Rectal Route Research Articles

Modeling HIV-1 Mucosal Transmission and Prevention in Humanized Mice.

The new generation humanized mice (hu-mice) that permit continuous de novo generation of human hematopoietic cells have led to novel strategies in studying HIV-1 pathogenesis, prevention and therapies. HIV-1 infection of hu-mice results in chronic viremia and CD4+ T cell loss, thus mimicking key aspects of the disease progression. In addition, the new generation hu-mice are permissive for HIV-1 sexual transmission by vaginal and rectal routes thus allowing in vivo efficacy testing of new anti-HIV-1 drugs for prevention. Two leading models are currently being used, namely the hu-HSC mice and the BLT mice. Here we describe the methodology for generating both hu-HSC and BLT mice and their use in the study of HIV-1 transmission and prevention of infection by topical and oral administration of anti-retroviral drugs. Practical aspects of the methodologies are emphasized.

The Analgesic Efficacy of Nonsteroidal Anti-inflammatory Agents (NSAIDs) in Patients Undergoing Cesarean Deliveries: A Meta-Analysis.

Postoperative pain after cesarean delivery, which accounts for approximately 1 in 3 live births in the United States, can be severe in many patients. Nonsteroidal anti-inflammatory agents (NSAIDs) are potent analgesics that are effective in the treatment of postoperative pain. In this meta-analysis, we assessed the analgesic efficacy of NSAIDs in postoperative cesarean delivery patients. An electronic literature search of the Library of Medicine's PubMed, Cochrane CENTRAL, Scopus, and EMBASE databases was conducted in May 2013 and updated in January 2015 (Appendix, Supplemental Digital Content 1, http://links.lww.com/AAP/A174). Searches were limited to randomized controlled trials. The primary outcome variable was visual analog scale or numerical rating scale pain scores. Secondary outcomes included cumulative postoperative opioid consumption and opioid-related adverse effects (drowsiness/sedation, nausea, and vomiting). Data extraction was performed independently by 2 reviewers. Extracted data were input into Review Manager. Twenty-two randomized controlled trials compared a NSAID (n = 639) to a control (n = 674). Patients in the NSAID group versus control reported lower pain scores at 12 hours (P = 0.003) and at 24 hours (P < 0.001). Subgroup analysis showed a significant difference in pain scores at 24 hours, with patients receiving NSAIDs via intravenous/intramuscular (P < 0.001) route, but not the oral (P = 0.39) or rectal routes (P = 0.99). Significantly lower average pain scores were reported for pain with movement at 24 hours in the NSAID group (P = 0.001). Patients in the NSAID group versus controls consumed significantly less opioids (P < 0.001) and had significantly less drowsiness/sedation (P = 0.03), but there was no significant difference between the groups with regard to nausea or vomiting (P = 0.48 and P = 0.17, respectively). The perioperative use of NSAIDs in cesarean delivery patients will result in a significantly lower pain scores, less opioid consumption, and less drowsiness/sedation but no difference in nausea or vomiting compared to those who did not receive NSAIDs. Further research should address the optimal NSAID regimen and examine the effect of improved analgesia on patient-centered outcomes such as patient satisfaction and quality of breastfeeding.

Oral Administration of Faecalibacterium prausnitzii Decreased the Incidence of Severe Diarrhea and Related Mortality Rate and Increased Weight Gain in Preweaned Dairy Heifers.

Probiotics are a promising alternative to improve food animal productivity and health. However, scientific evidence that specific microbes can be used to benefit animal health and performance is limited. The objective of this study was to evaluate the effects of administering a live culture of Faecalibacterium prausnitzii to newborn dairy calves on subsequent growth, health, and fecal microbiome. Initially, a safety trial was conducted using 30 newborn bull calves to assess potential adverse effects of the oral and rectal administration of F. prausnitzii to neonatal calves. No adverse reactions, such as increased body temperature or heart and respiratory rates, were observed after the administration of the treatments. All calves survived the experimental period, and there was no difference in fecal consistency score, attitude, appetite or dehydration between the treatment groups. The rectal route was not an efficient practice while the oral route ensures that the full dose is administered to the treated calves. Subsequently, a randomized field trial was completed in a commercial farm with preweaned calves. A total of 554 Holstein heifers were assigned to one of two treatment groups: treated calves (FPTRT) and non-treated calves (control). Treated calves received two oral doses of F. prausnitzii, one at treatment assignment (1st week) and another one week later. The FPTRT group presented significantly lower incidence of severe diarrhea (3.1%) compared with the control group (6.8%). Treated calves also had lower mortality rate associated with severe diarrhea (1.5%) compared to control calves (4.4%). Furthermore, FPTRT calves gained significantly more weight, 4.4 kg over the preweaning period, than controls calves. The relative abundance of F. prausnitzii in the fecal microbiota was significantly higher in the 3rd and 5th weeks of life of FPTRT calves than of the control calves, as revealed by sequencing of the 16S rRNA gene. Our findings showed that oral administration of F. prausnitzii improves gastrointestinal health and growth of preweaned calves, supporting its use as a potential probiotic.

