Clinical pharmacology of morphine in infants and children

Morphine is used to treat pain, for treatment of opioid dependence, and neonatal abstinence syndrome. Morphine is modestly absorbed from the gastrointestinal tract whereas after rectal administration, by intranasal or buccal application morphine is well absorbed. Morphine is eliminated by glomerular filtration and by conjugation with glucuronic acid; morphine-3-glucurinide and morphine-6-glucurinide are the main metabolites and the last has analgesic effect. In infants, morphine is used to treat severe or sustained pain, sedation, and pain relief. In children, morphine is used to control pain and morphine may be administered by subcutaneous or intravenous injection, orally, by rectum, or by continuous subcutaneous infusion and morphine dose varies according to the child age. Morphine has been found efficacy and safe in infants and children but may induce adverse-effects. The effects caused by morphine and the treatment with morphine have been studied in infants and children. In newborns, morphine elimination half-life ranges from 7.7 to 13.5 hours and decreases with infant maturation. In newborns, infants and children, the total body clearance of morphine ranges from 14.5 to 71.1 L/h/70kg and increases with infant maturation and child development. Morphine is transported in the human brain, poorly crosses the human placenta and accumulates in breast-milk. The aim of this study is to review the published data on morphine dosing, efficacy and safety, effects, adverse-effects, pharmacokinetics, metabolism, drug interaction, treatment, transport into human brain of infants and children and morphine transfer across the human placenta and migration into the breast-milk.

Effect of Arrabideae chica (crajiru) extract in a model of induced experimental colitis in rats

Objective: This study aimed to investigate the effect of A. chica extract on the evolution of experimental rectocolitis in rats, and the expression of the pro-inflammatory cytokines TNF-a, IL-1β and IL-6 in colonic tissue. Methods: Wistar rats weighing 275±23g were distributed into 4 groups of 6 animals each. Rectocolitis was induced in rats by rectal administration of trinitrobenzene sulfonic acid (TNBS). Seventy-two hours after TNBS injection, animals were treated daily for 6 days. Groups: 1. Normal control group without induction of rectocolitis. Received 0.9% saline injection v.o. by gavage during treatment. 2. TNBS rectocolitis group, treated with normal saline (SN) by gavage (TNBS+SN); 3. TNBS rectocolitis group treated with A. chica extract (ACE), receiving a daily dose of 300 mg of A. chica extract by gavage (TNBS+ACE);4. TNBS rectocolitis group treated with mesalazine, receiving a daily dose of 100 mg/kg of mesalazine orally (TNBS+MEZ). Macroscopic examination of the colon and dosing of TNF-α, IL-1β and IL-6 in colon tissue were performed. Results: There was a reduction in weight in animals treated only with TNBS+NS. No difference in weight was observed comparing the animals treated with ACE and MEZ. In the control group no mucosal ulcers or edema of the colon wall were observed. Several mucosal ulcers, edema and hyperemia occurred in the colon of rats in the TNBS+SN group. In two of the animals in this group there was colon perforation, tamponated by omentum. A reduction of mucosal ulcers number in the TNBS+ACE (crajiru) group was seen, compared to the TNBS+SN and TNBS+MEZ group. There was a significant reduction of TNF-α, IL-1β and IL-6 in the colon tissue of animals treated with crajiru extract, TCBS+ACE group, when compared to the control group (p<0.001), TNBS+SN group, and TNBS+MEZ groups (p<0.001). Conclusion: This is the first study to show that A. chica extract positively influences the treatment of TNBS/induced rectocolitis through its antiinflamatory activity. More comprehensive studies are needed to understand the underlying mechanisms.

Anti-Inflammatory, Antioxidant, and Healing-Promoting Effects of Aloe vera Extract in the Experimental Colitis in Rats

