To provide theoretical and practical basis for the successful formulation design of physically-mixed inhalation dry powder of proteins and peptides, related references were collected, analyzed and summarized. In this review drug micronization technology and commonly used carriers for inhalation dry powder preparation were introduced. For proteins and peptides, supercritical fluid technology and spray-drying are more suitable because of their capabilities of keeping drug activity. Being approved by U. S. Food and Drug Administration, lactose has been extensively used as carriers in many inhalation products. Formulation and process factors influencing drug deposition in the lung, including carrier properties, drug-carrier ratio, blending order, mixing methods, mixing time and the interaction between drug and carrier, were elucidated. The size, shape and surface properties of carries all influence the interaction between drug and carrier. Besides, influence of micromeritic properties of the dry powder, such as particle size, shape, density, flowability, charge, dispersibility and hygroscopicity, on drug deposition in the lung was elaborated. Among these particle size plays the most crucial role in particle deposition in the lung. Moreover, based on the mechanisms of powder dispersity, some strategies to improve drug lung deposition were put forward, such as adding carrier fines, adding adhesive-controlling materials and reprocessing micronized drug. In order to design physically-mixed inhalation dry powder for proteins and peptides with high lung deposition, it is essential to study drug-carriers interactions systematically and illustrate the potential influence of formulation, process parameters and micromeritic properties of the powder.
Administration, Inhalation ; Drug Carriers ; chemistry ; Dry Powder Inhalers ; Lactose ; chemistry ; Particle Size ; Peptides ; administration & dosage ; Powders ; administration & dosage ; Surface Properties ; Technology, Pharmaceutical

Animals ; Bacterial Toxins ; administration & dosage ; Biological Transport ; Cell Membrane Permeability ; Drug Delivery Systems ; Endocytosis ; Liposomes ; chemistry ; Peptides ; administration & dosage ; Viral Envelope Proteins ; administration & dosage

OBJECTIVETo investigate the therapeutic effect of Lugua polypeptide on active rheumatoid arthritis (RA).

METHODSFifty patients with active RA were selected for the study and were randomly divided into study group and control group. Patients in study group were treated with Lugua polypeptide intravenously at a dose of 16 mg per day and those in control group were given Celecoxib 200 mg twice a day for successive 2 weeks. Two groups were given the same basic treatment. Tenderness and swelling of joints, morning stiffness, erythrocyte sedimentation rate, C-reactive protein,rheumatoid factor and so on were recorded before and after treatment.

RESULTSThe above index on joints in study group was significantly improved compared with that in control group and the level before treament. No apparent side effects were observed.

CONCLUSIONLugua polypeptide is effective and safe on active RA. It is a promising agent in the treatment of RA.

Adult ; Aged ; Anti-Inflammatory Agents, Non-Steroidal ; administration & dosage ; Arthritis, Rheumatoid ; drug therapy ; Female ; Humans ; Injections ; Male ; Middle Aged ; Peptides ; administration & dosage

PURPOSE: Nociceptin/orphanin FQ (N/OFQ) as an endogeneous hexadecapeptide is known to exert antinociceptive effects spinally. The aims of this study were to demonstrate the antinociceptive effects of i.t. N/OFQ and to investigate the possible interaction between N/OFQ and endogenous opioid systems using selective opioid receptor antagonists in rat formalin tests. MATERIALS AND METHODS: I.t. N/OFQ was injected in different doses (1-10 nmol) via a lumbar catheter prior to a 50 microL injection of 5% formalin into the right hindpaw of rats. Flinching responses were measured from 0-10 min (phase I, an initial acute state) and 11-60 min (phase II, a prolonged tonic state). To observe which opioid receptors are involved in the anti-nociceptive effect of i.t. N/OFQ in the rat-formalin tests, naltrindole (5-20 nmol), beta-funaltrexamine (1-10 nmol), and norbinaltorphimine (10 nmol), selective delta-, micro- and kappa-opioid receptor antagonists, respectively, were administered intrathecally 5 min after i.t. N/OFQ. RESULTS: I.t. N/OFQ attenuated the formalin-induced flinching responses in a dose-dependent manner in both phases I and II. I.t. administration of naltrindole and beta-funaltrexamine dose-dependently reversed the N/OFQ-induced attenuation of flinching responses in both phases; however, norbinaltorphimine did not. CONCLUSION: I.t. N/OFQ exerted an antinociceptive effect in both phases of the rat-formalin test through the nociceptin opioid peptide receptor. In addition, the results suggested that delta- and micro-opioid receptors, but not kappa-opioid receptors, are involved in the antinociceptive effects of N/OFQ in the spinal cord of rats.
Analgesics/administration & dosage/*pharmacology ; Animals ; Formaldehyde/toxicity ; Injections, Spinal ; Male ; Naltrexone/administration & dosage/analogs & derivatives/pharmacology ; Narcotic Antagonists/administration & dosage/*pharmacology ; Opioid Peptides/administration & dosage/*pharmacology ; Pain Measurement ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid/*agonists/drug effects