Ultrasound-guided trans-rectal high-intensity focused ultrasound (HIFU) for advanced cervical cancer ablation is feasible: a case report.

IntroductionHigh-intensity focused ultrasound (HIFU) is an ablative treatment undergoing assessment for the treatment of benign and malignant disease. We describe the first reported intracavitary HIFU ablation for recurrent, unresectable and symptomatic cervical cancer.Case descriptionA 38 year old woman receiving palliative chemotherapy for metastatic cervical adenocarcinoma was offered ablative treatment from an intracavitary trans-rectal HIFU device (Sonablate® 500). Pre-treatment symptoms included vaginal bleeding and discharge that were sufficient to impede her quality of life. No peri-procedural adverse events occurred. Symptoms resolved completely immediately post-procedure, reappeared at 7 days, increasing to pre-procedural levels by day 30.Discussion and evaluationThis first time experience of intracavitary cervical HIFU suggests that it is feasible for palliation of advanced cervical cancer, with no early evidence of unexpected toxicity. Ethical approval had also been granted for the use of per-vaginal access if appropriate. This route, alone or in combination with the rectal route, may provide increased accessibility in future patients with a redesigned device more suited to trans-vaginal ablations.ConclusionIntracavitary HIFU is a potentially safe procedure for the treatment of cervical cancer and able to provide symptomatic improvement in the palliative setting.

Pharmacokinetic profiles of the analgesic flupirtine in dogs after the administration of four pharmaceutical formulations

ObjectiveFlupirtine (FLU) is a non-opioid analgesic with no antipyretic or anti-inflammatory effects which is used in the treatment of pain in humans. There is a substantial body of evidence on the efficacy of FLU in humans but this is inadequate for the recommendation of its off-label use in veterinary clinical practice. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after intravenous (IV), oral immediate release (POIR), oral prolonged release (POPR) and rectal (RC) administrations in healthy dogs. Study designFour-treatment, single-dose, four-phase, unpaired, cross-over design (4 × 4 Latin-square). AnimalsSix adult Labrador dogs. MethodsAnimals in groups 1, 2 and 4 received a single dose of 5 mg kg−1 FLU administered by IV, POIR and RC routes. Group 3 received a single dose of 200 mg subject−1 via the POPR route. The wash-out periods were 1 week. Blood samples (1 mL) were collected at assigned times for 48 hours and plasma FLU concentrations were analysed by a validated HPLC method. ResultsAdverse effects including salivation, tremors and vomiting were noted in the IV group and resolved spontaneously within 10 minutes. These effects did not occur in the other groups. The FLU plasma concentrations were detectable in all of the treatment groups for 36 hours following administration. The pharmacokinetic profiles after extravascular administrations showed similar trends. The bioavailability values after POIR, POPR and RC were 41.93%, 36.78% and 29.43%, respectively. There were no significant differences in pharmacokinetic profiles between the POIR and POPR formulations. A 5 mg kg−1 POIR dose or a 200 mg subject−1 POPR dose gave plasma concentrations similar to those reported in humans after clinical dosing. Conclusion and clinical relevanceThis study provides pharmacokinetic data that can be used to design further studies to investigate FLU in dogs.

Human Poisoning Through Atypical Routes of Exposure.

