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AAPS PharmSciTech Jul 2022The intranasal route of vaccination presents an attractive alternative to parenteral routes and offers numerous advantages, such as the induction of both mucosal and... (Review)
Review
The intranasal route of vaccination presents an attractive alternative to parenteral routes and offers numerous advantages, such as the induction of both mucosal and systemic immunity, needle-free delivery, and increased patient compliance. Despite demonstrating promising results in preclinical studies, however, few intranasal vaccine candidates progress beyond early clinical trials. This discrepancy likely stems in part from the limited predictive value of rodent models, which are used frequently in intranasal vaccine research. In this review, we explored the factors that limit the translatability of rodent-based intranasal vaccine research to humans, focusing on the differences in anatomy, immunology, and disease pathology between rodents and humans. We also discussed approaches that minimize these differences and examined alternative animal models that would produce more clinically relevant research.
Topics: Administration, Intranasal; Animals; Humans; Rodentia; Vaccination; Vaccines
PubMed: 35819736
DOI: 10.1208/s12249-022-02330-9 -
Anaesthesia Jan 2009This article is a review of the peri-operative use of paracetamol. It reviews the pharmacology of paracetamol, highlighting new information about the mechanism of... (Review)
Review
This article is a review of the peri-operative use of paracetamol. It reviews the pharmacology of paracetamol, highlighting new information about the mechanism of action, and examines its therapeutic use in the peri-operative period, focusing on efficacy, route of administration, and the use of a loading dose to improve early postoperative analgesia.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Drug Administration Routes; Drug Administration Schedule; Humans; Pain, Postoperative; Postoperative Care
PubMed: 19087009
DOI: 10.1111/j.1365-2044.2008.05674.x -
The International Journal of... Nov 2022The neuropeptide oxytocin (OXT) modulates social cognition by increasing attention to social cues and may have therapeutic potential for impaired social attention in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The neuropeptide oxytocin (OXT) modulates social cognition by increasing attention to social cues and may have therapeutic potential for impaired social attention in conditions such as autism spectrum disorder. Intranasal administration of OXT is widely used to examine the drug's functional effects in both adults and children and is assumed to enter the brain directly via this route. However, OXT can also influence brain function through increased blood concentrations, and we have recently shown that orally (lingual) administered OXT also modulates neural responses to emotional faces and may be better tolerated for therapeutic use. Here, we examine whether 24 IU OXT administered orally can facilitate social attention.
METHODS
In a randomized, placebo-controlled pharmacologic study, we used a validated emotional antisaccade eye-tracking paradigm to explore the effects of oral OXT on bottom-up and top-down attention processing in 80 healthy male participants.
RESULTS
Our findings showed that in terms of top-down attention, oral OXT increased errors for both social (angry, fearful, happy, sad, and neutral emotion faces) and nonsocial stimuli (oval shapes) in the antisaccade condition but increased response latencies only in the social condition. It also significantly reduced post-task state anxiety, but this reduction was not correlated with task performance. A comparison with our previous intranasal OXT study using the same task revealed that both routes have a similar effect on increasing antisaccade errors and response latencies and on reducing state anxiety.
CONCLUSIONS
Overall, our findings suggest that oral administration of OXT produces similar effects on top-down social attention control and anxiety to intranasal administration and may therefore have therapeutic utility.
Topics: Adult; Child; Male; Humans; Oxytocin; Administration, Intranasal; Facial Expression; Autism Spectrum Disorder; Double-Blind Method; Attention; Administration, Oral
PubMed: 36053298
DOI: 10.1093/ijnp/pyac059 -
The AAPS Journal Jan 2015Peptides are an important class of endogenous ligands that regulate key biological cascades. As such, peptides represent a promising therapeutic class with the potential... (Review)
Review
Peptides are an important class of endogenous ligands that regulate key biological cascades. As such, peptides represent a promising therapeutic class with the potential to alleviate many severe disease states. Despite their therapeutic potential, peptides frequently pose drug delivery challenges to scientists. This review introduces the physicochemical, biophysical, biopharmaceutical, and formulation developability aspects of peptides pertinent to the drug discovery-to-development interface. It introduces the relevance of these properties with respect to the delivery modalities available for peptide pharmaceuticals, with the parenteral route being the most prevalent route of administration. This review also presents characterization strategies for oral delivery of peptides with the aim of illuminating developability issues with the drug candidate. A brief overview of other routes of administration, including inhaled, transdermal, and intranasal routes, is provided as these routes are generally preferred by patients over injectables. Finally, this review presents formulation techniques to mitigate some of the developability obstacles associated with peptide delivery. The authors emphasize opportunities for the thoughtful application of pharmaceutical science to the development of peptide drugs and to the general advancement of this promising class of pharmaceuticals.
