Oxycodone. Pharmacological profile and clinical data in chronic pain management

Opioids are widely used as effective analgesic therapy for cancer pain. Despite years of controversy, their use has been also accepted in chronic non-cancer pain. Oxycodone alone and in combination has been used for over 80 years in the treatment of a variety of pain syndromes. As single agent, the controlled release (CR) oxycodone's market in the USA grew from 10% in 1996 to 53% in 2000 and it has become a leading opioid in the United States. Recent data showed that the fixed-combination oxycodone/acetaminophen (5 mg/325 mg) is the most often prescribed opioid across all the different chronic pain diagnoses. Compared with morphine, oxycodone has a higher oral bioavailability and is about twice as potent. Pharmacokinetic-pharmacodynamic data support oxycodone as a pharmacologically active opiod that does not require conversion to oxymoprhone for pharmacological activity. Seven studies addressed the safety and efficacy of oxycodone for the treatment of non-cancer pain (low back pain, osteoarthritis pain, and painful diabetic neuropathy). Both immediate release (IR) and CR oxycodone are equally effective and safe. Along these trials, mean daily dosage of oxycodone was approximately 40 mg, with a low incidence of intolerable typical opiate side effects. In cancer pain, oxycodone can be considered a valid alternative to oral morphine to be used for opioid rotation. No difference in analgesic efficacy between CR oxycodone and CR morphine was found. Controlled-release preparations, with a long duration of action, are attractive because they offer the advantage of longer dosing intervals and sustained analgesic effect.     

Transient facial nerve paralysis after mandibular sagittal osteotomy

Facial nerve injuries are rare complications after orthognathic surgery. A literature review shows that such damages can develop with various mechanisms and are usually transient. Two cases of delayed facial paralysis after mandibular osteotomy with spontaneous recovery are reported.     

Persistent B-cell lymphopenia, multiorgan disease, and erythema multiforme caused by Mycoplasma pneumoniae infection

We report a 6-year-old girl in whom Mycoplasma pneumoniae infection presenting with erythema multiforme, multiorgan, and hematologic dysfunctions induced a long-standing, marked B-cell lymphopenia. An increase of CD8+ lymphocytes was also detected. We suggest that a selective cytotoxic T lymphocyte-dependent B cell lysis and the expansion of super-antigen activated CD8+ T cells may account for the multiorgan and hematologic disturbances triggered by M. pneumoniae.     

Suicide by buflomedil HCl: a case report

A man was found dead in his bed by his relatives; a half-empty wrapping of Loftyl Plus (the trade name of a vasodilator medications containing buflomedil HCl marketed in Italy) was on the bedside table. GC/MS analysis of a blood sample collected during the autopsy revealed a buflomedil HCl concentration approximately of about 20 times the therapeutic values.     

CDX-2 homeobox gene product expression in neuroendocrine tumors: its role as a marker of intestinal neuroendocrine tumors

CDX-2 is a homeobox gene product essential for intestinal development and differentiation. It can be used as a specific marker of colorectal adenocarcinomas and other tumors with intestinal differentiation, but little is known about its expression in endocrine and neuroendocrine (NE) cells and NE primary and metastatic tumors. Using the Cdx-2-88 monoclonal antibody, we evaluated CDX-2 expression in routine samples of 20 normal endocrine/NE tissues and of 299 samples of well-differentiated NE tumors (WDNET) and high-grade NE carcinomas (NEC) from different sites. For 17 cases, we examined primary and corresponding metastatic lesions. We also examined 8 cytologic samples of liver metastases derived from 4 ileal WDNETs, 1 lung WDNET, and 3 pancreatic endocrine tumors. CDX-2 mRNA expression with RT-PCR technique on frozen material was evaluated in 5 WDNETs. CDX-2 was expressed in normal NE cells of the intestine and gastric fundus. High CDX-2 expression was seen in all ileal and appendiceal WDNET, while low levels were seen in WDNETs from stomach, duodenum, and rectum; no reactivity was seen in other WDNETs. Low levels of CDX-2 expression were seen in one third of nonfunctioning pancreatic WDNET where it was more frequently observed in cases with metastatic disease (P = 0.002). CDX-2 was identified in all cytologic specimens of metastatic ileal WDNETs. CDX-2 mRNA analysis confirmed immunohistochemical results. CDX-2 was expressed at high levels in 81% of intestinal NEC. Unexpectedly, variable levels of expression of CDX-2 were seen also in 39% of NEC of other sites, without any relation with the site of origin. This reactivity frequently overlapped TTF-1 expression, suggesting deregulated expression of homeobox genes in NEC. The restricted pattern of CDX-2 expression may have diagnostic value in the identification of the primary site of a metastatic WDNET. Conversely, a limited diagnostic role is suggested for CDX-2 in NEC because of its frequent expression in nongastrointestinal tumors.     