There are over 2 million human exposure cases reported to United States poison centers annually. Much of the data involves exposure through ingestion, dermal contact, inhalation, ocular, or parenteral routes. There is limited data characterizing exposure via atypical routes. We conducted a retrospective review of the California Poison Control System Database for a 24-month period from January 2012 to December 2013 for poison exposure that occurred through the otic, vaginal, or rectal route. There were a total of 634 cases involving single-route and single-substance atypical poison exposure. There were 287 (45%) cases of otic exposure, 190 (30.0%) cases of vaginal exposure, and 157 (25%) cases of rectal exposure. Five hundred forty (85%) of the cases were unintentional. Gasoline exposure through the otic route occurred in 83 (13.1%) cases, followed by hydrogen peroxide (4.7%), acetaminophen (3.8%), and miconazole (2.7%). Adverse effects occurred in 336 (53%) cases. No deaths were reported. The most common treatment was observation only, occurring in 396 (62.4%) cases. The majority of the cases did not warrant hospital evaluation (73.5%). This is the first retrospective characterization study of atypical routes of poison exposure. These results may provide education to providers and the public regarding risks of exposure to substances through atypical routes.

Periluminal Distribution of HIV-Binding Target Cells and Gp340 in the Oral, Cervical and Sigmoid/Rectal Mucosae: A Mapping Study.

Studies have shown that the transmission of HIV is most likely to occur via rectal or vaginal routes, and rarely through oral exposure. However, the mechanisms of virus entry at mucosal surfaces remain incompletely understood. Prophylactic strategies against HIV infection may be attainable once gaps in current knowledge are filled. To address these gaps, we evaluated essentially normal epithelial surfaces and mapped the periluminal distribution of CD4+ HIV target cells, including T cells and antigen-presenting cells, and an HIV-binding molecule gp340 that can be expressed by epithelial cells in secreted and cell-associated forms. Immunohistochemistry for CD4, CD16, CD3, CD1a and gp340 in human oral, rectal/sigmoid and cervical mucosal samples from HIV-negative subjects demonstrated that periluminal HIV target cells were more prevalent at rectal/sigmoid and endocervical surfaces lined by simple columnar epithelium, than at oral and ectocervical surfaces covered by multilayered stratified squamous epithelium (p<0.001). gp340 expression patterns at these sites were also distinct and strong in oral minor salivary gland acini and ducts, including ductal saliva, in individual rectum/sigmoid and endocervix periluminar columnar cells, and in ectocervix squamous cells. Only weak expression was noted in the oral non-ductal squamous epithelium. We conclude that periluminal HIV target cells, together with periluminal epithelial cell-associated gp340 appear to be most accessible for HIV transmission at rectal/sigmoid and endocervical surfaces. Our data help define vulnerable structural features of mucosal sites exposed to HIV.

Review of Neoadjuvant Chemotherapy Alone in Locally Advanced Rectal Cancer.

Currently, the standard management of locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy followed by resection. Despite the significant improvement in local recurrence, survival benefits are not gained due to distant failure and radiotherapy-associated toxicity. Compliance to adjuvant chemotherapy after preoperative chemoradiotherapy is also poor. Neoadjuvant chemotherapy alone followed by surgery may be an alternative. The objective of this review is to determine the efficacy of neoadjuvant chemotherapy alone in operable LARC. Electronic databases searched (from database inception-December 2013) were Medline, PubMed, Embase, Scopus, Cochrane library, and the Clinical Trials Register. Specific journals were also hand searched. The selection criteria were studies published in English investigating stage II-III non-metastatic rectal cancer patients treated with neoadjuvant chemotherapy (oral, intravenous or rectal route) followed by curative resection. The primary outcome measure was tumour response. Secondary outcome measures included acute toxicity, operative morbidity, R0 resection, local recurrence, overall survival (OS) and disease-free survival (DFS). One randomised phase III trial, six single-arm phase II trials and one retrospective case series study were eligible for inclusion. Six studies administered fluoropyrimidine-based multiple agent regimens and two studies administered fluorouracil-based monotherapy. The studies with multiple agents and stronger chemotherapy regimens (intravenous and/or oral) followed by delayed surgery showed better tumour response rates. The overall objective response rate was good and ranged from 62.5 to 93.7 %. Pathological complete response ranged from 3.8 to 33.3 %. The R0 resection and compliance rates were also high ranging from 90 to 100 % and 72 to 100 %, respectively. Grade 3-4 toxicities ranged from 2.3 to 39 %. Four- to 5-year OS and DFS ranged from 67.2 to 91 % and 60.5 to 84 %, respectively. This review demonstrates that neoadjuvant chemotherapy could be affectively administered in LARC and could provide a good alternative to chemoradiotherapy in moderate-risk rectal cancers without compromising short- and long-term outcomes.