Topics: Chemistry, Pharmaceutical; Drug Administration Routes; Drug Delivery Systems; Drug Design; Humans; Patient Preference; Peptides
PubMed: 25398427
DOI: 10.1208/s12248-014-9688-2 -
Molecular Vision Sep 2008Safety and efficiency are critical for successful gene therapy. Adeno-associated viral (AAV) vectors are commonly used for gene transfer in both human and animal...
PURPOSE
Safety and efficiency are critical for successful gene therapy. Adeno-associated viral (AAV) vectors are commonly used for gene transfer in both human and animal studies. However, administration of AAV vectors can lead to development of neutralizing antibodies against the vector capsid, thus decreasing the efficiency of therapeutic gene transfer and preventing effective vector readministration. We investigated immune responses to different routes of ocular administration and readministration of AAV vectors, and the effect of previous exposure of AAV vector in one eye on the transduction efficacy of subsequent intraocular AAV-mediated gene delivery to the partner eye.
METHODS
We tested two vector systems. One contained a cDNA encoding a secreted pigment epithelial derived factor (PEDF) cDNA under the control of a Cytomegalovirus (CMV) enhancer and chicken beta-actin promoter (CBA; AAV2-CBA-PEDF) and was tested in a murine model of laser-induced choroidal neovascularization (CNV). The other vector contained a cDNA encoding the intracellular reporter green fluorescent protein (GFP) under the control of the same promoter (AAV2-CBA-GFP). Animals were divided into groups and received sequential injections at different combinations of either intravitreal or subretinal routes. CNV was evaluated by fluorescein angiographic choroidal flat-mount image analysis. The expression of GFP was analyzed in retinal sections by direct fluorescence imaging. Antibodies against AAV2 capsid and transgenes were analyzed by ELISA using serum samples collected before injection and different time points after the injection. Neutralizing antibodies were characterized by in vitro assays.
RESULTS
Various ocular compartments responded to AAV administration differently. Intravitreal administration of AAV vectors, which resulted in transduction of inner retina (primarily retinal ganglion cells), generated a humoral immune response against AAV capsid that blocked vector expression upon readministration via the same route into the partner eye. In contrast, it had no effect on vector readministered into the subretinal space of the partner eye. Additionally, subretinal administration of vector did not trigger any humoral immune response against AAV capsid, and had no effect on subsequent administration of vector either intravitreally or subretinally into the partner eye.
CONCLUSIONS
These findings have important clinical implications for the design of AAV-mediated ocular gene transfer for retinal diseases, particularly if both eyes require sequential treatment.
Topics: Animals; Antibodies; Antibody Formation; Capsid; Cell Line; Choroidal Neovascularization; Dependovirus; Drug Administration Routes; Eye Proteins; Genetic Vectors; Green Fluorescent Proteins; Humans; Injections; Mice; Mice, Inbred C57BL; Nerve Growth Factors; Neutralization Tests; Retina; Serpins; Transgenes
PubMed: 18836574
DOI: No ID Found -
Respiratory Research Aug 2018Monoclonal antibodies (mAbs) approved for use as add-on therapy in patients with severe asthma target the underlying pathogenesis of asthma. (Comparative Study)
Comparative Study Review
BACKGROUND
Monoclonal antibodies (mAbs) approved for use as add-on therapy in patients with severe asthma target the underlying pathogenesis of asthma.