Supplemental nitric oxide and its effect on myocardial injury and function in patients undergoing cardiac surgery with extracorporeal circulation

BACKGROUND: Cardiopulmonary bypass induces a systemic inflammatory response that may contribute to clinical morbidity. Gaseous nitric oxide at relatively low concentrations may elicit peripheral anti-inflammatory effects in addition to a reduction of pulmonary resistances. We examined the effects of 20 ppm of inhaled nitric oxide administered for 8 hours during and after cardiopulmonary bypass. METHODS AND RESULTS: Twenty-nine consecutive patients undergoing aortic valve replacement combined with aortocoronary bypass were randomly allocated to either 20 ppm of inhaled nitric oxide (n = 14) or no additional inhalatory treatment (n = 15). Blood samples for total creatine kinase, creatine kinase MB fraction, and troponin I measurements were collected at 4, 12, 24, and 48 hours postsurgery. In addition, we collected perioperative blood samples for measurements of circulating nitric oxide by-products and brain natriuretic peptide. Soluble P-selectin was analyzed in blood samples withdrawn from the coronary sinus before and after aortic clamping. The area under the curve of creatine kinase MB fraction (P =.03), total creatine kinase (P =.04), and troponin I (P =.04) levels were significantly decreased in the nitric oxide-treated patients. Moreover, in the same group we observed blunted P-selectin and brain natriuretic peptide release (P =.01 and P =.02, respectively). Nitric oxide inhalation consistently enhanced nitric oxide metabolite levels (P =.01). CONCLUSIONS: Nitric oxide, when administered as a gas at low concentration, is able to blunt the release of markers of myocardial injury and to antagonize the left ventricular subclinical dysfunction during and immediately after cardiopulmonary bypass. The organ protection could be mediated, at least in part, by its anti-inflammatory properties.     

Characterization of an aquaporin-2 water channel gene mutation causing partial nephrogenic diabetes insipidus in a Mexican family: evidence of increased frequency of the mutation in the town of origin

A Mexican family with partial congenital nephrogenic diabetes insipidus (NDI) that resulted from a mutation in the aquaporin-2 water channel (AQP2) was characterized, and the source of this rare mutation was traced to the family's town of origin in Mexico. Affected individuals with profound polyuria and polydipsia were homozygous for an autosomal recessive missense V168M mutation in the AQP2 gene. Expression in oocytes revealed that, although retained in the endoplasmic reticulum (ER) to a great extent, a considerable amount of the partially functional AQP2-V168M was expressed at the plasma membrane, and that its ER retention was less than AQP2-T126M, a functional mutant in severe recessive NDI. None of the affected AQP2-V168M individuals had neurologic deficits, which also suggested a milder form of the disease. The homozygous individuals reported subjective improvement in polyuria and polydipsia with the use of dDAVP (1-desamino-8-D-arginine-vasopressin). When clinically tested, infusion of dDAVP at variable doses produced a partial increase in the urinary osmolality in homozygous individuals and decreased their water intake. Heterozygotes were unaffected when compared with controls. Samples were obtained from the population of the Mexican town of origin of the family; 30% of the population was heterozygous for the V168M AQP2 mutation and 1% was homozygous for the mutation. The high frequency of this rare mutation in the town provides evidence for an important health care problem in the village with consequences for future generations.     

Biological, histological, and clinical impact of preoperative IL-2 administration in radically operable gastric cancer patients

