A Clinical Trial on Biological Half Life of Bioactive Protein from Lumbricus rubellus, DLBS1033 in Healthy Volunteers.

BACKGROUND: DLBS1033 is a bioactive protein fraction extracted from Lumbricus rubellus, with fibrinogenolytic, fibrinolytic and anti-aggregation activities reported in an in vitro study. Plasma half-life is an important parameter to calculate its dose. This study was conducted to evaluate the biological half-life of DLBS1033 by measuring serial plasmin-antiplasmin (PAP) complex. PAP complex is a stable and inactive compound as a result of fibrinolysis process. METHODS: this was an open-label clinical trial in healthy adult subjects. Subjects were divided into two groups to receive single dose drugs (received 3 x 490 mg) or repeated administration until steady state conditions (3 x 490 mg/day for 3 days). Blood samples for PAP complex measurement were collected at time 0 (before drug administration for single dose group), then at 0.5, 1, 1.5, 2, 3, 6, 8, 10, 12, and 24 hours after drug administration. Safety parameters used in this study were creatinine, prothrombin time (PT), activated partial thromboplastin time (aPTT), SGOT, and SGPT. RESULTS: the biological half-life of DLBS1033 was calculated based on the mean of PAP complex concentration on each time sampling. In single dose group, the highest mean of PAP complex concentration was reached before drug administration. Our result showed that the activity of DLBS1033 could not be determined after single dose administration. In steady state condition, the PAP complex concentration increase in 2 hours after last drug administration. The biological half-life of DLBS1033 was 8.6 hours. There were no significant safety findings on all laboratory parameters and no serious adverse events. CONCLUSION: it is concluded that the fibrinolytic effects of DLBS1033 can be measured in steady state condition. The biological half-life of DLBS1033 in steady state condition was 8.6 hours. There were no serious adverse events on two groups of subjects.

HISTORICAL AND CURRENT PERSPECTIVE IN THE USE OF THYROID EXTRACTS FOR THE TREATMENT OF HYPOTHYROIDISM.

OBJECTIVE: To describe the history, refinements, implementation, physiology, and clinical outcomes achieved over the past several centuries of thyroid hormone replacement strategies. METHODS: A Medline search was initiated using the following search terms: bioidentical thyroid hormone, thyroid hormone extract, combination thyroxine (T4) and tri-iodothyronine (T3) therapy, homeopathic thyroid hormone therapy, and thyroid hormone replacement. Pertinent articles of interest were identified by title (and where available abstract) for further review. Additional references were identified during a review of the identified literature. RESULTS: A rich history of physician intervention in thyroid dysfunction was identified dating back more than 2 millennia. Although not precisely documented, thyroid ingestion from animal sources had been used for centuries but was finally scientifically described and documented in Europe over 130 years ago. Since the reports by Bettencourt and Murray, there has been a continuous documentation of outcomes, refinement of hormone preparation production, and updating of recommendations for the most effective and safe use of these hormones for relieving the symptoms of hypothyroidism. As the thyroid extract preparations contain both levothyroxine (LT4) and liothyronine (LT3), current guidelines do not endorse their use as controlled studies do not clearly document enhanced objective outcomes compared with LT4 monotherapy. Among current issues cited, the optimum ratio of LT4 to LT3 has yet to be determined, and the U.S. Food and Drug Administration (FDA) does not appear to be monitoring the thyroid hormone ratios or content in extract preparations on the market. Taken together, these limitations are important detriments to the use of thyroid extract products. CONCLUSION: The evolution of thyroid hormone therapies has been significant over the extended period of time they have been in use to treat hypothyroidism. Although numerous websites continue to advocate the use of thyroid hormone extracts as a superior therapy for hypothyroidism, none of the most recent guidelines of major endocrine societies recommend thyroid extract use for hypothyroidism.

Pharmacokinetics, tissue distribution and excretion of isoalantolactone and alantolactone in rats after oral administration of Radix Inulae extract.

