Incidence Of Local Side Effects Research Articles

Self-assembled polymeric nanocarriers for the targeted delivery of retinoic acid to the hair follicle.

Acne vulgaris is a highly prevalent dermatological disease of the pilosebaceous unit (PSU). An inability to target drug delivery to the PSU results in poor treatment efficacy and the incidence of local side-effects. Cutaneous application of nanoparticulate systems is reported to induce preferential accumulation in appendageal structures. The aim of this work was to prepare stable polymeric micelles containing retinoic acid (RA) using a biodegradable and biocompatible diblock methoxy-poly(ethylene glycol)-poly(hexylsubstituted lactic acid) copolymer (MPEG-dihexPLA) and to evaluate their ability to deliver RA to skin. An innovative punch biopsy sample preparation method was developed to selectively quantify follicular delivery; the amounts of RA present were compared to those in bulk skin, (i.e. without PSU), which served as the control. RA was successfully incorporated into micelle nanocarriers and protected from photoisomerization by inclusion of Quinoline Yellow. Incorporation into the spherical, homogeneous and nanometer-scale micelles (dn < 20 nm) increased the aqueous solubility of RA by >400-fold. Drug delivery experiments in vitro showed that micelles were able to deliver RA to porcine and human skins more efficiently than Retin-A(®) Micro (0.04%), a marketed gel containing RA loaded microspheres, (7.1 ± 1.1% vs. 0.4 ± 0.1% and 7.5 ± 0.8% vs. 0.8 ± 0.1% of the applied dose, respectively). In contrast to a non-colloidal RA solution, Effederm(®) (0.05%), both the RA loaded MPEG-dihexPLA polymeric micelles (0.005%) and Retin-A(®) Micro (0.04%) displayed selectivity for delivery to the PSU with 2-fold higher delivery to PSU containing samples than to control samples. Moreover, the micelle formulation outperformed Retin-A(®) Micro in terms of delivery efficiency to PSU presenting human skin (10.4 ± 3.2% vs. 0.6 ± 0.2%, respectively). The results indicate that the polymeric micelle formulation enabled an increased and targeted delivery of RA to the PSU, potentially translating to a safer and more efficient clinical management of acne.

Auxotrophic recombinant Mycobacterium bovis BCG overexpressing Ag85B enhances cytotoxicity on superficial bladder cancer cells in vitro

BCG therapy remains at the forefront of immunotherapy for treating patients with superficial bladder cancer. The high incidence of local side effects and the presence of non-responder diseases have led to efforts to improve the therapy. Hence, we proposed that an auxotrophic recombinant BCG strain overexpressing Ag85B (BCG ∆leuD/Ag85B), could enhance the cytotoxicity to the human bladder carcinoma cell line 5637. The rBCG was generated using an expression plasmid encoding the mycobacterial antigen Ag85B to transform a BCG ∆leuD strain. The inhibitory effect of BCG ∆leuD/Ag85B on 5637 cells was determined by the MTT method, morphology observation and a LIVE/DEAD assay. Gene expression profiles for apoptotic, cell cycle-related and oxidative stress-related genes were investigated by qRT-PCR. Bax, bcl-2 and p53 induction by BCG ∆leuD/Ag85B treatment was evaluated by Western blotting. BCG ∆leuD/Ag85B revealed a superior cytotoxicity effect compared to the control strains used in this study. The results showed that the expression level of pro-apoptotic and cell cycle-related genes increased after BCG ∆leuD/Ag85B treatment, whereas the mRNA levels of anti-apoptotic genes decreased. Interestingly, BCG ∆leuD/Ag85B also increased the mRNA level of antioxidant enzymes in the bladder cancer cell line. Bax and p53 proteins levels increased following treatment. In conclusion, these results suggest that treatment with BCG ∆leuD/Ag85B enhances cytotoxicity for superficial bladder cancer cells in vitro. Therefore, rBCG therapy may have potential benefits in the treatment of bladder cancer.

