Bisphosphonate-Associated Scleritis
Aminobisphosphonates, antiresorptive agents used to treat osteoporosis, inhibit bone resorption by limiting osteoclast activity. Gastrointestinal problems, such as esophagitis, esophageal reflux, and dyspepsia, have been the most commonly reported side effects.
Several of these drugs (pamidronate, alendronate, and risedronate) have also been associated, although rarely, with ocular inflammation. Most commonly associated with pamidronate therapy, all cases required discontinuation of the drug before inflammatory symptoms would completely subside.
Pamidronate produces an inflammatory response by stimulating production of a T-cell subset that inhibits bone resorption but may also activate other T-cells that lead to cytokine release. Clinically, patients may have a low-grade fever and flu-like symptoms when they receive pamidronate. In the reported cases, patients often had such symptoms before development of scleritis.
Because the mechanisms of action of this class of drugs are comparable, other bisphosphonates may produce similar changes. In a reported case of risedronate-related ocular inflammation, the inflammation reoccurred when the patient was subsequently treated with pamidronate. To date, only five cases of scleritis have been reported in patients taking alendronate; the authors present a case study in this article.
Although uncommon, scleritis is a serious side effect that can result in serious permanent eye damage. Immediate discontinuation of the bisphosphonate and referral to an ophthalmologist is essential.
Leung, S., Ashar, B. H., & Miller, R. G. (2005). Bisphosphonate-associated scleritis: A case report and review. Southern Medical Journal, 98(7), 733-735.
Reduction of Total Hip Dislocation in the Emergency Department
Hip dislocation occurs in up to 10% of patients after total hip arthroplasty (THA) and up to 26.6% of patients after revision THA. Closed reduction is the treatment of choice and can be performed in the emergency department (ED). Reduction has traditionally been performed by an orthopaedic surgeon alone or in conjunction with an emergency physician (EP).
Prompt reduction reduces pain and decreases ED time for the patient and may also decrease morbidity and potential neurovascular complications. This retrospective study was performed to establish characteristics of hip dislocation in the ED and determine the rate of successful reduction in the ED, as well as the rate of complications.
A chart review was conducted in an academic ED with an annual ED census of 55,000. Patients were identified using ED admission and discharge criteria; 116 patients were included in the study. Mean age was 65 years; 41% were male and 59% female. Seventy-five percent of the dislocations were posterior; 25% anterior. For 22% of the cases, this was a first-time dislocation, whereas 74% had a prior dislocation. For the remaining patients, it could not be determined if there had been a prior dislocation.
Four of the 116 patients were taken directly to the operating room (OR) without any attempt at reduction in the ED. Of the remaining 112, 102 (91%) had successful reductions performed in the ED. Eighty-one patients had hip reduction attempted by an EP with a 91% success rate. Twenty-eight (90%) of the remaining 31 patients had successful reduction performed by either an orthopaedic surgeon or by both an EP and an orthopaedic surgeon while in the ED. All of the failed ED reductions (10) went to the OR for successful closed reduction. No orthopaedic complication was recorded in any patient prereduction or postreduction.
Of the 112 patients who had reduction attempted in the ED, the mean time spent in the ED was 4 hours and 21 minutes. Of the 4 patients who had no attempts at reduction in the ED, total ED time averaged 6 hours and 3 minutes. The actual procedure time (as determined from conscious sedation flow sheets) for successful ED reduction ranged from 1 to 41 minutes, with a mean of 10 minutes. All 4 of the patients who had OR reduction were discharged after the procedure, as were 100 of the 112 patients who had reduction attempted in the ED.
Limitations of the study include its retrospective nature because neurovascular examination is crucial both before and after any reduction attempt, as is documentation of the examination. Also, complications from hip dislocation can be delayed. They would not have been documented because there was no systematic follow-up.
This retrospective study found no acute complications of closed reduction of THA dislocation performed in the ED by EPs. The study demonstrated that ED physicians could successfully reduce prosthetic hip dislocations while decreasing the patient's time of discomfort and promoting faster ED throughput.
Germann, C. A., Geyer, D. A., & Perron, A. D., (2005). Closed reduction of prosthetic hip dislocation by emergency physicians. American Journal of Emergency Medicine, 23, 800-805.
Inhaled Insulin for Diabetes Mellitus
Patients with type 1 diabetes mellitus require insulin therapy for glycemic control from the time of diagnosis. A range of injectable insulin products are available and differ significantly in their pharmacokinetic profiles. Insulin is a protein that has been a candidate for noninvasive delivery since its initial use, but efforts to develop commercially viable methods, particularly oral and nasal formulations, have been unsuccessful. The major problem is that both the nasal and the gastrointestinal epithelia are functionally impermeable to insulin.
The lungs, which are naturally permeable to some proteins, are an attractive site for the systemic delivery of insulin because of the large surface area for absorption. Pulmonary delivery of insulin could reduce the number of daily insulin injections, which should lead to improved compliance and long-term outcomes.