Radix Inulae is endemic to China and has been used in traditional medicine to treat upper body pain, emesis and diarrhoea, and to eliminate parasites. Here, an UPLC-MS/MS method was developed and applied to study the pharmacokinetics, distribution and excretion of isoalantolactone and alantolactone, which are two main active sesquiterpene lactones in Radix Inulae, in Sprague-Dawley rats following oral administration of total Radix Inulae extract. Isoalantolactone, alantolactone and osthole (internal standard) were prepared using acetonitrile precipitation, and the separation of isoalantolactone and alantolactone was achieved by isocratic elution using water (containing 0.1% formic acid) and acetonitrile as the mobile phase using a ZORBAX Eclipse Plus C18 column. The total run time was 6.4 min. The present study showed poor absorption of isoalantolactone and alantolactone in vivo. The apparent Cmax, Tmax, T1/2 and total exposure (AUC0-12h) in rat plasma were 37.8 ng/mL, 120 min, 351.7 min and 6112.3 ng-min/mL for isoalantolactone and 25.9 ng/mL, 90 min, 321.0 min and 4918.9 ng-min/mL for alantolactone, respectively. It was shown that the highest concentration was achieved in the small intestine and feces clearance was shown to be the dominant elimination pathway of the lactones.

Neurotoxicity in rats induced by the poisonous dreamfish (Sarpa salpa).

CONTEXT: Consumption of Sarpa salpa Linn. (Sparidae) in certain periods of the year is inadvisable because it can cause central nervous system disorders resulting in sea food poisoning. AIMS: The present study assesses the cytotoxic effects of compounds, not-yet identified, present in the organ extracts of S. salpa, collected in autumn, the period corresponding to the peak in human health problems. MATERIALS AND METHODS: The toxicity was assessed by mouse bioassay of aqueous extract of the fish organs. Wistar rats received daily extracts of different organs of S. salpa by gastric gavage for 7 d (0.3 mL of extract/100 g body weight BW). The dose of tissue extracts of viscera, liver, brain, and flesh of S. salpa administered to rats was as follows: 172, 313, 2050, and 2660 mg/kg BW, respectively. No deaths occurred during the period of treatment. RESULTS: The lethal dose (LD50) determined for the crude ciguatoxin (neurotoxins) extracts of viscera, liver, brain, and flesh of S. salpa was as follows: 1.2, 2.2, 14.4, and 18.6 g/kg mouse, respectively. Changes in locomotor activity during the first 2 h and failure in breathing and no evident signs of gastrointestinal problems were recorded. We observed (1) induction of oxidative stress, indicated by an increase in lipid peroxidation (TBARS) in groups that received extracts of liver (+425%) or viscera (+433%), and a significant decrease in antioxidant enzyme activities (SOD, CAT, and GPx) in cerebral cortex tissue by 13%, 25%, and 25% (LT: animals receiving liver extracts) and by 16%, 26%, and 27% (VT: animals receiving viscera extracts), respectively. In contrast, the administration of extracts of flesh and brain induced an increase in antioxidant enzyme activities (SOD, CAT, and GPx) in cerebral cortex tissue by 26%, 23%, and 44% (FT: flesh extract) and 28%, 24%, and 46% (BT: brain extract), respectively; (2) a significant decrease for acetylcholinesterase (AChE) activity in cerebral cortex was recorded in FT, BT, LT, and VT by 27, 34, 58, and 78%, respectively. Moreover, a significant decrease of AChE activity in plasma was recorded in FT, BT, LT, and VT by 16, 21, 38, and 48%, respectively; (3) the histological findings confirmed the biochemical results. CONCLUSIONS: Liver and especially the visceral part of S. salpa presented toxicity, which clearly indicates the danger of using this fish as food.

New agents for the management of castration-resistant prostate cancer.