Water-soluble benzodiazepine prodrug/enzyme combinations for intranasal rescue therapies.

Benzodiazepines (BZDs), including diazepam (DZP) and midazolam (MDZ), are drugs of choice for rapid treatment of seizure emergencies. Current approved use of these drugs involves administration via either intravenous or rectal routes. The former requires trained medical personnel, while the latter is socially unacceptable for many patients and caregivers. In recent years, efforts have been made to formulate BZDs for nasal administration. Because of the low solubility of these molecules, organic vehicles have been used to solubilize the drugs in the nasal products under development. However, organic solvents are irritating, potentially resulting in injury to nasal tissue. Here we report preliminary studies supporting a strategy in which water-soluble BZD prodrugs and a suitable converting enzyme are coadministered in an aqueous vehicle. Diazepam and midazolam prodrugs were synthesized and were readily converted to their active forms by a protease from Aspergillus oryzae. Using a permeation assay based on monolayers of Madin-Darby canine kidney II-wild type cells, we found that enzymatically produced BZDs could be maintained at high degrees of supersaturation, enabling faster transport across the membrane than can be achieved using saturated solutions. This strategy not only obviates the need for organic solvents, but it also suggests more rapid absorption and earlier peak concentrations than can be otherwise achieved. This article is part of a Special Issue entitled "Status Epilepticus".

In Vivo and Ex Vivo Imaging Reveals a Long-Lasting Chlamydial Infection in the Mouse Gastrointestinal Tract following Genital Tract Inoculation.

Intravaginal infection with Chlamydia muridarum in mice can ascend to the upper genital tract, resulting in hydrosalpinx, a pathological hallmark for tubal infertility in women infected with C. trachomatis. Here, we utilized in vivo imaging of C. muridarum infection in mice following an intravaginal inoculation and confirmed the rapid ascent of the chlamydial organisms from the lower to upper genital tracts. Unexpectedly, the C. muridarum-derived signal was still detectable in the abdominal area 100 days after inoculation. Ex vivo imaging of the mouse organs revealed that the long-lasting presence of the chlamydial signal was restricted to the gastrointestinal (GI) tract, which was validated by directly measuring the chlamydial live organisms and genomes in the same organs. The C. muridarum organisms spreading from the genital to the GI tracts were detected in different mouse strains and appeared to be independent of oral or rectal routes. Mice prevented from orally taking up excretions also developed the long-lasting GI tract infection. Inoculation of C. muridarum directly into the upper genital tract, which resulted in a delayed vaginal shedding of live organisms, accelerated the chlamydial spreading to the GI tract. Thus, we have demonstrated that the genital tract chlamydial organisms may use a systemic route to spread to and establish a long-lasting infection in the GI tract. The significance of the chlamydial spreading from the genital to GI tracts is discussed.

Macaque models of enhanced susceptibility to HIV

There are few nonhuman primate models of enhanced HIV susceptibility. Such models can improve comprehension of HIV acquisition risk factors and provide rigorous testing platforms for preclinical prevention strategies. This paper reviews past, current, and proposed research on macaque HIV acquisition risk models and identifies areas where modeling is significantly lacking. We compare different experimental approaches and provide practical considerations for designing macaque susceptibility studies. Modifiable (mucosal and systemic coinfections, hormonal contraception, and rectal lubricants) and non-modifiable (hormonal fluctuations) risk factors are highlighted. Risk acquisition models via vaginal, rectal, and penile challenge routes are discussed. There is no consensus on the best statistical model for evaluating increased susceptibility, and additional research is required. The use of enhanced susceptibility macaque models would benefit multiple facets of the HIV research field, including basic acquisition and pathogenesis studies as well as the vaccine and other biomedical preventions pipeline.