BACKGROUND AND OBJECTIVES: Surgery induces lymphocytopenia and this decrease of host defenses, related to interleukin-2 (IL-2) endogenous imbalance during postoperative period could promote the proliferation of possible micrometastases and the implantation of surgically disseminated tumor cells. Moreover, tumor infiltrating lymphocytes (TILs), activated by endogenous IL-2 release, are linked to prognosis in cancer patients. The aim of this randomized study is to assess the biological (peripheral blood cells count, related to the grade of immunosuppression), histological (TILs), and clinical (overall and disease-free survival) impact of preoperative low doses administration of IL-2 in patients with radically operable gastric cancer. METHODS: This prospective study enrolled 69 consecutive patients with histologically proven gastric adenocarcinoma who underwent radical surgery from October 1999 to December 2002 (M/F 39/30; mean age 66; range 42-82) who underwent radical surgery from October 1999 to December 2000. Patients were randomized to be treated with surgery alone as controls (35 patients) or surgery plus preoperative treatment with recombinant human IL-2 (34 patients). We considered the total lymphocyte count and lymphocyte subset (CD4, CD4/CD8) during the preoperative period, before IL-2 administration, and on the 14th and 50th day, peritumoral stromal (fibrosis) reaction, neutrophils, lymphocytes, and eosinophils infiltration in tumor histology, and morbidity disease free and overall survival were evaluated. RESULTS: Two groups were well matched for type of surgery and extent of disease. All the patients underwent radical surgery plus D2 lymphadenectomy. At baseline, there were no significant differences in total lymphocyte and lymphocyte subsets between groups. The control group showed a significant decrease of total lymphocytes, CD4 cells, and CD4/CD8 ratio at the 14th postoperative day relative to the baseline value. In the control group 65% of patients had a decrease of CD4 under 500 cells/mmc. Instead it has been observed in IL-2 group a significant increase over the control group values of total lymphocytes and CD4 cells (14th total lymphocytes and CD4: IL-2 vs. control P < 0.05). Moreover in this group only 15% patients had CD4 under 500 cells/mmc. This difference, in CD4 count, is significant even at the 50th postoperative day (P = 0.006). IL-2 group showed lower postoperative complications (2/34 vs. 11/35; P < 0.05), and higher lymphocyte/eosinophil infiltration into the tumor (P < 0.0002). Median follow-up was 26 months (range 10-48) and median overall and disease-free survivals were longer, even if not significantly, in the IL-2 group than in the control arm (P = 0.07 and P = 0.06 respectively). CONCLUSIONS: This randomized study would suggest that a preoperative immunotherapy with IL-2 is a well-tolerated treatment able to prevent surgery-induced lymphocytopenia. IL-2 seems to neutralize the immunosuppression induced by operation and so to stimulate the host reaction against tumor tissue (lymphocytes/eosinophils infiltration). Furthermore IL-2 seems to have an impact on clinical course reducing morbidity of surgery and ameliorating overall and disease-free survival.     

Altered pathways for auditory discrimination and recognition memory in preterm infants

Preterm infants are at increased risk for cognitive disorders, including impairments in recognition memory. This study evaluated the effects of extreme prematurity on the neural pathway for auditory recognition memory using event-related potentials (ERPs), a neurophysiological technique widely used in cognitive neuroscience. ERPs were recorded at term postmenstrual age in 35 preterm infants born at less than 32 weeks' gestation (22 males, 13 females; mean birthweight ([BW] 1154g, SD 374g) with normal brain ultrasounds, compared with 40 healthy, term newborns (1 to 3 days of age; 20 males, 20 females; BW 3672g, SD 420g). Because infants must be able to detect and discriminate sounds before recognizing them, two paradigms were used to assess these functions. The first evaluated the detection and discrimination of speech sounds. The second tested recognition of the mother's voice compared with a stranger's. Results showed significantly different patterns of speech sound discrimination in preterm infants compared with term infants. No evidence of maternal voice recognition was elicited from the preterm infants. No specific patterns of auditory detection or discrimination were associated with patterns of recognition memory, suggesting that the function of multiple neural pathways may have been altered in this group of preterm infants. These results provide a functional corroboration of magnetic resonance imaging studies showing effects of prematurity on early brain development, even among preterm infants with normal cranial ultrasonography.     

Prenatal diagnosis of ductus venosus agenesis and its association with cytogenetic/congenital anomalies

OBJECTIVES: We present an observational study of 12 cases of anomalies of the umbilical and portal vein systems associated with absence of the ductus venosus (DV) diagnosed over the past 5 years. The hemodynamic implications of each pattern of umbilico-portal system anomalies associated with absence of the DV have been investigated, as well as the frequency and types of associated anomalies and their embryological origin. METHODS: In all cases ultrasound, color Doppler, and cytogenetic investigations were performed. RESULTS: Four main patterns of abnormal venous circulation were documented: (1). the umbilical vein (UV) bypasses the liver and drains into the right atrium directly or through a dilated coronary sinus (three cases); (2). the UV bypasses the liver, with an infrahepatic or suprahepatic connection directly to the inferior vena cava (IVC) (two cases); (3). the UV bypasses the liver and drains directly into the iliac or renal veins (four cases); and (4). the UV drains directly into the portal veins (three cases). Among seven cases with other associated anomalies (58%), there were three cases of Turner's and Noonan's syndromes. Two fetuses and two neonates died and there were two terminations of pregnancy (TOP). CONCLUSIONS: In utero diagnosis of ultrasound patterns associated with DV anomalies is feasible. Fetal karyotyping should be considered, serial ultrasound examinations recommended and, in the presence of heart failure, delivery can be anticipated.