MAIN BODY
Omalizumab binds immunoglobulin E (IgE), thereby inhibiting its interaction with the high-affinity IgE receptor and reducing the quantity of free IgE available to trigger the allergic cascade. Anti-interleukin (IL)-5 mAbs mepolizumab, benralizumab and reslizumab block the interaction between IL-5 and its receptor on eosinophils, thus targeting the eosinophilic pathway in asthma. Most mAbs are available as intravenous (IV) or subcutaneous (SC) formulations, as their high molecular weight and gastric degradation preclude oral administration. This review compares the pharmacology, efficacy, immunogenicity, injection- and infusion-related adverse drug reactions of subcutaneously administered omalizumab and mepolizumab with the intravenously administered reslizumab. In terms of pharmacokinetics, IV route of administration appears to be superior to the SC route due to quicker absorption, greater bioavailability, shorter time to maximum serum concentration and similar elimination half-life. Route of administration does not appear to translate into striking differences in efficacy and safety of mAbs used for the treatment of severe asthma, as all are generally considered to be effective and well tolerated. Hypersensitivity and administration-related reactions have been described with both IV and SC mAbs.
CONCLUSION
mABs are effective and have low immunogenicity due to their nature as humanised antibodies. Evidence on the use of mAbs in indications other than severe asthma suggest that both the SC and the IV routes of administrations have their respective advantages and disadvantages; but their full utility remains to be elucidated.
Topics: Administration, Intravenous; Anti-Asthmatic Agents; Antibodies, Monoclonal; Asthma; Humans; Injections, Subcutaneous; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome
PubMed: 30115042
DOI: 10.1186/s12931-018-0859-z -
Mucosal Immunology Nov 2010Research has yielded an abundance of vaccine candidates against mucosal infections, but only few mucosal vaccines have been registered for human use. Extensive research... (Review)
Review
Research has yielded an abundance of vaccine candidates against mucosal infections, but only few mucosal vaccines have been registered for human use. Extensive research is being carried out to identify new and safe adjuvants for mucosal immunization, novel delivery systems, including live vectors and reporter molecules for tissue- and cell-specific targeting of vaccine antigens. If these candidates are to reach those in need, several lessons from clinical and field research carried out under resource-poor settings must be considered. These lessons include the need to develop new vaccines that can be administered topically onto the skin or to the mucosa, without needles or expensive delivery devices. Such topical vaccines must be able to protect all age groups at risk, be safe and effective in immunocompromised people, and be able to contain epidemics following complex emergencies. The anatomical compartmentalization of immune responses imposes constraints on the selection of topical route(s) of vaccine administration and on strategies for measuring these responses, especially in young infants. Thus, the selection of any particular route of immunization is critical when designing and formulating vaccines against organ-specific infections.
Topics: Administration, Topical; Age Factors; Animals; Drug Delivery Systems; Humans; Immunity, Mucosal; Immunization; Infection Control; Organ Specificity; Vaccines
PubMed: 20861833
DOI: 10.1038/mi.2010.55 -
Annals of the Rheumatic Diseases Jul 2009To review systematically the available literature on the optimal dosage and route of administration of methotrexate in patients with rheumatoid arthritis (RA), as an... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To review systematically the available literature on the optimal dosage and route of administration of methotrexate in patients with rheumatoid arthritis (RA), as an evidence base for generating clinical practice recommendations.
METHODS
A systematic literature search was carried out in MEDLINE, EMBASE, Cochrane Library and American College of Rheumatology/European League Against Rheumatism meeting abstracts, searching for randomised controlled trials evaluating various dosages or routes of administration of methotrexate in RA. Articles that fulfilled predefined inclusion criteria were systematically reviewed and the quality was appraised. Effect sizes and odds ratios for clinical, radiological and toxicity outcomes were calculated and directly or indirectly compared between study groups using methotrexate in different dosages or by different routes.
RESULTS
A total of 38 publications out of 1748 identified references was included in the review. Start doses of 25 mg/week or fast escalation with 5 mg/month to 25-30 mg/week were associated with higher clinical effect sizes and more (gastrointestinal) adverse events in comparison with doses of 5-15 mg/week or slow escalation. Starting with 15 mg/week subcutaneous versus oral methotrexate was associated with higher clinical efficacy but more withdrawal due to toxicity in early RA. In longstanding RA, after failure on 15-20 mg/week orally, a switch to 15 mg/week intramuscularly with subsequent dose escalation did not result in increased efficacy.
