Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting

The aim of this study is to observe the synergistically enhanced percutaneous penetration and skin analgesia of tetracaine gel containing menthol and ethanol through experimental and clinical studies. Four anesthetic gels containing 4% tetracaine in carbomer vehicle named T-gel (containing no menthol or ethanol), 5%M/T-gel (containing 5% menthol), 70%E/T-gel (containing 70% ethanol, an optimal concentration for antiseptic), and 5%M+70%E/T-gel (containing both 5% menthol and 70% ethanol), respectively, were fabricated. The in vitro mouse skin permeation was investigated using a Franz diffusion cell. The mouse skin morphology was examined by a scanning electron microscope. The in vivo skin analgesic effect in mice was evaluated using the von Frey tests. To determine the efficacy of tetracaine gels for managing the pain in human volunteers, a paralleled, double-blinded, placebo-controlled, randomized controlled trial design combined with verbal pain scores (VPS) was performed. The combination of menthol and ethanol (5%M+70%E/T-gel) conferred significantly higher tetracaine diffusion across full-thickness mouse skin than 5%M/T-gel, 70%E/T-gel, and T-gel. The ultra structure changes of mouse skin stratum corneum treated with 5%M+70%E/T-gel were more marked compared with those of any other tetracaine gel. von Frey tests in mice showed a synergistically enhanced effect of menthol and ethanol on the analgesia of tetracaine gel. The mean VPS were significantly lower for volunteers treated with 5%M+70%E/T-gel than those receiving other gels or the EMLA cream. 5%M+70%E/T-gel possessed the shortest anesthesia onset time, the longest anesthesia duration and the strongest anesthesia efficacy. Seventy percent ethanol in 5%M+70%E/T-gel not only improved the analgesic efficacy of the tetracaine gel through synergistically enhanced percutaneous permeation with menthol but also served as an antiseptic agent keeping drug application site from infection. 5%M+70%E/T-gel is a potential topical anesthesia preparation for clinical use.     

Oral levofloxacin-induced optic neuritis progressing in loss of vision

This case report highlights a rare adverse drug reaction caused by levofloxacin, resulting in optic neuritis progressing into unilateral loss of vision. A 49-year-old male patient was diagnosed to suffer from left maxillary and ethmoid sinusitis and was only prescribed oral levofloxacin 500 mg tablets once daily for 5 days. Within a few minutes after taking the first dose of the drug, the patient experienced respiratory distress, dizziness, confusion with pain, and loss of color vision, followed by almost complete loss of vision in the right eye. The left eye was normal. After ophthalmologic examinations and investigations, he was diagnosed to suffer from optic neuritis, probably (according to Naranjo adverse drug reaction probability scale) induced by levofloxacin.     

Comparison of two recently published algorithms for assessing the probability of adverse drug reactions.

1 A simple valid and reliable method for estimating the probability of adverse drug reactions (adverse drug reactions probability scale, APS) has been recently described (Naranjo et al., 1981a). 2 The results using APS were compared to those obtained with another more detailed algorithm (adverse reactions scoring system, ASS) described by Kramer et al. (1979). 3 Sixty-three randomly selected adverse drug reactions (ADRs) were rated by two observers, using APS and ASS one year apart. The cases were ordered in a random sequence. Between-raters reliability using APS (R(est) = 0.96 and ASS (R(est) = 0.86), was very high. 4 ADR scores obtained with both methods were highly correlated (r = 0.82, P less than 0.001). However, time spent using ASS was significantly longer (paired t-test, t = 1.70, P less than 0.05). 5 These results suggest that while ASS is somewhat more complex than APS both are equally reliable and will give very similar conclusions regarding the probability of ADRs. Such algorithms must be used if the clinical assessment of ADRs is to become acceptably reliable.     

Oral aripiprazole-induced severe hypoglycemia

This case report highlights a very rare adverse drug reaction caused by oral aripiprazole resulting in severe hypoglycemia. A 72-year-old-male patient suffering from Parkinson disease on prolonged carbidopa plus levodopa combination therapy (carbidopa 25 mg plus levodopa 100 mg, thrice daily) for 1.3 years was recently diagnosed with psychosis and was initiated 10 mg/day oral aripiprazole. After 10 days of aripiprazole therapy, the patient experienced symptoms of hypoglycemia and on the 21st day, he was hospitalized for severe hypoglycemia. Other long-term concomitant medications taken by this patient were oral losartan (25 mg/day) and rosuvastatin (40 mg/day). Dechallenge and rechallenge with aripiprazole revealed that there is a "definite" (according to Naranjo adverse drug reaction probability scale) relationship between administration of aripiprazole and onset of hypoglycemic events.     