Intramuscular and rectal therapies of acute seizures

The intramuscular (IM) and rectal routes are alternative routes of delivery for antiepileptic drugs (AEDs) when the intravenous route is not practical or possible. For treatment of acute seizures, the AED used should have a short time to maximum concentration (Tmax). Some AEDs have preparations that may be given intramuscularly. These include the benzodiazepines (diazepam, lorazepam, and midazolam) and others (fosphenytoin, levetiracetam). Although phenytoin and valproate have parenteral preparations, these should not be given intramuscularly. A recent study of prehospital treatment of status epilepticus evaluated a midazolam (MDZ) autoinjector delivering IM drug compared to IV lorazepam (LZP). Seizures were absent on arrival to the emergency department in 73.4% of the IM MDZ compared to a 63.4% response in LZP-treated subjects (p < 0.001 for superiority). Almost all AEDs have been evaluated for rectal administration as solutions, gels, and suppositories. In a placebo-controlled study, diazepam (DZP) was administered at home by caregivers in doses that ranged from 0.2 to 0.5 mg/kg. Diazepam was superior to placebo in reduced seizure frequency in children (p < 0.001) and in adults (p = 0.02) and time to recurrent seizures after an initial treatment (p < 0.001). Thus, at this time, only MZD given intramuscularly and DZP given rectally appear to have the properties required for rapid enough absorption to be useful when intravenous routes are not possible. Some drugs cannot be administered rectally owing to factors such as poor absorption or poor solubility in aqueous solutions. The relative rectal bioavailability of gabapentin, oxcarbazepine, and phenytoin is so low that the current formulations are not considered to be suitable for administration by this route. When administered as a solution, diazepam is rapidly absorbed rectally, reaching the Tmax within 5-20 min in children. By contrast, rectal administration of lorazepam is relatively slow, with a Tmax of 1-2h. The dependence of gabapentin on an active transport system, and the much-reduced surface area of the rectum compared with the small intestine, may be responsible for its lack of absorption from the rectum. This article is part of a Special Issue entitled "Status Epilepticus".

Use of misoprostol in myomectomy: a systematic review and meta-analysis.

Misoprostol, a prostaglandin derivative, reduces blood flow to uterus, facilitating every surgical operation on myometrium. PubMed, Scopus and Cochrane databases were systematically searched and five studies met the inclusion criteria for our meta-analysis. In total, 283 patients were included. The intention to treat population included 142 patients. The mean age of the patients was 34 years old. The vaginal route of administration was preferred in 117 out of 142 patients and the rectal route in 25 patients. Three studies were included in the analysis regarding duration of operation, estimated blood loss, preoperative/postoperative hemoglobin, transfusions needed and febrile morbidity. No significant difference was observed between vaginal suppository and placebo group concerning the duration of operation, the fall of preoperative hemoglobin, transfusions needed and the febrile morbidity. Regarding the estimated blood loss, the mean difference observed between the misoprostol and placebo groups was -148.55 mL per operation (95 % CI, -233.10 to -64), p < 0.001. As far as the postoperative Hgb, the misoprostol group presented significantly smaller reduction, 0.68 gr/dL per operation (95 % CI, 0.38-0.97), p < 0.001. Easy to use, minor or no side effects, and good clinical outcomes are the properties that render misoprostol useful in the realization myomectomy independently of the surgical technique applied.

¿Qué inyectables pueden ser administrados por vía oral o enteral?

Which injectable medication can be administered orally or enterally? In this article we collect the ethical and legal principles when we have to decide on the use of a drug in conditions other than those on its data sheet. Medicines are not always available in formulations which are suitable for patients with swallowing difficulties or patients with enteral feeding tubes. The alteration of medication formulations may therefore be necessary. This text provides a list of injectables that can be administered orally or via enteral feeding tubes when there are no available alternatives. However, they vary widely in their suitability for oral or enteral feeding administration. In this paper we do not consider the rectal route, as an adequate enteral route for administration of injectables.

Honeybee (Apis mellifera) Venom Reinforces Viral Clearance during the Early Stage of Infection with Porcine Reproductive and Respiratory Syndrome Virus through the Up-Regulation of Th1-Specific Immune Responses.

Porcine reproductive and respiratory syndrome (PRRS) is a chronic and immunosuppressive viral disease that is responsible for substantial economic losses for the swine industry. Honeybee venom (HBV) is known to possess several beneficial biological properties, particularly, immunomodulatory effects. Therefore, this study aimed at evaluating the effects of HBV on the immune response and viral clearance during the early stage of infection with porcine reproductive and respiratory syndrome virus (PRRSV) in pigs. HBV was administered via three routes of nasal, neck, and rectal and then the pigs were inoculated with PRRSV intranasally. The CD4+/CD8+ cell ratio and levels of interferon (IFN)-γ and interleukin (IL)-12 were significantly increased in the HBV-administered healthy pigs via nasal and rectal administration. In experimentally PRRSV-challenged pigs with virus, the viral genome load in the serum, lung, bronchial lymph nodes and tonsil was significantly decreased, as was the severity of interstitial pneumonia, in the nasal and rectal administration group. Furthermore, the levels of Th1 cytokines (IFN-γ and IL-12) were significantly increased, along with up-regulation of pro-inflammatory cytokines (TNF-α and IL-1β) with HBV administration. Thus, HBV administration—especially via the nasal or rectal route—could be a suitable strategy for immune enhancement and prevention of PRRSV infection in pigs.