The oral administration of bioactive macromolecular drugs such as proteins, peptides and nucleic acids represents unprecedented challenges from the drug delivery point of view. One key consideration is how to overcome the gastrointestinal tract absorption barrier. Recent studies suggest that microfold cell (M cell), a kind of specialized antigen-sampling epithelial cell which is characterized by a high endocytic rate and low degradation ability, may play an important role in macromolecule oral absorption. The development of an in vitro M cell coculture system and its modified models greatly advanced the study of M cells and the development of oral delivery system for macromolecular drugs. The special structure, function and formation characteristics, and biomarkers of M cell are summarized in this review. The applications of in vitro M cell models in developing oral delivery system ofbioactive macromolecular drugs are discussed.
Administration, Oral ; Animals ; Drug Delivery Systems ; methods ; Humans ; Intestinal Mucosa ; cytology ; Macromolecular Substances ; administration & dosage ; pharmacokinetics ; Models, Biological ; Peptides ; administration & dosage ; pharmacokinetics ; Peyer's Patches ; cytology ; Proteins ; administration & dosage ; pharmacokinetics ; Vaccines ; pharmacokinetics

The combined use of batifiban, a synthetic platelet GPII b/ IIIa receptor antagonist, and antithrombin agents is an attractive option for the treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) and those scheduled for percutaneous coronary intervention. To observe whether antithrombin agents affect the pharmacokinetic and pharmacodynamic properties of batifiban in combination therapy and optimize clinical administration dosage of batifiban, an open-label and parallel study was conducted. Thirty healthy subjects were randomly divided into three groups, which were sequentially treated with batifiban alone, or oral coadministration of clopidogrel, aspirin and UFH, or batifiban coadministered with these antithrombin agents. Blood samples were collected at pre-specified time points. The evaluation index included the inhibition of platelet aggregation and pharmacokinetic parameters. The pharmacokinetic parameters of batifiban and batifiban coadministered with antithrombin agents showed no significant differences. The mean inhibition rate of platelet aggregation (%) suggested that neither batifiban alone nor antithrombin agents alone could provide such potent inhibition rate (>80%) to obtain the best clinical efficacy, but they had a synergistic effect on platelet inhibition. No serious adverse effects were observed. The results in these healthy subjects suggest that batifiban coadministrated with antithrombin agents could achieve optimum clinical treatment effect for patients with NSTE ACS, and also those scheduled for percutaneous coronary intervention.
Administration, Oral ; Adolescent ; Adult ; Area Under Curve ; Aspirin ; administration & dosage ; pharmacology ; China ; Drug Administration Schedule ; Female ; Fibrinolytic Agents ; administration & dosage ; pharmacology ; Heparin ; administration & dosage ; pharmacology ; Humans ; Infusions, Intravenous ; Injections, Intravenous ; Male ; Metabolic Clearance Rate ; drug effects ; Peptides, Cyclic ; administration & dosage ; pharmacokinetics ; Platelet Aggregation Inhibitors ; administration & dosage ; pharmacokinetics ; Ticlopidine ; administration & dosage ; analogs & derivatives ; pharmacology ; Time Factors ; Young Adult

Lipoproteins are biological lipids carriers. The natural and reconstituted lipoprotein based drug delivery systems have been extensively developed in recent years. This article reviews the development of natural and reconstituted low-density lipoprotein and high-density lipoprotein based vehicles in the antitumor area.
Animals ; Antineoplastic Agents ; administration & dosage ; chemistry ; Apolipoproteins B ; administration & dosage ; chemistry ; Drug Carriers ; administration & dosage ; chemistry ; Humans ; Lipoproteins ; administration & dosage ; chemistry ; Lipoproteins, HDL ; administration & dosage ; chemistry ; Lipoproteins, LDL ; administration & dosage ; chemistry ; Nanoparticles ; Neoplasms ; drug therapy ; Peptides ; administration & dosage ; chemistry ; Pharmaceutical Vehicles ; chemistry

OBJECTIVETo elucidate the inhibitory effects of recombinant Chinese scorpion neurotoxin BmK IM on seizures induced by pentylenetetrazol (PTZ) and the possible mechanism.

METHODSAfter purifying recombinant BmK IM from an E. coli cell line, its toxicity (both LD50 and minimum lethal dose) on rats was determined. BmK IM was then microinjected into the CA3 region of the right hippocampus and its ability to inhibit the effects of an intraperitoneal injection of PTZ was assessed. The effects of BmK IM on the electrophysiological properties of isolated CA3 pyramidal neurons were then studied using whole-cell patch clamp techniques.