A surveillance method for the early identification of idiosyncratic adverse drug reactions.

BACKGROUND: Pemoline is a CNS stimulant that was introduced in 1975 in the US and was used to treat children with attention deficit hyperactivity disorder. Pemoline was withdrawn from the market 30 years later because of fatal hepatotoxicity associated with its use. OBJECTIVE: To create a system that will estimate the potential association between a serious adverse event and a medication early in its marketing cycle. METHOD: All case reports of acute liver failure associated with pemoline and reported to the US FDA from 1975 through 1999 were reviewed. All published articles on pemoline-induced hepatotoxicity were reviewed, and the Naranjo adverse drug reaction probability scale was applied. The incidence rate of idiopathic acute liver failure was estimated from the published literature. The data were analyzed using Fisher's Exact test and relative risks (RR) were calculated. RESULTS: As early as 1978, there was a significant signal indicating that pemoline was associated with acute liver failure, with an RR of 24.08 (95% CI 4.67, 124.10; p < 0.05). With an increased number of cases, the significance of the association had been steadily increased. CONCLUSION: This method enables researchers, clinicians, drug companies and regulators to identify uncommon adverse drug reactions, caused mostly by new medications, earlier than they currently are in the course of marketing and thus quantify serious adverse events.     

丁卡因胶桨在男性导尿术的应用分析

目的探讨丁卡因胶桨在男性导尿术中应用的临床疗效。方法回顾分析观察组78例男性患者在行导尿管术前应用丁卡因胶桨作局麻及对照组40例男性患者未作丁卡因胶桨作局麻患者的的临床疗效。使用四点口述分级疼痛评分法及导尿成功率进行评分。结果观察组术前应用应用丁卡因胶桨作局麻患者的镇痛效果及导尿成功率明显优于对照组,统计学有显著差异。结论术前应用丁卡因胶桨作局麻在男性导尿术中能有效减轻男性导尿患者的疼痛及增加导尿成功率,应用安全可靠,值得临床推广应用。     

Atypical warfarin-induced skin necrosis

Warfarin-induced skin necrosis (WISN) is a disorder of unclear etiology that predominantly affects obese women. Although WISN typically occurs within the first 10 days of warfarin therapy, some patients develop the complication several years after warfarin exposure. We describe the case of a 43-year-old Caucasian woman with a history of recurrent thromboembolic disorders, protein S deficiency, and multiple exposures to warfarin who came to the emergency room with complaints of worsening dermatitis that had progressed over a 15-hour period. Examination revealed multiple, diffuse "lace-like" erythematous eruptions with superimposed lesions that were tender, ulcerated, and crusted. A biopsy was performed, and histopathologic findings were consistent with WISN. Based on the Naranjo adverse drug reaction probability scale, a probable causal relationship existed between warfarin and skin necrosis in this patient. Since treatment is generally supportive, prompt and prudent evaluation of suspicious skin lesions is necessary to prevent the serious sequelae associated with WISN.     

A Raman spectroscopic investigation of bioadhesive tetracaine local anaesthetic formulations

Raman spectroscopy at 785 nm has been employed to characterise the properties of tetracaine in bioadhesive gel and patch formulations. In the first study, interactions between the drug and excipients in novel bioadhesive patch systems were characterised. It was determined that the drug did not interact with any of its formulation components, and that this was an important factor in its clinical performance, particularly the rapid onset of anaesthesia. Investigations of drug uptake in the stratum corneum from a gel formulation suggested that tetracaine rapidly undergoes a phase-change upon application to the skin. The intensity of the tetracaine Raman bands at approximately 1600 cm(-1) suggests that the local anaesthetic is rapidly absorbed into the skin. Decreases in Raman tetracaine band intensities, along with an absence in the concomitant alteration in the internal standard spectra, indicates an decrease in the tetracaine concentration present in the gel. Further, a baseline indicating complete tetracaine absorption appears to be reached after approximately 40 min of exposure. After this time little further absorption was observed, suggesting that the stratum corneum "reservoir" was saturated with tetracaine at this time. This is consistent with the optimum application time required for tetracaine gels to attain maximum clinical efficacy. This study has indicated the effectiveness of Raman spectroscopy in the analysis of gel-based pharmaceutical preparations, showing it to be a simple, rapid, virtually non-invasive technique for determination of tetracaine.     