Immunogenicity of mucosally-administered modified vaccinia Ankara expressing HIV-1 Env protein gp120 in rabbits (VAC8P.1047)

Abstract Modified vaccinia Ankara (MVA) used as a vaccine vector expressing heterologous antigens has been demonstrated to be immunogenic when delivered parenterally while its immunogenicity after mucosal delivery is less defined. To determine the immunogenicity of MVA when administered via different mucosal routes, NZW rabbits were vaccinated on day 0 and 28 with 3 x 108 PFU MVA expressing HIV-1 gp120 by nasal, rectal, or gastric routes. Intramuscular immunization with 1 x 108 PFU of the MVA vaccine was used as the positive control. Serum was collected on days 21 and 42 and antigen-specific antibodies were determined by ELISA. While intramuscular vaccination was the only route that induced a significantly elevated anti-gp120 serum IgG titer, nasal vaccination induced detectable anti-gp120 IgG response on day 42. Immunization by rectal or gastric routes did not induce measurable anti-gp120 IgG responses. Intramuscular and intranasal vaccination, but not gastric or rectal vaccination with MVA, induced significantly elevated serum IgG responses to pox proteins A33R and B5R. We conclude that, under the conditions tested, MVA vaccine vectors are immunogenic when delivered intramuscularly and intranasally but not gastrically or rectally. Insert specific responses after nasal vaccination were not comparable to those achieved by intramuscular vaccination, indicating that use of MVA as a nasal vaccine vector will need to be optimized.

Alternate Routes of Administration of Antidepressant and Antipsychotic Medications.

To review the administration of antidepressant and antipsychotic medications via inhaled, intranasal, buccal, sublingual, transdermal, and rectal routes. A PubMed search was conducted for all data through March 31, 2015 to identify pertinent literature. Search terms included the generic name of each antidepressant and antipsychotic medication in combination with the following terms: alternate routes of administration, inhaled, intranasal, buccal, sublingual, transdermal, and rectal. English-language case reports, studies, and reviews describing medication administration in human subjects were included. Commercially available products that use an alternative route of administration include loxapine for inhalation, asenapine for sublingual administration, and selegiline for transdermal administration. Case reports and studies describe intranasal, sublingual, and transdermal routes of administration of antipsychotic medications as well as buccal, sublingual, transdermal, and rectal administration of antidepressant medications. The concordance between the physicochemical properties possessed by some antipsychotic and antidepressant agents and the physicochemical properties required for nontraditional routes of administration suggest that administration via alternative routes may be feasible for some of these drugs. Further exploration of drug absorption via alternative routes in addition to consideration of patient and formulation factors may yield improvements in medication therapy for patients with psychiatric illnesses. For patients unable to tolerate oral or injectable therapy, administration of psychotropic medications via nontraditional routes may be feasible. The development of alternative routes of drug delivery could prevent discontinuation of needed medication therapy.

Effect of chenodeoxycholic acid and sodium hydrogen sulfide in dinitro benzene sulfonic acid (DNBS) – Induced ulcerative colitis in rats

BackgroundUlcerative colitis is a chronic inflammatory condition in which the inflammatory response confined to the colon. There is a need to explore the new targets for UC such as Farnesoid X receptor and hydrogen sulfide pathway. MethodsWistar rats of either sex (200–250g) were used. 2,4-Dinitrobenzene sulfonic acid (DNBS) (25mg/rat) given by rectal route into the colon to induced symptoms of ulcerative colitis. Chenodeoxycholic acid (CDCA) (10 and 20mg/kg) and sodium hydrogen sulfide (NaHS) (10 and 30μmol/kg) and a inhibitor of cystathionine-γ-lyase enzyme (CSE) i.e. dl-propargylglycine (10mg/kg) treatment given along with 2,4-dinitrobenzene sulfonic acid. The disease activity index was assessed by daily change in body weight and rectal bleed score and change in length of colon. Oxidative stress markers (reduced glutathione, malondialdehyde (MDA), nitrite, and catalase and myeloperoxidase enzyme activity), serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels in blood serum, and cardiac hemodynamic were performed on last day. ResultsThe administration of DNBS intra-rectally in rats produced loss of body weight and bloody diarrhea with significant increase in oxidative stress markers in the colon. CDCA (10 and 20mg/kg) and NaHS (10 and 30μmol/kg) significantly attenuated DNBS-induced UC in rats. The combination of CDCA (10mg/kg) and NaHS (10μmol/kg) showed synergetic effect whereas; dl-propargylglycine reversed the protective effect of CDCA. ConclusionThe observed beneficial effects following CDCA may be due to its action through activation of CSE enzyme which leads to hydrogen sulfide generation.