Immediateversusas-needed acetaminophen for post-immunisation pyrexia

Local and minor systemic adverse events are frequently seen after routine immunisation with diphtheria-pertussis-tetanus. Antipyretics are frequently prescribed for these events and prophylactic administration of acetaminophen is occasionally recommended. To determine whether prophylactic administration of acetaminophen has any effect in reducing the incidence of post-vaccination side-effects. A prospective, comparative trial with telephone interview-based outcome assessment. OPD and immunisation room of a tertiary-care paediatric hospital. 167 children aged between 1·5 and 24 months presenting for routine immunisation were enrolled and allocated to the 'immediate' or 'as-needed' group. The immediate group had received acetaminophen syrup (10-15 mg/kg, single dose) immediately after vaccination (n=89); children in the as-needed group were not given prophylactic acetaminophen (n=78). Parents of both groups were free to give further doses of acetaminophen for fever, pain or irritability. The primary outcome was the incidence of parent-reported fever needing rescue acetaminophen, and the secondary outcome was the incidence of local side-effects. There was a statistically significant higher incidence of fever and irritability in the 1st 6 hours following vaccination in the as-needed group (p=0·04). No difference was observed in the incidence of local and systemic side-effects or the median number of acetaminophen doses required by the children in the two groups. Routine prophylactic acetaminophen after DPT vaccination was effective in reducing the frequency of fever and irritability in the initial 6 hours. However, given that a similar number of doses of acetaminophen was required in both groups, it seems inappropriate to expose all infants receiving DPT vaccination to the possible adverse effects of routine administration of acetaminophen.

Bacillus Calmette–Guerin Immunotherapy for Urothelial Carcinoma of the Bladder

Mycobacterium bovis bacille Calmette-Guerin (BCG) is one of the great success stories of immunotherapy as a treatment for superficial urothelial carcinoma of the bladder. Despite clinical effectiveness in over 50% of patients, the high incidence of local side effects and presence of nonresponders has led to efforts to improve the therapy. Recent advances have suggested a role for neutrophils and TNF-related apoptosis-inducing ligand (TRAIL) in the antitumor inflammatory response. Cell wall components of mycobacteria alone, lowered doses of BCG, and combination with cytokines have been studied as ways to improve the immune response associated with BCG and/or reduce toxicity. This review will discuss the clinical use of BCG, its proposed mechanism of action, and directions of future research to improve efficacy and decrease side effects.

Local oropharyngeal side effects of inhaled corticosteroids in patients with asthma

The widespread use of inhaled corticosteroids (ICS) for the treatment of persistent asthma, although highly effective, may be associated with both systemic and local side effects. Systemic side effects of ICS have been extensively studied. In contrast, relatively few studies have been performed to specifically evaluate local side effects of ICS. These local side effects--including oropharyngeal candidiasis, dysphonia, pharyngitis, and cough--are generally viewed as minor complications of therapy. However, they can be clinically significant, affect patient quality of life, hinder compliance with therapy, and mask symptoms of more serious disease. Local side effects result from deposition of an active ICS in the oropharynx during administration of the drug. Numerous factors can influence the proportion of an inhaled dose that is deposited in the oropharyngeal cavity, including the ICS formulation, type of delivery system, and patient compliance with administration instructions. Therefore, the incidence of local side effects can vary widely. The goal in developing a new ICS is to include key pharmacologic characteristics that reduce oropharyngeal exposure to active drug while maintaining efficacy comparable with currently available ICS.

A new combination vaccine for measles, mumps, rubella and varicella

ProQuad is a recently approved combination vaccine for simultaneous vaccination against measles, mumps, rubella and varicella in children aged 12 months to 12 years. It combines two well-established vaccines: Measles, Mumps, Rubella Virus Vaccine Live (M-M-R II) and Varicella Virus Vaccine Live (Varivax with higher varicella-zoster titer). Whereas vaccination against measles, mumps and rubella has almost 100% coverage, vaccination against varicella shows a significantly lower uptake of approximately 84%. Clinical studies on the immunogenicity and efficacy of ProQuad demonstrated seroconversion rates and a magnitude of antibody response similar to those observed after administration of its individual components, M-M-R II and Varivax vaccines. The incidence of local side effects (pain/tenderness/soreness, erythema, swelling, ecchymosis and rash) and systemic adverse effects (fever, irritability, rash, upper respiratory infection, viral exanthema and diarrhea) is similar to or lower than that observed in component vaccines. ProQuad is a highly immunogenic combination vaccine with a good safety profile. The use of ProQuad combination vaccine will simplify immunization delivery by providing protection against more diseases with fewer injections and less pain, improve timely vaccination coverage and reduce the health-care costs for additional health visits. The ProQuad combination vaccine facilitates implementation of varicella vaccination into routine childhood immunization schedules and will help to protect children against these four potentially serious diseases.