Nonbloody, red stools from coadministration of cefdinir and iron-supplemented infant formulas

Cefdinir is an extended-spectrum, third-generation cephalosporin that may be used for treatment of acute otitis media in patients allergic to penicillin. When administered with iron-containing products, including infant formulas, cefdinir or one of its metabolites may bind to ferric ions, forming a nonabsorbable complex that imparts a reddish color to the stool. We describe a 9-month-old infant with failure to thrive and acute otitis media who developed an erythematous maculopapular rash during treatment with amoxicillin-clavulanate. His antibiotic therapy was changed to cefdinir. Five days into a 10-day course of therapy, the infant's mother brought him to the pediatric clinic and reported the appearance of red stools. He had no associated gastrointestinal symptoms (vomiting, abdominal pain, or diarrhea). His hematocrit and hemoglobin level were normal, and Clostridium difficile antigen studies and tests for species of Shigella, Salmonella, and Camphylobacter as well as ova and parasites were all negative. Cefdinir was discontinued, and his stools returned to normal within 48 hours. Three weeks later, he again received cefdinir for recurrent otitis media. Red stools reappeared 48 hours later, were determined to be guaiac negative, and resolved within hours of drug discontinuation. During both occurrences of red stools, the infant had been breastfed and was receiving supplemental feedings with an iron-containing infant formula. In the product labeling of cefdinir, this adverse event is described as a consequence of the drug-drug interaction; however, it is not listed in the adverse drug reaction section of the labeling. As such, one may miss the association between cefdinir and reddish stools when investigating this event as a potential adverse reaction to cefdinir. When using the Naranjo adverse drug reaction probability scale to assess causality in our patient's case, this adverse drug reaction was determined as highly probable. As this infant had been breastfed, the use of a supplemental iron-containing infant formula was not identified as a potential contributing factor until the second occurrence of red stools. Health care professionals should review the entire product labeling, including the drug-drug interaction section, when investigating a potential adverse drug reaction. With the recent approval of generic formulations of cefdinir, clinicians should be aware of this drug-drug interaction with iron-containing products to prevent unnecessary alarm by parents and caregivers, as well as costly medical evaluations for gastrointestinal bleeding.     

右旋布洛芬凝胶的抗炎镇痛作用

目的 考察右旋布洛芬凝胶的抗炎、镇痛作用。方法 以角叉菜胶致大鼠足跖肿胀、二甲苯致小鼠耳廓肿胀、大鼠辐射热刺激及小鼠醋酸扭体法，观察右旋布洛芬凝胶的局部抗炎、镇痛作用。结果 2.5%、4.0%右旋布洛芬凝胶局部涂药能显著抑制角叉菜胶所致大鼠足跖肿胀及二甲苯所致小鼠耳廓肿胀，并能明显提高大鼠对光热刺激的痛阈，减少小鼠醋酸刺激的扭体次数。结论 2.5%右旋布洛芬凝胶局部外用具有显著的抗炎、镇痛活性。     

Severe Rash Associated with Dexmedetomidine Use During Mechanical Ventilation

Dexmedetomidine, a sedative administered by continuous infusion, is used to facilitate mechanical ventilation through α₂-receptor activation. The drug's most common adverse reactions include hypotension, hypertension, nausea, bradycardia, and dry mouth. However, to our knowledge, no reports of dermatologic allergic reactions from dexmedetomidine use have been published. We describe a 22-year-old man who was intubated after being injured in a motor vehicle collision. He had been receiving propofol and fentanyl infusions for sedation during mechanical ventilation and was transitioning to dexmedetomidine. Within 4 hours of receiving dexmedetomidine 0.2 μg/kg/hour, the patient developed a wheal-and-flare rash encompassing 60% of his body surface area. The infusion was immediately discontinued; over the next 24 hours most of the rash receded, and within 48 hours of drug discontinuation the rash had completely resolved. According to the Naranjo adverse drug reaction probability scale, the likelihood that this rash was induced by dexmedetomidine was probable. Clinicians should be aware of this potential dermatologic adverse effect from dexmedetomidine, and patients receiving the drug should be closely monitored.     