Conserved molecular signatures in gp120 are associated with the genetic bottleneck during simian immunodeficiency virus (SIV), SIV-human immunodeficiency virus (SHIV), and HIV type 1 (HIV-1) transmission.

Human immunodeficiency virus (HIV) transmission typically results from infection by a single transmitted/founder (T/F) variant. Are T/F variants chosen uniformly at random from the donor pool, or are they selected based on advantageous traits facilitating transmission? Finding evidence for selection during transmission is of particular interest, because it would indicate that phenotypic and/or genetic properties of the viruses might be harnessed as potential vaccine targets or immunotherapies. Here, we systematically evaluated the differences between the Env proteins of simian immunodeficiency virus/simian HIV (SIV/SHIV) stock and T/F variants in search of "signature" sites of transmission. We also surveyed residue preferences in HIV at the SIV/SHIV signature sites. Four sites of gp120 showed significant selection, and an additional two sites showed a similar trend. Therefore, the six sites clearly differentiate T/F viruses from the majority of circulating variants in the stocks. The selection of SIV/SHIV could be inferred reasonably across both vaccinated and unvaccinated subjects, with infections resulting from vaginal, rectal, and intravenous routes of transmission and regardless of viral dosage. The evidence for selection in SIV and SHIV T/F variants is strong and plentiful, and in HIV the evidence is suggestive though commensurate with the availability of suitable data for analysis. Two of the signature residues are completely conserved across the SIV, SHIV, and HIV variants we examined. Five of the signature residues map to the C1 region of gp120 and one to the signal peptide. Our data raise the possibility that C1, while governing the association between gp120 and gp41, modulates transmission efficiency, replicative fitness, and/or host cell tropism at the level of virus-cell attachment and entry. The present study finds significant evidence of selection on gp120 molecules of SIV/SHIV T/F viruses. The data provide ancillary evidence suggesting the same sites are under selection in HIV. Our findings suggest that the signature residues are involved in increasing the transmissibility of infecting viruses; therefore, they are potential targets for developing a vaccine or other protective measures. A recent study identified the same T/F signature motif but interpreted it as an effect of neutralization resistance. Here, we show that the T/F motif has broader functional significance beyond neutralization sensitivity, because it is present in nonimmune subjects. Also, a vaccine regimen popular in animal trials might have increased the transmission of variants with otherwise low transmission fitness. Our observations might explain why many animal vaccine trials have not faithfully predicted outcomes in human vaccine trials and suggest that current practices in vaccine design need to be reexamined accordingly.

Various Emerging Trends in Insulin Drug Delivery Systems

Lowering of blood glucose level in patients can be achieved by insulin therapy as it plays a key role in the control of hyperglycaemia for type 1 diabetes. Insulin delivery systems that are currently available include syringes, infusion pumps, jet injectors and pens. The tedious part for the type 1 diabetes patients is to tolerate needle after needle injections while undergoing treatment for both glucose measurement and to deliver insulin. A rigorous research effort has been undertaken worldwide to replace the authentic subcutaneous route by a more accurate and non-invasive route. The newer methods explored include the artificial pancreas with closed-loop system, transdermal insulin, and buccal, oral, pulmonary, nasal, ocular and rectal routes. The future trends include use of insulin inhalers, trandermal patches, pills, pumps etc. Some of the non-invasive delivery systems include polymeric hydrogels and insulin loaded bioadhesive poly (D,L-lactide-co-glycolide) nanoparticles for oral delivery, aerosolized liposomes with dipalmitoyl phosphatidylcholine for pulmonary delivery, β cyclodextrins for nasal delivery, microneedle arrays fabricated from hyaluronic acid and iontophoresis for trandermal delivery, chitosan-zinc-insulin complex for the controlled delivery of insulin.