High lung deposition of 99mTc-labeled ciclesonide administered via HFA-MDI to patients with asthma

To examine the deposition and pharmacokinetics of ciclesonide administered via hydrofluoroalkane-metered dose inhaler (HFA-MDI) in patients with asthma. Twelve patients with mild asthma (FEV1, 95% predicted) inhaled a single dose of 99mtechnetium (Tc)-ciclesonide 320 microg ex-actuator (400 microg ex-valve). Deposition of ciclesonide in the lung and oropharynx was quantified using two-dimensional (2D)-gamma scintigraphy. Three-dimensional single photon emission computed tomography (3D SPECT) was used to assess the regional distribution of ciclesonide in the lung. The pharmacokinetics of ciclesonide and its active metabolite, desisobutyryl-ciclesonide (des-CIC), were determined by liquid chromatography-tandem mass spectrometry. Ciclesonide and des-CIC concentrations were determined in mouth-rinsing solutions. 2D-gamma scintigraphy indicated that ciclesonide deposition was higher in the whole lung (52%) than in the oropharynx (32.9%). Furthermore, 3D SPECT revealed that ciclesonide deposition within the lungs was highest in the peripheral regions that contain the small airways and alveoli. The pharmacokinetic profile of Tc-labeled ciclesonide and des-CIC was similar to that obtained after inhalation of non-labeled formulations in previous studies. Des-CIC accounted for 14.9% of the total molar concentration of ciclesonide/des-CIC in mouth-rinsing solutions obtained between 7 and 12min after inhalation. Inhalation of ciclesonide via HFA-MDI results in high pulmonary deposition, especially in the peripheral regions of the lung. High pulmonary deposition contributes to ciclesonide's ability to maintain lung function and control symptoms in patients with asthma. Deposition and activation of ciclesonide in the oropharynx is low, consistent with previous reports of low oropharyngeal deposition and a reduced incidence of local side effects in patients receiving ciclesonide therapy.

Effects of lowering the aluminium content of a dTpa vaccine on its immunogenicity and reactogenicity when given as a booster to adolescents

As aluminium in vaccines has been associated with the incidence of local side effects occurring after vaccination, this observer-blind randomised clinical trial was designed to evaluate the effect of lowering the aluminium content of a combined reduced-antigen-content dTpa vaccine on immunogenicity and safety when administered to healthy adolescents aged 10–18 years. A total of 647 subjects were enrolled, 224 (35%) received a dTpa formulation with 0.5 mg aluminium, 209 (32%) a formulation with 0.3 mg aluminium and 214 (33%) a formulation with 0.133 mg aluminium. One month after boostering, all subjects were seroprotected against diphtheria and tetanus toxoids. All subjects were seropositive for anti-FHA and anti-PRN but 4% of the initially seronegatives in both reduced aluminium groups did not seroconvert for anti-PT. Booster responses did not differ significantly between groups for any antibody, but post booster vaccination anti-PT GMC's differed significantly between groups and decreased when vaccine aluminium content decreased. No clear difference between study groups in local or general side effects was demonstrated. The most frequently reported symptoms after vaccination were injection site pain (89.5–90.7%), fatigue (42.1–47.4%) and headache (41.1–45.1%). This study showed that the aluminium content has a specific influence on the immunogenicity of this dTpa vaccine.

Side Effects of Influenza Vaccination in Healthy Older People: A Randomised Single-Blind Placebo-Controlled Trial

Objectives: To investigate the frequency of side effects following influenza vaccination in healthy participants aged 65–74 years. Materials and Methods: A single-blind randomised placebo-controlled trial was performed in general practices in central Liverpool on 729 healthy individuals (341 females and 388 males) aged 65–74 (median age 68.9) years, of whom 552 received influenza vaccine and 177 received placebo. The main outcome measures were analysed from adverse reactions reported by the subjects on a postal questionnaire 3 days after vaccination. Results: 724 (99.3%) questionnaires were returned. 62 (11.3%) participants who received influenza vaccination complained of local symptoms compared with 9 (5.1%) participants who received placebo (difference 6.2%; 95% CI 1.3 to 10.0%; p = 0.02). 192 (35.1%) individuals who received influenza vaccine complained of one or more systemic side effects compared with 75 (42.4%) who received placebo (difference –7.3%; 95% CI –15.6 to 0.9%; p = 0.10). Conclusion: Healthy people belonging to this age group can be reassured that, when compared with placebo, influenza vaccination causes few, if any, systemic side effects and only a low incidence of local side effects.

Local Side Effects of Subcutaneous and Intramuscular Urinary Gonadotropins for Ovarian Stimulation in In Vitro Fertilization: A Prospective, Randomized Study

Objective: To compare the incidence and severity of local side effects of urinary-derived gonadotropins administered SC and IM. Design: Prospective randomized study of women undergoing IVF treatment. Setting: Tertiary referral center for assisted reproduction. Patient(s): A total of 71 patients were randomized to receive gonadotropins by the SC (n = 41) or IM (n = 30) route. Intervention(s): One cycle of IVF with gonadotropins administered either SC or IM for ovarian stimulation. Main Outcome Measure(s): Incidence and severity of local side effects, such as redness, itching, swelling, pain, and bruising. Result(s): Pain was the most common side effect, with 55.3% and 70.1% of IM and SC injections, respectively, resulting in pain. There were no statistically significant differences in the incidence of itching or bruising after IM and SC injections. Although there was a higher incidence of redness and swelling in the SC group compared with the IM group, most cases were classified as mild. Conclusion(s): There was a significantly higher incidence of some local side effects after SC gonadotropin administration but most of these were mild and well tolerated by patients.