Factors Affecting the Pulmonary Delivery of Insulin
The most important features of inhalation affecting drug deposition are inhaled volume, flow rate, and any breath-holding pause maintained at the end of inspiration. The greater the inhaled volume, the more peripherally the particles will be distributed into the lungs. By contrast, as the inhaled flow rate is increased, particles are more likely to be deposited in the oropharynx or in the large central airways of the lungs. A period of breath-holding enhances deposition in the more peripheral parts of the lungs by gravity.
The vital physical property of the aerosol is the size of the particles. As the particle size increases, less reaches the most peripheral parts of the lung because more particles are deposited in the oropharynx and large conducting airways of the lungs as the drug passes through these areas.
Products Under Development
Several pharmaceutical companies are developing pulmonary insulin delivery systems. In various stages of development the products fall into two main groups: solution and dry powder formulations. All are based on regular human insulin.
The most widely studied insulin product for pulmonary delivery is Exubera, a rapid-acting insulin in powder form. A specialized inhaler that generates a pulse of compressed air is used for delivery. This product has been studied extensively in patients with type 1 and type 2 diabetes. Bioavailability is approximately 10% compared with regular human insulin administered by subcutaneous injection.
The AERx Insulin Diabetes Management System (AERx iDMS) delivers a liquid form of human insulin. The delivery device includes a breath-guidance system that allows patients to breath optimally and reproducibly. The drug is delivered to the lung only when the breathing is correct. This product also features a data downloading system that allows review of dose-administration data and breathing technique. Bioavailability of insulin using AERx iDMS is 13-17%.
Several other systems under development include ProMaxx, AIR, Spiros, and Technosphere. Information about each of these systems is provided in the article.
Pharmacokinetic Considerations
In humans, inhaled regular insulin is more rapidly absorbed (peak concentrations achieved in 49-65 minutes) than insulin from subcutaneous injection (peak concentrations achieved in 119 minutes). The time to reach maximum insulin concentration in blood after inhalation is comparable to that of subcutaneous injection with the two fast-acting DNA recombinant insulin analogs Humalog and Novolog. Duration of action of inhaled insulin is slightly longer than that after subcutaneous administration of these insulins.
The quick absorption profiles after inhalation suggest that rapid glycemic control at mealtimes may be achieved with inhaled insulin. Patients may be able to inhale a dose 5-10 minutes before a meal to achieve adequate glycemic control rather than the 20-30 minutes necessary with subcutaneous insulin injections. However, inhaled regular insulin should be used in combination with a once-daily injection of long-acting insulin because of the shorter duration of action after absorption through the pulmonary route.
Regardless of the system used for pulmonary delivery, the bioavailability of inhaled insulin is relatively low (less than 20%), so a high dose, as much as eight to nine times the subcutaneous dose, is required to achieve the same glucose lowering effect. The dosage requirements for orally inhaled insulin may lead to a significantly higher cost per treatment, but the manufacturers have not yet addressed this issue.
Absorption of inhaled insulin may also be affected by age or the presence of an upper respiratory tract infection or disease. In a study of young (18-45 years old) and elderly (65 years of age or older) patients with type 2 diabetes, absorption was comparable after a single inhalation of insulin using AERx iDMS, but less glucose reduction was reported in the elderly patients. Absorption of orally inhaled insulin has not been studied in patients with common lung diseases, such as asthma and cystic fibrosis.
Absorption of inhaled insulin is also affected by smoking. In a study of nondiabetic active smokers without apparent pulmonary disease, the absorption rate of inhaled insulin increased by as much as 50%, and the time to reach peak concentration was decreased up to 40%. Additional study is needed to determine the effects of smoking on the pharmacokinetics and efficacy of orally inhaled insulin in patients with diabetes.
Safety
Many clinicians are concerned about the possibility of long-term effects from the intraalveolar deposition of insulin within the lungs, because insulin has growth-producing properties. To date, clinical data have not indicated increased cellular proliferation or growth promotion in patients receiving orally inhaled insulin, but these studies have not exceeded 4 years in duration.
The most important concern is the immunologic safety of these products. The high dose of inhaled insulin, delivered to the large alveolar surface, triggers the lungs' respiratory defenses, including humoral and cellular immunity, resulting in the production of antiinsulin antibodies. (These antibodies also occur with subcutaneous administration of insulin.) Antibodies are produced primarily in response to drug impurities. Irrespective of the type of pulmonary delivery system, inhaled insulin produced more insulin antibodies compared to subcutaneous injection.
Results of numerous clinical trials with inhaled insulin have shown a high degree of patient compliance and acceptance.
Mandal, T. K. (2005). Inhaled insulin for diabetes mellitus. American Journal of Health-System Pharmacy, 62(13), 1359-1364.