Topical ketoprofen patch

Although oral nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the treatment of a variety of acute and chronic pain conditions, their use may be associated with serious systemic adverse effects, particularly gastrointestinal disorders. In order to minimise the incidence of systemic events related to such agents, topical NSAIDs have been developed. Topical NSAIDs, applied as gels, creams or sprays, penetrate the skin, subcutaneous fatty tissue and muscle in amounts that are sufficient to exert a therapeutic effect on peripheral and central mechanisms in the absence of high plasma concentrations. Data indicate that topical NSAIDs are effective at relieving pain in a number of acute and chronic pain indications. This review article discusses the pharmacokinetics, efficacy and tolerability of a new formulation of ketoprofen available as a topical patch. The topical patch containing ketoprofen 100mg as the active principle has been developed using a novel delivery system that dispenses therapeutic doses of the drug directly to the site of injury. Pharmacokinetic data indicate that although plasma levels of ketoprofen are higher when the drug is administered as a patch versus a gel, the total systemic bioavailability of ketoprofen 100 mg administered via a patch is no more than 10% of that reported for ketoprofen 100 mg administered orally. Because the patch facilitates ketoprofen delivery over a 24-hour period, the drug remains continually present in the tissue subjacent to the site of application. High tissue but low plasma ketoprofen concentrations mean that while tissue concentrations are high enough to exert a therapeutic effect, plasma concentrations remain low enough to not result in systemic adverse events caused by elevated serum NSAID levels. Phase III clinical trials in patients with non-articular rheumatism and traumatic painful soft tissue injuries showed that the topical ketoprofen patch was significantly more effective than placebo at reducing pain during daily activities and spontaneous pain after 7 days' treatment. Moreover, the topical ketoprofen patch was well tolerated; adverse events were primarily cutaneous in nature and occurred in a similar number of ketoprofen and placebo recipients suggesting that these events were related to the patch itself rather than the active ingredient. The incidence of gastrointestinal adverse events was low (<8% of all patients), and occurred in a similar proportion of patients receiving ketoprofen and placebo. Thus, the topical ketoprofen patch appears to be a simple, effective and safe therapeutic option for the treatment of local painful inflammation.     

Tigecycline-induced acute pancreatitis: case report and literature review

Tigecycline is a broad-spectrum antimicrobial agent structurally related to minocycline. Pancreatitis has been associated with the tetracycline class of antibiotics and concerns about tigecycline-induced acute pancreatitis have recently been raised. We describe a 69-year-old female who received tigecycline for treatment of a complicated skin and skin-structure infection. Following 7 days of tigecycline she developed severe abdominal pain and elevated pancreatic enzymes suggesting acute pancreatitis. According to the Naranjo adverse drug reaction probability scale, tigecycline was the probable cause of her acute pancreatitis. Clinicians should be aware of this potential adverse effect of tigecycline. We recommend that clinicians monitor patients for signs and symptoms of pancreatitis, including abdominal pain, during treatment with tigecycline.     

Acute erythema and edematous skin reaction and ectropion following docetaxel in a patient with non-small cell lung cancer

Docetaxel can cause skin reactions such as hypersensitivity, edema, and erythrodysesthesia syndrome as well as side effects involving the skin, including alopecia, nail onycholysis, nail pigmentation, photosensitivity, scleroderma, and paresthesia. In this case report, a patient was admitted to the hospital with widespread erythematous and edematous eruption in the head, neck, trunk, and lower and upper extremities, erythema around the eyes, and drooping of the lower eyelids that developed about 2 hours after receiving chemotherapy consisting of docetaxel. Use of the Naranjo Adverse Drug Reaction Probability Scale--a method for estimating the probability of adverse drug reactions--indicated a probable relationship between the skin reaction and docetaxel therapy in this patient. Docetaxel-associated skin reactions that are so extensive and severe as to lead to eye madarosis and ectropion are reported rarely in the literature.     

我院2006～2010年住院患者抗生素不良反应分析

目的探讨抗生素致不良反应的发生情况,为临床规范、合理用药提供参考。方法对我院2006年2月至2010年12月住院患者上报的47例抗生素致不良反应病例,对患者的年龄、性别、不良反应史、用药途径、所用药物、不良反应临床表现等进行统计分析。结果抗生素致不良反应主要发生在41～60岁;β-内酰胺类抗生素致不良反应/事件最多;主要临床表现为皮肤过敏反应。结论医疗机构应重视抗生素引起的不良反应,加强抗生素的合理应用。     

Emphysematous cholecystitis in a patient with gastrointestinal stromal tumor treated with sunitinib

A 50-year-old man had a metastatic gastrointestinal stromal tumor that was refractory to imatinib. He was prescribed a 6-week course of treatment with oral sunitinib 50 mg/day. During the fourth week of his first cycle of treatment with the drug, the patient developed acute-onset, right upper quadrant pain associated with nausea, vomiting, and fever; laboratory tests revealed leukocytosis and mild hyperbilirubinemia. He was diagnosed with acute emphysematous cholecystitis, which was treated with broad-spectrum antibiotics and percutaneous cholecystostomy. His symptoms resolved, and he successfully completed his course of therapy with sunitinib. Using the Naranjo adverse drug reaction probability scale, a score of 5 was derived, which indicates that the likelihood was probable that this adverse event was caused by sunitinib.     

