Common deficiencies with bioequivalence submissions in abbreviated new drug applications assessed by FDA.

Purpose: A generic product must meet the standards established by the Food and Drug Administration (FDA) to be approved for marketing in the USA. FDA approves a generic product for marketing if it is proved to be therapeutically equivalent to the reference product. Bioequivalence (BE) between a proposed generic product and its corresponding reference product is one of the major components of therapeutic equivalence.

Activation of group I mGlu receptors contributes to facilitation of NMDA receptor membrane current in spinal dorsal horn neurons after hind paw inflammation in rats.

The interaction between the group I metabotropic glutamate (mGlu) receptors and N-methyl-D-aspartate (NMDA) receptors plays a critical role in spinal hyperexcitability and hyperalgesia. The cellular mechanisms underlying this interaction remain unknown. Utilizing an ex vivo spinal slice preparation from young adult rats, we investigated the group I mGlu receptor modulation of NMDA receptor-mediated current in superficial dorsal horn neurons by patch clamp recording after complete Freund's adjuvant (CFA)-induced hind paw inflammation.

Spinal 5-HT(3) receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade.

Recent studies indicate that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT(3) receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT(3) receptor and its contribution to facilitation of pain remain unclear. In the present study, activation of spinal 5-HT(3) receptor by intrathecal injection of a selective 5-HT(3) receptor agonist, SR57227, induced spinal glial hyperactivity, neuronal hyperexcitability, and pain hypersensitivity in rats.

The effects of opioid receptor antagonists on electroacupuncture-produced anti-allodynia/hyperalgesia in rats with paclitaxel-evoked peripheral neuropathy.

Research supports the effectiveness of acupuncture for conditions such as chronic low back and knee pain. In a five-patient pilot study the modality also improved the symptoms of chemotherapy-induced neuropathic pain. Using an established rat model of paclitaxel-induced peripheral neuropathy, we evaluated the effect of electroacupuncture (EA) on paclitaxel-induced hyperalgesia and allodynia that has not been studied in an animal model.

Serotonin Receptor 2A/C Is Involved in Electroacupuncture Inhibition of Pain in an Osteoarthritis Rat Model.

Osteoarthritis currently has no cure. Acupuncture can benefit patients with knee osteoarthritis by providing pain relief, improving joint function and serving as an effective complement to standard care. However, the underlying mechanisms of its effects are still not completely understood.

The role of trigeminal interpolaris-caudalis transition zone in persistent orofacial pain.

Previous studies have established the role of the medullary dorsal horn or the subnucleus caudalis of the spinal trigeminal complex, a homolog of the dorsal horn of the spinal cord, in trigeminal pain processing. In addition to the medullary dorsal horn, recent studies have pointed out increased excitability and sensitization of trigeminal interpolaris and caudalis transition zone (Vi/Vc) following deep orofacial injury, involving neuron-glia-cytokine interactions. The Vi/Vc transition zone accesses rostral brain regions that are important for descending pain modulation, and somatovisceral and somatoautonomic processing and plays a unique role in coordinating trigeminal nocifensive responses.

Acupuncture alleviates the affective dimension of pain in a rat model of inflammatory hyperalgesia.

Although studies demonstrate that electroacupuncture (EA) alleviates the sensory dimension of pain, they have not addressed EA's effect on the affective dimension. An inflammatory pain rat model, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a conditioned place avoidance test to determine EA's effects and its underpinning mechanism on the affective dimension of pain. CFA-injected rats showed place aversion, i.

Bone marrow stromal cells produce long-term pain relief in rat models of persistent pain.

Chronic pain conditions are difficult to treat and are major health problems. Bone marrow stromal cells (BMSCs) have generated considerable interest as a candidate for cell-based therapy. BMSCs are readily accessible and are easy to isolate and expand ex vivo.

[The operative treatment of Ruedi II-III Pilon fractures with the ventr-lateral approach].

Objective: To investigate the effects of the ventralateral approach in treating severe Pilon fracture.

Methods: From February 2002 to March 2008, 63 patients with Ruedi II-III Pilon fractures were treated with the ventralateral approach, including 36 males and 27 females with an average age of 37 years ranging from 19 to 71 years. The mean time from injury to operation was 8 days (ranged for 2 h-19 d).