OBJECTIVE: To review the activity of 3 new agents approved for the management of advanced castration-resistant prostate cancer (CRPC): sipuleucel-T, cabazitaxel, and abiraterone acetate. DATA SOURCES: Literature was accessed through MEDLINE (1977-June 2012) and abstracts from the American Society of Clinical Oncology (2000-2012) using the terms castration-resistant and hormone-refractory prostate cancer, sipuleucel-T, cabazitaxel, abiraterone, Provenge, Jevtana, and Zytiga. Reference citations from publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Articles identified from the data sources in English on human subjects were evaluated. DATA SYNTHESIS: Options for patients with CRPC have been limited, with little to offer those who failed or could not tolerate docetaxel-based therapy. Three new drugs, with very different mechanisms of action, have changed that and will undoubtedly change the treatment paradigm for these patients. Each agent has demonstrated an impact on patient survival. Sipuleucel-T, the first immunotherapy approved for treatment of CRPC, improved median overall survival by 4.1 months and reduced the risk of death by 22% in a placebo-controlled trial of asymptomatic patients. Sipuleucel-T can be administered prior to docetaxel-based therapy. Cabazitaxel, a taxane chemotherapy agent, improved median overall survival by 2.4 months and reduced the risk of death by 30% in a Phase 3 trial of patients whose cancer progressed during or after docetaxel-based therapy. Abiraterone acetate, a hormonal therapy, improved median overall survival by 3.9 months and reduced the risk of death by 35% in patients with relapse during or after docetaxel-based therapy. CONCLUSIONS: The advent of new agents for the management of advanced CRPC has increased the choices for patients whose options were limited. Additional experience will determine the optimal sequencing of these agents, their roles in combination therapy, and their activity in patients with earlier disease.

Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome.

PURPOSE: Antitumor activity of cancer immunotherapies may elicit immune responses to nontargeted (secondary) tumor antigens, or antigen spread. We evaluated humoral antigen spread after treatment with sipuleucel-T, an immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), designed to target prostatic acid phosphatase (PAP; primary antigen). EXPERIMENTAL DESIGN: Serum samples from patients with mCRPC enrolled in the placebo-controlled phase III IMPACT study (evaluable n = 142) were used to assess humoral antigen spread after treatment with sipuleucel-T. Immunoglobulin G (IgG) responses to self-antigens (including tumor antigens) were surveyed using protein microarrays and confirmed using Luminex xMAP. IgG responses were subsequently validated in ProACT (n = 33), an independent phase II study of sipuleucel-T. Association of IgG responses with overall survival (OS) was assessed using multivariate Cox models adjusted for baseline prostate-specific antigen (PSA) and lactate dehydrogenase levels. RESULTS: In patients from IMPACT and ProACT, levels of IgG against multiple secondary antigens, including PSA, KLK2/hK2, K-Ras, E-Ras, LGALS8/PCTA-1/galectin-8, and LGALS3/galectin-3, were elevated after treatment with sipuleucel-T (P < 0.01), but not control. IgG responses (≥ 2-fold elevation posttreatment) occurred in ≥ 25% of patients, appeared by 2 weeks after sipuleucel-T treatment, and persisted for up to 6 months. IgG responses to PSA and LGALS3 were associated with improved OS in sipuleucel-T-treated patients from IMPACT (P ≤ 0.05). CONCLUSIONS: Sipuleucel-T induced humoral antigen spread in patients with mCRPC. IgG responses were associated with improved OS in IMPACT. The methods and results reported may identify pharmacodynamic biomarkers of clinical outcome after sipuleucel-T treatment, and help in clinical assessments of other cancer immunotherapies. See related commentary by Hellstrom and Hellstrom, p. 3581.

Lysosomal trapping as an important mechanism involved in the cellular distribution of perazine and in pharmacokinetic interaction with antidepressants.