Roxithromycin-induced toxic epidermal necrolysis

This case report highlights a very rare adverse drug reaction of oral roxithromycin causing toxic epidermal necrolysis (TEN). A 54-year-old male patient diagnosed with upper respiratory tract infection was prescribed oral roxithromycin 150 mg twice daily for 7 days. On the 10th day, the patient was admitted to the emergency with sore throat, redness, watering of eyes, painful micturition, and severe skin lesions. The skin lesions were multiple, severely painful, burning, coalesced, and filled with fluid-producing large blisters appearing on the lip, face, and trunk and then gradually spreading to legs, arms, palms, hands, and feet extensively involving much >30% of body surface area. Clinical examination, blood investigation, and histopathological examination of the skin confirmed the diagnosis of TEN. There was no history of any concomitant medications, drug allergy, burn injury, recent graft, or transplant or any coexisting infections such as herpes simplex. Other resembling skin diseases were eliminated after proper dermatological examination. This episode of TEN was probably drug (roxithromycin) induced. The drug was immediately stopped, and the patient was treated meticulously resulting in gradual reversal of the diseased state. Naranjo adverse drug reaction probability scale suggested the likelihood that oral administration of roxithromycin was responsible for the TEN was 'probable.'     

Lidocaine/tetracaine medicated plaster: in minor dermatological and needle puncture procedures

The lidocaine/tetracaine medicated plaster comprises a lidocaine/tetracaine 70?mg/70?mg patch and a controlled heat-assisted drug delivery pod that increases the diffusion of lidocaine and tetracaine into the dermis. Following a 1-hour application period, systemic absorption of lidocaine or tetracaine from the plaster was minimal. The lidocaine/tetracaine medicated plaster provided effective pain relief for adult (including elderly) patients undergoing minor dermatological procedures and for adult and paediatric patients undergoing vascular access procedures. In randomized, double-blind clinical trials, patient-reported median pain scores were significantly lower with the lidocaine/tetracaine medicated plaster than with an identical plaster containing placebo in patients undergoing minor dermatological or vascular access procedures. Furthermore, patient-reported median pain scores were significantly lower with the lidocaine/tetracaine medicated plaster than with a lidocaine/prilocaine cream in patients undergoing vascular access procedures. In a large, randomized, double-blind trial in paediatric patients undergoing venipuncture, the overall incidence of pain was significantly lower with the lidocaine/tetracaine medicated plaster than with a lidocaine/prilocaine plaster. The lidocaine/tetracaine medicated plaster was well tolerated, with the most frequent treatment-related adverse events resolving spontaneously.     

Pulmonary sarcoidosis associated with etanercept therapy

We present a case of probable pulmonary sarcoidosis associated with the use of etanercept for psoriatic arthritis. Other cases of etanercept-induced granulomas and skin sarcoidosis were recently published in the medical literature, but we found only one case that involved lung sarcoidosis during etanercept therapy. We describe a 40-year-old man who was receiving etanercept for severe psoriatic arthritis and was admitted to the hospital with dyspnea and subfebrile illness several months after the start of treatment. His diagnosis was consistent exclusively with sarcoidosis. The patient's symptoms improved when etanercept was discontinued, but they did not resolve completely. Treatment with prednisone 40 mg led to complete improvement of his pulmonary disease. Etanercept therapy can induce or exacerbate sarcoidosis. The disease disappears when etanercept is discontinued, although treatment with corticosteroids is sometimes required, as in our patient. Use of the Naranjo adverse drug reaction probability scale revealed a probable likelihood (score of 6) that the adverse reaction was related to etanercept. The association of etanercept with sarcoidosis is still a rare finding. This case highlights the importance of monitoring and possibly discontinuing the drug when sarcoidosis is suspected. Patients should be monitored during and after etanercept therapy for manifestations suggesting sarcoidosis, and we recommend patients receive baseline chest radiography at the start of therapy with follow-up of respiratory symptoms.     

Establishing causality in pediatric adverse drug reactions: use of the Naranjo probability scale

Carbamazepine hypersensitivity syndrome is a rare, life-threatening condition. Its diagnosis is critical to avoid future exposure to aromatic anticonvulsants. Pediatricians rarely use a systematic approach to establish the cause of drug reactions in the clinical setting. We describe the use of the Naranjo adverse drug reaction probability scale to establish causality in three cases of suspected anticonvulsant hypersensitivity syndrome with the aim of introducing clinicians to this effective tool. Our analysis reveals that this method is useful, but also highlights potential areas for its improvement.