Long-term safety and, tolerability profiles and lipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: a multicenter, randomized, double-blind, placebo-controlled, 48-week extension study

BACKGROUND: Ezetimibe (EZE) is a cholesterol-lowering drug that inhibits absorption of dietary and biliary cholesterol across the intestinal wall without affecting absorption of bile acids, fatty acids, fat-soluble vitamins, or triglycerides. It has a complementary mechanism of action to the statins, which inhibit cholesterol synthesis in the liver. Coadministration of EZE and statins provides inhibition of 2 sources of cholesterol, leading to greater reductions in low-density lipoprotein cholesterol (LDL-C) than with either agent alone. OBJECTIVES: This study evaluated the long-term safety and tolerability profiles and lipid-modifying efficacy of treatment with EZE 10 mg/d plus simvastatin (SIMVA) 10, 20, 40, or 80 mg/d for 48 weeks in patients with primary hypercholesterolemia. METHODS: This was an extension of a multicenter, double-blind, placebo (PBO)-controlled base study in which hypercholesterolemic patients were randomized to receive EZE 10 mg/d or PBO in addition to their current statin for 8 weeks. Patients who successfully completed the base study could enter the extension study if they were willing to switch from their current statin to an approximately equipotent dose of SIMVA for the 54-week study period. After a 6-week open-label SIMVA run-in phase, patients were rerandomized to receive EZE 10 mg/d or PBO in a 4:1 ratio, respectively, for 48 weeks. At each clinic visit, beginning at week 12, the dose of SIMVA was titrated upward until patients reached their National Cholesterol Education Program Adult Treatment Panel II LDL-C goal or the maximum SIMVA dose of 80 mg/d. Safety/tolerability and lipid efficacy parameters were assessed at 12-week intervals. RESULTS: Of 433 patients entering the extension study, 355 were randomized to receive EZE and 78 were randomized to receive PBO. Baseline demographic characteristics and lipid levels were similar between treatment groups. Overall, coadministration of EZE + SIMVA was well tolerated. There were no clinically meaningful differences between the EZE and PBO groups with regard to the incidence of treatment-related adverse events (AEs) (19% vs 17%, respectively), discontinuations due to AEs (7% vs 10%), serious AEs (12% vs 17%), consecutive elevations in liver function tests > or =3 times the upper limit of normal (ULN) (0.3% vs 0%), or elevations in creatine kinase > or =10 times the ULN (both, 0%). As in the base study, LDL-C levels were significantly lower with the addition of EZE to SIMVA compared with the addition of PBO (-24% vs 3%; P < 0.001). CONCLUSION: In these patients with primary hypercholesterolemia, EZE 10 mg/d added to ongoing SIMVA treatment for 48 weeks had a favorable safety and tolerability profile and was more efficacious than SIMVA monotherapy.     

Metabotropic glutamate receptor antagonist AIDA blocks induction of mossy fiber-CA3 LTP in vivo

Metabotropic glutamate receptors (mGluR) are implicated in long-term memory storage. mGluR-I and mGluR-II antagonists impede various forms of learning and long-term potentiation (LTP) in animals. Despite the evidence linking mGluR to learning mechanisms, their role in mossy fiber-CA3 long-term potentiation (LTP) is not yet clear. To explain the involvement of mGluR-I in memory mechanisms, we examined the function of the mGluR-I antagonist 1-aminoindan-1, 5-dicarboxylic acid (AIDA) on the induction of mossy fiber-CA3 LTP in vivo in male Sprague Dawley and Fischer 344 (F344) rats. Acute extracellular mossy fiber (MF) responses were evoked by stimulation of the MF bundle and recorded in the stratum lucidum of CA3. The excitatory postsynaptic potential (EPSP) magnitude was measured by using the initial slope of the field EPSP slope measured 2-3 ms after response onset. After collection of baseline MF-CA3 responses at 0.05 Hz, animals received either ((+/-))-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (N-methyl-D-aspartate-R antagonist, 10 mg/kg ip), naloxone (opioid-R antagonist, 10 mg/kg ip), or AIDA (mGluR antagonist, 1 mg/kg ip or 37.5 nmol ic). LTP was induced by two 100-Hz trains at the intensity sufficient to evoke 50% of the maximal response. Responses were collected for an additional 1 h. AIDA blocked induction of LTP in the mossy fiber pathway (P < 0.05) in both strains of rats after systemic and in Sprague Dawley rats after intrahippocampal injection.     

Aneurysmal bone cyst of the sphenoid sinus

Aneurysmal bone cyst is an uncommon lesion that occurs mainly in long bones and vertebrae, being the location in the sphenoid sinus extremely rare. Its origin is unknown, but it can be considered as a vascular phenomenon secondary to a primary lesion. Other primary diseases that may be associated to aneurysmal bone cyst are polyostotic fibrous dysplasia and giant-cell tumors. We report the case of a patient with an aneurysmal bone cyst in the sphenoid sinus causing vision dysfunction.     