Background. Ulcerative colitis is a worldwide chronic gastrointestinal disease characterized by variable extensions of colon mucosal inflammation. The available drugs have an incomplete response with various side effects and socioeconomic impacts. Aloe barbadensis Miller (Aloe vera) is a well-known medicinal plant with diverse pharmacological and therapeutic activities. As a result, in the current study, Aloe vera was selected to evaluate its therapeutic effects on experimental colitis in rats. Methods. This study is intended to evaluate the possible beneficial effect of Aloe vera for the treatment of experimental colitis. Trinitrobenzenesulfonic acid (TNBS) was used to induce experimental colitis in 60 of 70 Wistar rats. The rats were grouped in 7 clusters including healthy control, negative, positive control (received sulfasalazine), and test groups treated with Aloe vera extracts via oral or rectal routes. Macroscopic and histologic factors as well as the biochemical parameters were evaluated on day 7. Results. In the present study, it was found that serum levels of tumor necrosis factor-α (75 vs. 44 pg./ml), interleukin-6 (41 vs. 21 pg/ml), and nitric oxide (24 vs. 6 μm/ml) in TNBS-induced untreated colitis treatment were significantly increased as compared to healthy control. Similar patterns were also observed in malondialdehyde (76.41 vs. 236.35 μg/mg) and myeloperoxidase (4.24 vs. 29.38 U/mg) in colonic tissue. Among different treatments, rectal administration of Aloe vera extract (400 mg/kg) exhibited the best result in which serum concentration of tumor necrosis factor-α (55 pg/ml), interleukin-6 (24 pg/ml), and nitric oxide (10 μm/ml) and the levels of malondialdehyde (102.67 μg/mg), as well as myeloperoxidase (12.29 U/mg) in colon tissue, were reduced as compared to the untreated group. Also, the body weight and colon weight/length ratios were more improved in the treated group with 400 mg/kg Aloe vera extract, rectally. Conclusion. Aloe vera extract exhibited a therapeutic effect in TNBS-induced colitis, and local, rectal administration of Aloe vera extract was more effective than oral administration.

Comparative study of specific activity of rectal suppositories with clopidogrel

One of the most effective platelet antiaggregants is clopidogrel, inhibiting platelet activation by selectively binding adenosine diphosphate (ADP) with specific receptors. However, in a number of clinical situations it is necessary to have a pronounced antithrombotic effect in the shortest possible time which gives rise to interest in the transmucose use of the drug, in particular, rectal route. The theoretical preconditions for the development of a rectal administration of clopidogrel are based on the data that the anti-aggregation effect of a substance is carried out by its main metabolite formed after “first hepatic passage”, while clopidogrel itself in this aspect is inactive. On the base of complex physico-chemical, pharmaceutical, biopharmaceutical, rheological and microbiological investigations, the rational composition of clopidogrel rectal dosage form – suppository on a hydrophilic base to prevent atherothrombotic events in patients with myocardial infarction, acute coronary syndrome, ischemic stroke, peripheral arterial occlusion, is proposed by the employees of the Department of Technology of Medications of the Zaporizhzhia State Medical University. The aim of the work is to investigate the specific activity of rectal suppositories with clopidogrel. Materials and methods. Experimental suppositories with clopidogrel 0,075 g for rectal administration were used as the objects in pre-line studies. The ability of clopidogrel to reduce the inhibitory effect of ADP on adenylate cyclase activity and decrease the number of binding sites for 2-methylthio-ADP (analogue of ADP) without altering the receptor topography is used as a base of the method of comparative study of its specific activity in the rectal dosage form (suppository) and in comparison with the reference medication Plavix (SANOFI WINTHROP INDUSTRIE, France) in the tablet form. Studies were performed on white non-linear rats of different sexes with different mass 150–210 g, aged 3.5–5.0 months. Results. Statistically significant differences in the inhibition of induced platelet aggregation were registered after 6 hours of rectal administration of clopidogrel and gastric administration of the reference medication, indicating the effectiveness of the rectal applicative transmucosal route for this active pharmaceutical ingredient (API). On the 5th day of administration, inhibition of induced platelet aggregation significantly increased, and that is supported by literature on the cumulative effect of clopidogrel in daily life. When comparing the digital material of the table, it is obvious that the rectal administration of clopidogrel is more effective in comparison with oral route which is probably due to the rapid delivery of API to the liver and the formation of an active metabolite of clopidogrel inhibiting the induction and spontaneous aggregation of platelets in human’s and animal’s blood. Obtained data provide with sound arguments for development of rectal suppositories with clopidogrel because in clinical care faster achievement of an anti-aggregation effect in patients with acute coronary syndrome is the primary task of clinical pharmacology and pharmacy. Conclusions. Using the biochemical model of pathology, it was established that the applicative semisolid medication of clopidogrel in the form of rectal suppository exhibited inductive anti-aggregation activity and its administration didn’t reveal any side effects and undesirable events. Rectal suppositories with clopidogrel have been shown to exhibit faster reliable anti-aggregation effect in comparison with intragastric administration.

