Major Systemic Side Effects Research Articles

Cutaneous Hypersensitivity Reaction to Injectable Hyaluronic Acid Gel

Injectable hyaluronic acid gel is a non-animal biomaterial used for soft tissue augmentation. The dermal implantation of this naturally occurring polysaccharide is reported to be well tolerated by patients, with a longer duration in tissue than bovine collagen without any major local or systemic side effects. We report a case of an acute hypersensitivity reaction in a woman after her third injection for improvement of melolabial fold wrinkles. An adverse granulomatous-like response to the intradermal injection of a modified hyaluronic acid gel is described. The patient developed indurated and erythematous papulocystic nodules in the melolabial folds bilaterally at the sites of injection. Injectable hyaluronic acid gel can be associated with severe allergic reactions and patients should be warned of this possible treatment side effect.

A pharmacokinetic/pharmacodynamic approach to predict the cumulative cortisol suppression of inhaled corticosteroids.

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16-21% was predicted for FP 250 micrograms, FLU 500 micrograms, and TCA 1000 micrograms. For multiple dosing, a respective CCS of 28-33% was calculated for FLU 500 micrograms bid, FP 250 micrograms, bid, and TCA 1000 micrograms bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.

Dependency of cortisol suppression on the administration time of inhaled corticosteroids.

Endogenous cortisol suppression is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. A previously developed pharmacokinetic/ pharmacodynamic approach was used to evaluate the influence of administration time on the cumulative cortisol suppression (CCS) after single doses of the inhaled corticosteroids flunisolide and fluticasone propionate. Administration time-dependent simulations of CCS were performed with drug-specific pharmacokinetic and pharmacodynamic parameters obtained from previous clinical trials. Both drugs showed similar diurnal variation in CCS, dependent on the administration time, with maximum suppression when administered in the early morning at approximately 3 AM. The optimum administration time for minimized CCS was in the afternoon but was shifted from 3 PM for fluticasone propionate to later time points around 7 PM for flunisolide, probably because of the shorter terminal elimination half-life of flunisolide. Regarding peak to trough fluctuation, however, CCS after fluticasone propionate showed only half the administration time dependency as after flunisolide. Therefore, the ratio between CCS after flunisolide and after fluticasone propionate also followed administration time-dependent variations. This led to the conclusion that administration time has to be considered as a pivotal influential factor in clinical studies comparing CCS among different inhaled corticosteroids.

Mathematical modeling of cortisol circadian rhythm and cortisol suppression

One of the major systemic side effects of topically administered corticosteroids is the suppression of endogenous cortisol production by a negative feedback mechanism. Due to the marked circadian rhythm in cortisol release, the precise quantification of this cortisol suppression is quite complex. It was the purpose of these studies to look for novel approaches to describe the circadian variation of cortisol secretion and develop a consistent PK/PD model to evaluate the effect of administered exogenous corticosteroids. A proposed linear release model allows characterization of the cortisol baseline and cortisol suppresion in a better way than other approaches proposed in the literature. The model assumes a linear decrease in cortisol production during the day from approximately 4–5 a.m. to about midnight followed by a shorter linear increase of secretion rate from midnight to approximately 4–5 a.m. on the following day. Furthermore, the model takes into account the elimination of cortisol. Comparison of experimentally measured cortisol levels over 72 h with the respective model predictions showed good agreement. The model was also able to account for the suppressive effect of triamcinolone acetonide after intravenous, oral and pulmonary administration.

Combined modality treatment of advanced cancers of the oral cavity and oropharynx

From May 1985 to June 1988, 70 evaluable patients with advanced squamous cell cancers of the oral cavity and the oropharynx were treated with preoperative combined radio-chemotherapy. Treatment consisted of 50 Gy/25 fractions/5 weeks, combined with concomitant administration of mitomycin C on day 1 (15 mg/m 2, i.v. bolus) and 5-fluorouracil during the first 5 days of irradiation (750 mg/m 2/24 hours, continuous infusion). Surgery was performed 3 to 5 weeks following irradiation. Treatment tolerance was good and local mucosal reaction was increased, but no major systemic side effects were recorded. At surgery, 3–5 weeks following irradiation, 48.6°10 of the operation specimens did not contain any histologically detectable residual tumor. Overall survival is 61%, being 69% in T2 and T3, while none of the patients with bone invasion has survived. Median survival is 28, 26, and 9 months in T2, T3 and T4 stages, respectively. Loco-regional relapses have been recorded in 33% of the patients, occurring in 27% of T2, 25% of T3, and 88% of T4 stages. Patients have been spared mutilating radical neck dissection because of combined presurgical treatment without impaired survival or loco-regional relapse rate.