Internal carotid artery vasculitis originated by cervicofacial actinomycosis as a predisponing factor to stroke

Actinomycosis is a chronic, suppurative, fibrotic infection produced by a gram-positive anaerobic bacteria of the normal mouth flora, the infection having tendency to fistulate and to extend without respecting tissue layers. Initial diagnosis is usually delayed due to its painless evolution. Three clinical forms are known: cervicofacial, abdominal and thoracic. Occasionally, there is vascular involvement which is mainly associated with venous thrombotic phenomena with low clinical expresion and hematogenous dissemination that can result in a formation of abscess or meningitis in the central nervous system. We report the case of a 28 year old female patient with type I diabetes and microangiopathyc complication with a internal carotid artery stenosis adjacent to mandibular angle actinomicosis. A few months later and after a miscarriage she suffered from ischemic stroke. The anticardiolipin antibody were positive at the time of stroke with post-operative period and over the next two years. To our knowledge (Medline, 1984-2004), it is the first report of internal carotid vasculitis originated by cervicofacial actinomicosis. We discuss the neuroradiological aspects of our case.     

Diseases affecting the peribronchovascular interstitium: CT findings and pathologic correlation

Central bronchi and pulmonary arteries are surrounded and enveloped by a strong connective-tissue sheath termed the peribronchovascular interstitium, extending from the level of the pulmonary hila into the peripheral lung. Thickening of the peribronchovascular interstitium can be seen in a wide variety of diseases. The CT appearance can be smooth, nodular, or irregular depending on the underlying cause. Many of the diseases affecting the peribronchovascular interstitium are entities that show a predilection for lymphatic routes, such as sarcoidosis, pulmonary lymphangitic carcinomatosis, silicosis, and lymphoproliferative disorders. There are other entities that mainly affect the peribronchovascular interstitium without a predominant perilymphatic distribution, such as hydrostatic pulmonary edema, cryptogenic organizing pneumonia, Kaposi's sarcoma, interstitial pulmonary emphysema, and interstitial hemorrhage. Although there is an overlap in radiologic features, some CT findings are useful in differentiating among these entities. When CT shows mainly peribronchovascular abnormality, the differential diagnosis is considerably reduced, and it is generally possible to reach the correct diagnosis by considering the clinical context. We illustrate the CT findings and pathologic correlation for a number of different disorders that mainly affect the peribronchovascular interstitium.     

Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency

BACKGROUND: Lung damage progression is the most frequent condition in patients with common variable immunodeficiency (CVID). Appropriate immunoglobulin dose adjustments and follow-up guidelines to evaluate this have not been well established. Objective: To assess the evolution of lung damage once stable residual serum levels of IgG over 600 mg/dl had been achieved. METHODS: A prospective study was conducted in 24 adult patients consecutively diagnosed with CVID, with no previous intravenous immunoglobulin (IVIG) treatment. IVIG dose, total serum IgG level, bacterial infection rate, pulmonary function tests (PFTs) and high resolution computed tomography (HRCT) of the thorax were monitored over 2 years. Moreover, outcome data were determined by measurement of chronic pulmonary disease (CPD). RESULTS: IVIG dose variability (205-372 mg/kg/21 days) to obtain the required serum IgG levels was determined. Patients with CPD needed higher doses than those without CPD (p=0.045). A significant reduction in severe and mild infections/patient-year was observed during treatment. Overall, there were no changes in PFTs and HRCT scores in patients without CPD, but both improved in patients with CPD. An increase of over 15% in overall HRCT score was detected in two patients without evidence of impairment in either clinical status or PFT values. CONCLUSIONS: Residual levels of total IgG over 600 mg/dl may help prevent progression of lung damage in patients with CVID. Levels of IgG, clinical manifestations and PFTs seem sufficient for routine follow-up. HRCT examination of the thorax, at least biennially, may help to identify patients in whom lung injury is progressing even though they may remain symptom-free and with stable PFTs.     

Squamous cell carcinoma of the penis: a retrospective review of forty-five patients in northwest Louisiana

BACKGROUND: Squamous cell carcinoma of the penis is a rare malignancy in the United States, accounting for only 0.4% of all cancers in men. METHODS: From June 1975 to June 2000, 45 patients were diagnosed and treated for squamous cell carcinoma of the penis at our institution. Their medical records were reviewed retrospectively. RESULTS: The mean age at diagnosis was 63 years; 62% were white and 38% African American. Eighty-nine percent of our population was uncircumcised. Twenty patients had primary ilioinguinal lymph node dissections, with 11 positive for squamous cell carcinoma. Follow-up was documented for 42 patients, with a mean of 47 months. Four patients had local penile recurrence at a mean of 22 months after initial treatment. Nine patients had died of penile carcinoma at a mean of 18 months. CONCLUSION: Squamous cell carcinoma of the penis accounts for 0.3% of malignancies in men seen at our institution. Nodal metastasis was a poor prognostic indicator. Although local penile recurrence was rare (8.8%), patients should be counseled on the importance of self-examination.