Perazine, a piperazine-type phenothiazine neuroleptic, is the most frequently chosen drug for combination with antidepressants in the therapy of complex or 'treatment-resistant' psychiatric illnesses. The aim of the present study was to investigate the contribution of lysosomal trapping to the total tissue uptake of perazine, and the pharmacokinetic interaction between the neuroleptic and antidepressants. Experiments were carried out on slices of different rat organs regarded as a system with functional lysosomes. To distinguish between lysosomal trapping and tissue binding, the experiments were performed in the absence or presence of 'lysosomal inhibitors', i.e. the lysosomotropic compound ammonium chloride or [H+] ionophore monensin, which abolish the pH-gradient of lysosomes. Under steady-state conditions, the highest tissue uptake of perazine was observed for the adipose tissue, which descended in the following order: the adipose tissue>lungs>liver>heart=brain>kidneys>muscles. The contribution of lysosomal trapping to the total tissue uptake amounted to about 40% in the liver, brain and muscles, to 30% in the kidneys, and to 25% in the heart and lungs. In the adipose tissue, no lysosomotropism of perazine was observed. Of the psychotropics studied, perazine was the only drug showing such a high degree of lysosomal trapping in muscles and distinct lysosomotropic properties in the heart. Perazine and the antidepressants used, both tricyclic (imipramine, amitriptyline) and selective serotonin reuptake inhibitors (fluoxetine, sertraline), mutually decreased their tissue uptake. The potency of imipramine to decrease perazine uptake was similar to that of the 'lysosomal inhibitors'. Other antidepressants seemed to exert a somewhat weaker effect. The above interactions between perazine and antidepressants were not observed in the presence of ammonium chloride, which indicates that they proceeded at the level of lysosomal trapping. The adipose tissue in which the drug uptake was not affected by the 'lysosomal inhibitors' was not the site of such an interaction. Ammonium chloride did not affect the drug metabolism in liver slices; other tissues displayed only a negligible biotransformation of the psychotropics studied. A parallel metabolic interaction between perazine and tricyclic antidepressants took part in liver slices (i.e. perazine and antidepressants mutually inhibited their metabolic pathways), but the influence of such an interaction on the lysosomal uptake of the parent compounds in liver slices did not seem to be great. A substantial decrease in concentrations of the drugs in lysosomes (depot form) observed in vitro may lead to an increase in the concentration in vivo of the neuroleptic and antidepressants at the site of action, which, in turn, may increase the risk of cardiotoxic and anticholinergic side-effects of tricyclic antidepressants and sedative and extrapyramidal effects of the neuroleptic.

[Pharmaokinetics of beta-escin after administration of various Aesculus extract containing formulations]. / Pharmakokinetik von beta-Aescin nach Gabe verschiedener Aesculus-Extrakt enthaltender Formulierungen.

With a specific radioimmunoassay the pharmacokinetics and relative bioavailability of escin was measured after administration of different formulations containing Aesculus-extract. Of special interest was the relative bioavailability of escin after administration of a newly developed film-coated tablet with sustained release in comparison to a reference formulation. In a cross-over steady-state study in 24 volunteers bioequivalence of test and reference preparation could be demonstrated. The 90% confidence interval of the AUC (O-tau) was 98.3 to 120.9%.

[Percutaneous penetration of mucopolysaccharide-polysulfate ester from a combination preparation]. / Zur perkutanen Penetration von Mucopolysaccharid-polyschwefelsäureester aus einem Kombinationspräparat.

The cutaneous penetration of mucopolysaccharide polysulfate (MPS) from a commercial available combination drug (Mobilat) could be shown by means of histochemical and immunohistological methods. Deposition of MPS from ointment and gel in corium and subcutis of different animal species has been improved by the keratolytic activity of the salicylic acid component. There are differences in the intensity of absorption of MPS not only in the various animal species, but also caused by the particular galenic preparations investigated.

Calcium bioavailability of a total bone extract (TBE) and its effects on bone metabolism in rats.

The effects of a total bone extract (TBE), a new mineral preparation made from bovine bone rendered soluble by lactic acid and citric acid under decompression, on the bone metabolism and apparent calcium absorption were examined for an ovariectomized (OVX) rat model of osteoporosis. The apparent calcium absorption from TBE was significantly higher than that from calcium carbonate. There were no significant differences in serum biochemical indices. Although there were no significant differences in the dry weight, ash and calcium content in the tibia, or in the bone mineral density of the femur, TBE feeding increased the cortical thickness index of the femur. A positive effect of TBE on bone formation is thus suggested.