Continuous Epidural Infusion of Morphine for Treatment of Pain after Thoracic Surgery

We evaluated postoperative pain relief and the incidence of side effects of three methods of thoracic epidural analgesia. Ninety patients, divided into three equal groups, received postoperative analgesia after thoracic surgery either as intermittent epidural injections of bupivacaine (25 mg/5 ml, 0.5% solution) as needed, or, intermittent epidural injections of morphine (5 mg/5 ml of normal saline, 0.1% solution) as needed, or continuous epidural infusion of morphine (0.1 mg, in 1 ml of normal saline) per hour supplemented with intravenous morphine (2 mg) upon request. Pain relief was evaluated by each patient on a pain scale visual analogue and by pain relief questionnaire for a period of 72 hr. Postoperative pain relief was achieved equally with these three methods of epidural analgesia in all patients with no significant difference between groups. Intermittent epidural injection of bupivacaine relieved pain for 4.9 +/- 1.9 (SD) hr/injection and was associated with urinary retention in all patients, with numbness and weakness of the hands in 12 patients, and with severe hypotension in 7 patients. Intermittent epidural injection of morphine relieved pain for 5.8 +/- 2.3 hr/injection and was associated with urinary retention in all patients, with pruritus in 12 patients, and with central narcosis and respiratory depression in 8 patients. Continuous epidural infusion of morphine with occasional intravenous morphine (2 mg) supplementation also effectively relieved postoperative pain and was associated with minimal systemic side effects. One patient complained of pruritus, and two patients developed urinary retention.(ABSTRACT TRUNCATED AT 250 WORDS)

COMPARISON OF FLUBENDAZOLE AND DIETHYLCARBAMAZINE IN TREATMENT OF ONCHOCERCIASIS

Flubendazole, an injectable benzimidazole drug, was compared with diethylcarbamazine (DEC) in a prospective double-blind study of the treatment of onchocerciasis. Nineteen Mexican men were randomly assigned to receive either flubendazole 750 mg intramuscularly once a week for 5 doses, or DEC 100 mg twice daily for 14 days, and they were then followed up for 12 months. Major systemic side-effects during the first 3 weeks were common in the DEC group but not in the flubendazole group in which there was considerable inflammation at the injection site instead. Ocular complications (limbitis, punctate keratitis, and uveitis) were also common in the DEC group, whereas in the flubendazole group they consisted only of one new punctate opacity at day 4 in one subject. One DEC patient also had several new areas of chorioretinal changes on day 2 but these had disappeared by 2 months. Skin microfilaria counts fell rapidly in the DEC group, but returned to the pretreatment levels. In contrast, skin microfilaria counts in the flubendazole group fell slowly, but by 6 and 12 months were lower than in the DEC group (at 12 months 0·2 vs 7·3 mf/mg, p<0·001). In addition, by 6 months none of the flubendazole subjects had intracorneal microfilariae, and only one had microfilariae in the anterior chamber, whereas the numbers of intraocular microfilariae in the DEC group had returned to pretreatment levels. The results suggest that flubendazole is safer and more effective than DEC in the treatment of onchocerciasis.

Drug toxicity in pediatric ophthalmology

The current, clinically pertinent literature on nonallergic ocular side effects of drugs and systemic side effects of ocular medications is reviewed in relation to the pediatric age group, including eyedrop dosage considerations. The broad range of such agents includes corticosteroids, anesthetics, chemotherapeutic antimicrobial, antiamebic, antimalarial, and antineoplastic agents, as well as autonomically active eyedrops.Some coverage is given to teratogenic drugs that may produce ocular defects. In addition, the drug-induced syndromes of malignant hyperthermia and benign intracranial hypertension are briefly discussed.A broad pediatric perspective requires the inclusion of some of the major systemic side effects of certain systemic agents that produce ocular side effects, for example, chloramphenicol and vitamin A. This pediatric orientation also justifies mention of immunizations, even though the agents used may not ordinarily be considered drugs. Other miscellaneous agents are also reviewed.The National Registry for Drug-Induced Ocular Side Effects is located at the Oregon Health Sciences University in Portland. Reports of findings or experiences are invited from all readers, and the interested physician or researcher is invited to make specific inquiries for information from the Registry. This exchange of information is offered as a free service.