CONCLUSIONS
Starting on methotrexate 15 mg/week orally, escalating with 5 mg/month to 25-30 mg/week, or the highest tolerable dose, with a subsequent switch to subcutaneous administration in the case of an insufficient response, seems to be the optimal evidence-based dosing and routing recommendation for methotrexate in RA.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Administration Routes; Drug Administration Schedule; Humans; Methotrexate; Randomized Controlled Trials as Topic
PubMed: 19033290
DOI: 10.1136/ard.2008.092668 -
Journal of Pain and Symptom Management Sep 1998Current guidelines on the treatment of moderate to severe cancer pain recommend the use of scheduled doses of opioids for persistent pain combined with "as needed" doses... (Review)
Review
Current guidelines on the treatment of moderate to severe cancer pain recommend the use of scheduled doses of opioids for persistent pain combined with "as needed" doses of similar agents for breakthrough pain. Oral drugs given on an "as needed" basis can be problematic for patients with difficulty in swallowing or for those who suffer from nausea and vomiting. Further, breakthrough pain can become excruciating in a relatively short time, a drawback for analgesics that require gastrointestinal (GI) absorption before pain relief can begin. Hence, there is considerable interest in the development of novel drug administration routes to provide rapid relief of breakthrough pain, particularly through a route that bypasses the GI system. Sublingually administered morphine has sometimes been used in the treatment of breakthrough pain because some believe it provides effective analgesia via an appropriate alternate route. Available pharmacological data, however, do not consistently support the rapid absorption of morphine through the sublingual mucosa, and clinical data concerning the efficacy of sublingual morphine for the treatment of cancer pain are limited, not well-controlled, and inconclusive. While there seems to be a need for provision of rapid, effective analgesia to cancer patients by an alternative route, sublingual morphine may not satisfy this requirement. Newer formulations of analgesics should be tested in the treatment of breakthrough pain due to cancer.
Topics: Administration, Sublingual; Analgesics, Opioid; Humans; Morphine
PubMed: 9769621
DOI: 10.1016/s0885-3924(98)00046-3 -
Basic & Clinical Pharmacology &... Feb 2016Oral delivery of biopharmaceuticals, for example peptides and proteins, constitutes a great challenge in drug delivery due to their low chemical stability and poor... (Review)
Review
Oral delivery of biopharmaceuticals, for example peptides and proteins, constitutes a great challenge in drug delivery due to their low chemical stability and poor permeation across the intestinal mucosa, to a large extent limiting the mode of administration to injections, which is not favouring patient compliance. Nevertheless, cell-penetrating peptides (CPPs) have shown promising potential as carriers to overcome the epithelium, and this minireview highlights recent knowledge gained within the field of CPP-mediated transepithelial delivery of therapeutic peptides and proteins from the intestine. Two approaches may be pursued: co-administration of the carrier and therapeutic peptide in the form of complexes obtained by simple bulk mixing, or administration of covalent conjugates demanding more advanced production methodologies. These formulation approaches have their pros and cons, and which is to be preferred depends on the physicochemical properties of both the specific CPP and the specific cargo. In addition to the physical epithelial barrier, a metabolic barrier must be overcome in order to obtain CPP-mediated delivery of a cargo drug from the intestine, and a number of strategies have been employed to delay enzymatic degradation of the CPP. The mechanisms by which CPPs translocate across membranes are not fully understood, but possibly involve endocytosis as well as direct translocation, and the CPP-mediated transepithelial delivery of cargo drugs thus likely involves similar mechanisms for the initial membrane interaction and translocation. However, the mechanisms responsible for transcytosis of the cargo drug, if taken up by an endocytic mechanism, or direct translocation across the epithelium are so far not known.
Topics: Cell-Penetrating Peptides; Dosage Forms; Drug Administration Routes; Drug Delivery Systems; Humans
PubMed: 26525297
DOI: 10.1111/bcpt.12515