HIGH-DOSE INHALED STEROIDS

Most guidelines presently recommend high-dose inhaled steroids (1000 µLg/d or more) as first-line maintenance therapy for moderate to severe asthma. Numerous studies have established the superiority of high-dose inhaled steroids over placebo in reduction or discontinuation of oral steroids and improvement of symptoms and objective lung function. It is surprising to note, however, that the studies of the doseresponse relationship have not shown consistent or conclusive results. This discrepancy in results is most likely due to varying study designs. The inhaled steroid preparations currently available appear to have comparable efficacy with only slight differences. Newer non-CFC delivery systems may improve bronchial delivery. High-dose inhaled steroids appear to cause HPA suppression and to affect bone metabolism to a mild degree with no clear clinical correlation at this time. Long-term studies of these effects are ongoing. There may be a beneficial effect of inhaled steroids on insulin sensitivity and glucose tolerance. Dermal thinning and purpura have been reported. The risk of posterior subcapsular cataracts is minimal. Local effects are mild and reversible and include dysphonia, oral candidiasis, and reflex cough. The use of delivery devices such as spacers and holding chambers improves delivery to the lungs and decreases the incidence of local side effects and systemic absorption. The risk/benefit ratio of high-dose inhaled steroids is excellent based on current data, and these medications should continue to be used as primary maintenance therapy in patients with moderate to severe asthma.

Inhaled Pentamidine

Pentamidine is an aromatic diamidine derivative which has become one of the standard therapies for Pneumocystis carinii pneumonia (PCP), particularly in patients with acquired immunodeficiency syndrome (AIDS). However, with parenteral administration of the drug there is a high risk of toxicity. Inhaled pentamidine produces much higher concentrations of drug on the bronchoalveolar surface with minimal systemic absorption. It has been used successfully for the treatment of PCP in AIDS patients, but its most valuable contribution has been as prophylaxis in AIDS patients at high risk of developing PCP. In prospective controlled studies there has been greater than 80% reduction in relapse rate with pentamidine. The reduction in relapse rate among patients who have experienced one previous episode of PCP has been 50 to 100% compared with historical control groups, over a follow-up period averaging about 6 months. Significant systemic adverse effects to inhaled pentamidine are rare. Respiratory effects associated with inhalation are common but usually controllable without treatment discontinuation. The ideal particle size for even distribution of pentamidine throughout the lung is considered to be 1 to 2 microns. Jet nebulisers such as the 'Respirgard II' system produce a mass median aerodynamic diameter (MMAD) of particles in this range. Ultrasonic nebulisers produce larger particles. The implication from this difference is that while ultrasonic nebulisers may have poorer alveolar distribution and the incidence of local side effects (common with all formulations) may be higher, total drug delivery may be more efficient allowing effective PCP prophylaxis with lower dosages (120 mg vs 300 mg monthly). However, there are no data available comparing the efficacies and tolerabilities of the different formulations of inhaled pentamidine. Nevertheless, inhaled pentamidine would seem poised to become routine prophylaxis in patients with AIDS or AIDS-related complex at risk of developing PCP.

The use of low molecular weight heparins for postsurgical deep vein thrombosis prevention in orthopaedic patients.

The prophylactic antithrombotic efficacy of a low molecular weight heparin was compared with a traditional unfractionated calcium heparin after orthopaedic surgery in 140 patients. Deep vein thromboses were detected in legs either by Doppler sonography or [125I]fibrinogen uptake tests in five (7.1%) and seven (10%) patients, respectively. The capacity of both drugs to prevent deep vein thrombosis was demonstrated. Compared with the control group, those who used low molecular weight heparin showed a significant increase of activated factor X inhibition and smaller increases in activated partial thromboplastin times. Tolerability of both drugs was good, with a low incidence of local side-effects.

Effect of treatment with botulinum toxin on neurogenic blepharospasm.

Botulinum toxin type A creates temporary localised flaccid paralysis after injection into skeletal muscle. Thirty four patients with blepharospasm, of whom 28 also had the oromandibular dystonia syndrome, were treated with injections of botulinum toxin type A into the orbicularis oculi, and 28 showed functional improvement after the treatment. A high incidence of local side effects occurred, especially partial ptosis, which was well tolerated. There were no systemic side effects. The average period of relief was 2.5 months, increasing to 2.8 months after a second injection. Functional improvement was limited in patients with severe associated dystonia.