Rostral ventromedial medulla μ, but not κ, opioid receptors are involved in electroacupuncture anti-hyperalgesia in an inflammatory pain rat model.

It has been reported that intracerebroventricular injection of a μ receptor antagonist blocked 2 but not 100Hz electroacupuncture (EA)-produced analgesia in an uninjured animal model. Because persistent pain changes neural response to external stimulation, we hypothesized that the mechanisms of EA anti-hyperalgesia may be different in persistent pain than in health. Hyperalgesia, decreased paw withdrawal latency (PWL) to a noxious thermal stimulus, was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the hind paws of rats.

Involvement of spinal serotonin receptors in electroacupuncture anti-hyperalgesia in an inflammatory pain rat model.

We previously showed that electroacupuncture (EA) activates medulla-spinal serotonin-containing neurons. The present study investigated the effects of intrathecal 5,7-dihydroxytryptamine creatinine sulfate, a selective neurotoxin for serotonergic terminals, the 5-hydroxytryptamine 1A receptor (5-HT1AR) antagonist NAN-190 hydrobromide and the 5-HT2C receptor (5-HT2CR) antagonist SB-242,084 on EA anti-hyperalgesia. EA was given twice at acupoint GB30 after complete Freund's adjuvant (CFA) injection into hind paw.

Early detection and treatment of wear particle-induced inflammation and bone loss in a mouse calvarial osteolysis model using HPMA copolymer conjugates.

Wear particle-induced inflammation is considered to be the major cause of aseptic implant loosening and clinical failure after total joint replacement. Due to the frequent absence of symptoms, early detection and intervention prior to implant failure presents a significant challenge. To address this issue, a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based optical imaging contrast agent (P-IRDye) was developed and used for the detection of wear particle-induced inflammation employing a murine calvaria osteolysis model.

Enhanced aqueous solubility and bioavailability of capsaicin by the preparation of an inclusion complex.

To increase the aqueous solubility and poor bioavailability of capsaicin (CAS 404-86-4), in this paper, the effects of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the aqueous solubility and the pharmacokinetic characteristics of capsaicin were investigated. The corresponding inclusion complex of capsaicin/HP-beta-CD at the molar ratio of 1:1 was obtained by the method of saturated aqueous solution and characterized by differential scanning calorimetry and X-ray diffractometry. The dissolution rate of capsaicin was significantly increased by the complexation with HP-beta-CD, due to its solubilizing activity.

Interactions between the immune and nervous systems in pain.

Immune cells and glia interact with neurons to alter pain sensitivity and to mediate the transition from acute to chronic pain. In response to injury, resident immune cells are activated and blood-borne immune cells are recruited to the site of injury. Immune cells not only contribute to immune protection but also initiate the sensitization of peripheral nociceptors.

Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia.

Background: Several classes of histone deacetylases (HDACs) are expressed in the spinal cord that is a critical structure of the nociceptive pathway. HDAC-regulated histone acetylation is an important component of chromatin remodeling leading to epigenetic regulation of gene transcription. To understand the role of histone acetylation in epigenetic regulation of pathological pain, we have studied the impact of different classes of HDACs in the spinal cord on inflammatory hyperalgesia induced by complete Freund's adjuvant (CFA).

Long lasting pain hypersensitivity following ligation of the tendon of the masseter muscle in rats: a model of myogenic orofacial pain.

Background: A major subgroup of patients with temporomandibular joint (TMJ) disorders have masticatory muscle hypersensitivity. To study myofacial temporomandibular pain, a number of preclinical models have been developed to induce myogenic pain of the masseter muscle, one of the four muscles involved in mastication. The currently used models, however, generate pain that decreases over time and only lasts from hours to weeks and hence are not suitable for studying chronicity of the myogenic pain in TMJ disorders.

Ectopic over-expression of oncogene Pim-2 induce malignant transformation of nontumorous human liver cell line L02.

In order to prove that ectopic over-expression of Pim-2 could induce malignant transformation of human liver cell line L02, three groups of cells were set up including human liver cell line L02 (L02), L02 cells transfected with Pim-2 gene (L02/Pim-2) and L02 cells transfected with empty-vector (L02/Vector). Pim-2 expression levels were detected. The morphology, proliferation level, apoptosis rate and migration ability of the cells were detected respectively.

Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain.

