1 will support different outcomes.