RESULTSBmK IM can significantly prolong the latent period of epileptic seizures, decrease the degree of seizures, and decrease the frequency of epileptiform discharges induced by PTZ. At the same time, 24h after injection of BmK IM into the hippocampal tissue, BmK IM significantly reduces the concentration of the neurotransmitter glutamate and alleviates PTZ-induced lesions in the hippocampus. Whole-cell patch clamp recordings indicate that BmK IM inhibits INa of rat hippocampal neurons in a dose-dependent manner. BmK IM significantly shifts the activation curve of INa in a positive direction, indicating that BmK IM enhances the threshold potential of INa.

CONCLUSIONSBmK IM has significant anti-epileptic properties, and may prove useful as a drug in the therapy of epilepsy. The inhibitory effects of BmK IM on seizures caused by pentylenetetrazol might depend on reductions in the release of presynaptic glutamate via the blocking of Na+ channels.

Animals ; Glutamine ; secretion ; Hippocampus ; drug effects ; Male ; Microinjections ; Pentylenetetrazole ; Peptides ; administration & dosage ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins ; administration & dosage ; therapeutic use ; Scorpion Venoms ; administration & dosage ; therapeutic use ; Seizures ; chemically induced ; prevention & control ; Sodium Channels ; drug effects

This study was aimed to investigate the effect of bortezomib combined with bisphosphonates on serum levels of DKK-1 and RANKL in multiple myeloma patients, and to evaluate its role in the therapy of osteolytic lesion. Fourty-three patients with newly diagnosed and relapsed myeloma were divided into 2 groups. Twenty-three patients were treated with bortezomib combined with bisphosphonates (A group) and 20 patients were treated with bisphosphonates combined with traditional chemotherapy (B group). Serum levels of DKK-1 and RANKL were measured by ELISA before and after 4 cycles of chemotherapy. The results indicated that serum DKK-1 level significantly decreased in patients of A group (43.2 µg/L before vs 30.4 µg/L after 4 cycles of chemotherapy), and so did for serum RANKL level in A group (0.83 pmmol/L before vs 0.45 pmmol/L after 4 cycles of chemotherapy). While there was no significant differences in DKK-1 and RANKL serum level before therapy between A and B groups, but there was significant differences in DKK-1 and RANKL levels after 4 cycles of chemotherapy (P < 0.05). It is concluded that bortezomib combined with bisphosphonates obviously reduce the serum levels of DKK-1 and RANKL, thus has beneficial effect on osteolytic lesion.
Adult ; Aged ; Boronic Acids ; administration & dosage ; therapeutic use ; Bortezomib ; Diphosphonates ; administration & dosage ; therapeutic use ; Drug Therapy, Combination ; Female ; Humans ; Intercellular Signaling Peptides and Proteins ; blood ; Male ; Middle Aged ; Multiple Myeloma ; blood ; drug therapy ; Pyrazines ; administration & dosage ; therapeutic use ; RANK Ligand ; blood

OBJECTIVETo explore the difference of effects of two regimens (bortezomib and dexamethasone, BD; and thalidomide and dexamethasone, TD) on bone disease in multiple myeloma (MM).

METHODSForty patients with newly diagnosed and refractory or relapsed MM were treated with BD or TD regimens from Dec 2006 to Sep 2008. Bone pain score and X-ray examination were carried out before and after therapy. Serum levels of DKK-1, sRANKL, OPG and TRACP-5b were measured by ELISA before and 3 months after therapy.

RESULTSSerum TRACP-5b concentration was significantly decreased in patients received TD regimen (5.94 U/L before therapy vs 4.84 U/L 3 months after therapy, P < 0.05), and so did for serum DKK-1 concentration in patients responded to BD regimen (35.11 µg/L before vs 32.03 µg/L 3 months after therapy, P < 0.05); for serum concentration of sRANKL in patients responded to BD regimen (1.05 pmol/L before vs 0.67 pmol/L 3 months after therapy, P < 0.05); and for serum concentration of TRACP-5b in responders to BD regimen (5.57 U/L before therapy vs 4.90 U/L 3 months after therapy, P < 0.05).

CONCLUSIONBortezomib lowers levels of serum DKK-1 and RANKL in responders, thus leads to normalization of abnormal bone remodeling through the increase of bone formation and reduction of bone resorption. Thalidomide decreases bone resorption regardless of treatment response.

Adult ; Aged ; Antineoplastic Agents ; administration & dosage ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; therapeutic use ; Bone Resorption ; drug therapy ; Boronic Acids ; administration & dosage ; Bortezomib ; Dexamethasone ; administration & dosage ; Female ; Humans ; Intercellular Signaling Peptides and Proteins ; blood ; Male ; Middle Aged ; Multiple Myeloma ; drug therapy ; Pyrazines ; administration & dosage ; RANK Ligand ; blood ; Thalidomide ; administration & dosage