Recent studies indicate that persistent pain after tissue or nerve injury is accompanied by an enhanced net descending facilitatory drive that contributes to an amplification and spread of pain. Although 5-HT-containing neurons in the rostral ventromedial medulla (RVM) provide the major descending serotonergic projection to the spinal cord, it is not clear whether the neurotransmitter 5-HT itself released from RVM-spinal neurons contributes to descending pain modulation. In the present study, we determined the role of the descending 5-HT in rat nocifensive behaviors after persistent pain by selectively depleting functional phenotypes of 5-HT in RVM neurons with regional shRNA interference (RNAi) of tryptophan hydroxylase-2 (Tph-2), the rate-limiting enzyme in the synthesis of neuronal 5-HT.

[Hath1 gene transfer inhibits the proliferation of colonic cancer cells in vitro].

Objective: To study the effect of Hath1 gene transfer on the proliferation of colonic cancer cells in vitro.

Methods: The recombinant plasmid pcDNA3.1(+)-Hath1 was transfected into HT29 colonic cancer cells, and 3 positive cell clones were randomly selected to test the levels of Hath1 mRNA, Muc2 mRNA, Hath1, Muc2, cyclin D1 and p27 by quantitative real-time RT-PCR and Western blotting.

Emerging role of astroglia in pain hypersensitivity.

Recent studies suggest that astroglia, a major non-neuronal cell type in the central nervous system, actively participate in synaptic activity and potentially contribute to neurological disorders including chronic pain. Astroglia exhibit a hyperactive phenotype, also referred to as reactive astrocytosis, in response to peripheral injury. This process is often referred to as astroglial activation.

Lipid nanoparticles loaded with 10-hydroxycamptothecin-phospholipid complex developed for the treatment of hepatoma in clinical application.

For the purpose of clinical intravenous injection of 10-hydroxycamptothecin, a novel formulation of lipid nanoparticles loaded with 10-hydroxycamptothecin-phospholipid complex (HCPT-PC-LNs) was prepared by solvent evaporation and high-pressure homogenization methods. Spherical particles with a mean particle size of 200 nm and high encapsulation efficiency of 97.39 +/- 0.

Differential involvement of trigeminal transition zone and laminated subnucleus caudalis in orofacial deep and cutaneous hyperalgesia: the effects of interleukin-10 and glial inhibitors.

Background: In addition to caudal subnucleus caudalis (Vc) of the spinal trigeminal complex, recent studies indicate that the subnuclei interpolaris/caudalis (Vi/Vc) transition zone plays a unique role in processing deep orofacial nociceptive input. Studies also suggest that glia and inflammatory cytokines contribute to the development of persistent pain. By systematically comparing the effects of microinjection of the antiinflammatory cytokine interleukin (IL)-10 and two glial inhibitors, fluorocitrate and minocycline, we tested the hypothesis that there was a differential involvement of Vi/Vc and caudal Vc structures in deep and cutaneous orofacial pain.

Pim-2 activates API-5 to inhibit the apoptosis of hepatocellular carcinoma cells through NF-kappaB pathway.

Pim-2 is proved to be relevant to the tumorigenesis of hepatocellular carcinoma (HCC), but the mechanism is unclear. We studied the relationship among Pim-2, NF-kappaB and API-5. In our experiment, expression level of the three factors and phosphorylation level of API-5, as well as NF-kappaB activity, were detected in HCC tissues and the nontumorous controls.

Physicochemical characteristics and oral bioavailability of andrographolide complexed with hydroxypropyl-beta-cyclodextrin.

A significant increase in solubility of andrographolide (AND), a slightly water soluble anti-inflammatory and antimicrobial drug, was achieved by inclusion with hydroxypropyl-beta-cyclodextrin (HP-beta-CD). The inclusion complex was prepared by solvent evaporation and characterized by the phase solubility method, X-ray diffractometry and differential scanning calorimetry. The solubility of AND increased linearly as a function of HP-beta-CD concentration, resulting in A(L)-type phase solubility diagram.

Self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of Zedoary essential oil: formulation and bioavailability studies.

The aim of the present study was to develop a self-nanoemulsifying drug delivery system (SNEDDS) for the oral delivery of Zedoary turmeric oil (ZTO), an essential oil extracted from the dry rhizome of Curcuma zedoaria. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification regions. ZTO could serve as a partial oil phase with the aid of the second oil phase to enhance drug loading.