Colon Innervating TRPA1 Positive Nociceptors Influence Mucosal Health In Mice

Introduction: Transient receptor potential ankyrin-1 positive (TRPA1+ve) nociceptors, primarily present as peptidergic neuronal afferents in the colon are sensors of disturbance in lower gastrointestinal tract including pain induced by different pathologies. Their therapeutic role in the alleviation of chronic pain (receptor antagonism and receptor desensitization) associated with inflammatory bowel diseases (IBD) is reported. However, there is limited literature available about their role in formation and sustenance of the mucosal layer, and its interaction with host physiology as well as luminal microbial community. The aim of this study focuses on the effects of nociceptive TRPA1 channel desensitization on colonic mucus production and gut health. Methods: TRPA1+ve nociceptors were desensitized by rectal administration of capsazepine. Ileum, colon was harvested and cecum content was collected. We performed morphological/histological analysis, gut permeability alteration, gene expression changes, colon metabolite profiling, and gut microbial abundance in these animals. Results: We found that presence of TRPA1-positive nociceptors is required for mucus layer integrity, using an intra-rectal capsazepine-induced TRPA1 desensitization model. Desensitization of TRPA1 positive nociceptors resulted in damaged mucosal lining, resultant increase in gut permeability and altered transcriptional profile of genes for goblet cell markers, mucus regulation, immune response and tight junction proteins. The damage to mucosal lining prevented its role in enterosyne (short chain fatty acids) actions. Conclusion: These results suggest that caution may need to be exercised before employing TRPA1 desensitization as a therapeutic option to alleviate pain caused due to IBD.

ASSORTMENT ANALYSIS OF DRUGS FOR THE TREATMENT OF MILD AND MODERATE ULCERATIVE COLITIS

The article is devoted to the assortment analysis of 5-aminosalicylic acid drugs used for the treatment of mild and moderate ulcerative colitis. A brief description of dosage forms for oral and rectal administration used for the treatment of this disease is given. It is shown that therapeutic efficacy of the drug is associated with the concentration of the active substance in the large intestine. Therefore, in order to increase its effectiveness it is important to use such dosage forms that would help to prevent and reduce mesalazine absorption in the proximal small intestine and contribute to maximum release in the large intestine. It is shown that the rectal suspension of mesalazine, which is a first-line drug and is included in the list of essential medicines, is not produced in the Republic of Belarus. Special attention is paid to the possibility of expanding the range of mesalazine drugs if there is a possibility of extemporal suspension production from tablets presented in the assortment including a domestic manufacturer.

Pathways for Oral and Rectal Delivery of Gold Nanoparticles (1.7 nm) and Gold Nanoclusters into the Colon: Enteric-Coated Capsules and Suppositories

Two ways to deliver ultrasmall gold nanoparticles and gold-bovine serum albumin (BSA) nanoclusters to the colon were developed. First, oral administration is possible by incorporation into gelatin capsules that were coated with an enteric polymer. These permit the transfer across the stomach whose acidic environment damages many drugs. The enteric coating dissolves due to the neutral pH of the colon and releases the capsule’s cargo. Second, rectal administration is possible by incorporation into hard-fat suppositories that melt in the colon and then release the nanocarriers. The feasibility of the two concepts was demonstrated by in-vitro release studies and cell culture studies that showed the easy redispersibility after dissolution of the respective transport system. This clears a pathway for therapeutic applications of drug-loaded nanoparticles to address colon diseases, such as chronic inflammation and cancer.

Rectal Administration of Ibuprofen: Comparison of Enema and Suppository Form

Ibuprofen is a widely used and well-tolerated analgesic and antipyretic. It is desirable to have a formulation with a rapid rate of absorption because it is required for rapid pain relief and temperature reduction. Previous studies have described the pharmacokinetic profiles of ibuprofen suppository and the mean peak times of ibuprofen suppository were around 1.8 hours, indicating a slower rate of absorption. The aim of this study is to compare the pharmacokinetic parameters of rectal administration of ibuprofen between enema and suppository form in order to provide evidence for the faster absorption rates of ibuprofen enema. This study was a phase-1 clinical study, open-label, randomized and two-way crossover with one-week washout period comparing the absorption profile of equal dose of ibuprofen administered rectally in two treatment phases: ibuprofen suppository and enema. Blood samples were collected post dose for pharmacokinetic analyses. Tmax was analyzed using a Wilcoxon matched paired test. A standard ANOVA model, appropriate for bioequivalence studies was used and ratios of 90% confidence intervals were calculated. This study showed that Tmax for ibuprofen enema was less than half that of ibuprofen suppository (median 40 min vs. 90 min, respectively; p-value=0.0003). Cmax and AUC0–12 for ibuprofen enema were bioequivalent to ibuprofen suppository, as the ratio of test/reference=104.52%, 90% CI 93.41–116.95% and the ratio of test/reference=98.12%, 90%CI 93.34–103.16%, respectively, which fell within 80–125% bioequivalence limit. The overall extent of absorption was similar to the both, which were all well tolerated. In terms of Tmax, Ibuprofen enema was absorbed twice as quickly as from ibuprofen suppository. Therefore it is expected that an ibuprofen enema may provide faster onset of analgesic and antipyretic benefit.