Effects of addition of a 2-methyl group to ethyl nipecotates (beta-meperidines) on receptor affinities and opiate agonist/antagonist activities

A series of 2-methyl-3-carbethoxy-3-(m-hydroxyphenyl)piperidine opiates (13a-d) with N-substituent variations have been synthesized, and their receptor affinities and in vivo agonist and antagonist activities and energy-conformational profiles have been determined. These are racemates of the alpha-epimer at the C-2 position, with a methyl group cis to the 3-phenyl group. One of the main goals of this study was to compare the conformational and pharmacological behavior of these 2-methyl "beta-meperidine" analogues to their 2-desmethyl racemic counterparts (14a-c) previously reported in the literature. The 2-desmethyl and 2-methyl analogues were found to have very similar phenyl equatorial conformers as their lowest energy forms with the addition of a 2-methyl group diminishing conformational flexibility. The presence of the 2-methyl group appears to diminish affinity at the mu-receptor and also to somewhat diminish already weak antinociceptic agonist activity. Given the similarity in lowest energy conformation, this reduction is most likely caused by the unfavorable interaction of the methyl group itself with a local mu-receptor binding site. Superposition of the phenol OH and protonated amine nitrogen NH of either 2-methyl enantiomer of 13a in its lowest energy conformer with the same OH and NH groups of metazocine, used as a high affinity rigid analogue, leads to reasonable overlap. However, the N-substituents and the piperidine and phenyl rings do not overlap in this proposed pharmacophore, perhaps accounting for the rather poor affinities found for these 3-phenylpiperidines and the lack of N-substituent modulation of affinity and efficacy as in fused ring opioids.     

Device life of the Provox Vega voice prosthesis

Device life of the Provox Vega Indwelling voice prosthesis is as yet untested outside Europe. The current study examined device life and reasons for replacement within an Australian clinical setting. Twenty-three participants were monitored for device life and reasons for replacement. Main outcome measure was days to failure of initial device. Average device life and reasons for replacement were secondary measures. Initial device life data revealed 67 % had functioning devices at 3 months, 52 % at 6 months and 29 % at 12 months. Average device life was 207 days (median of 222). The majority of devices (97 %) failed due to leakage through the prosthesis. The Provox Vega Indwelling voice prosthesis had favourable device life in this cohort of patients and in comparison to European data. Reasons for replacement were consistent with international literature.     

Long-term functional results after endoscopic cricopharyngeal myotomy with CO2 laser: a retrospective study of 32 cases

Endoscopic cricopharyngeal myotomy (ECPM) with CO₂ laser is indicated in cases with swallowing disorders when a dysfunction of the cricopharyngeal muscle is diagnosed. We present the results of a retrospective study including 32 of the 65 consecutive patients who underwent ECPM in our center between 2002 and 2009. The aim of this study is to evaluate the postoperative complications and complaints, the improvement of swallowing after surgery, the global satisfaction of the surgery and the swallowing improvement according to the deglutition handicap index (DHI). No major postoperative complication was reported. Postoperative pain was present in 46.9 % of the patients and estimated on an analog scale at 4.4/10. For the others, this surgery was painless. Improvement in swallowing liquids was present in 75 % of the patients and 81 % of the patients could swallow solids. The overall patients’ satisfaction on a scale of 10 was 7.2; if needed, 83.9 % of the patients would do the surgery again. Concerning the DHI, we report a significant improvement of all items except the last one. ECPM is a safe procedure which provides improvement of symptoms and satisfaction for the majority of patients.     

INVASIVE ASPERGILLOSIS OF THE SMALL BOWEL IN AN INFANT WITH ACUTE MYELOID LEUKEMIA AND INTESTINAL OBSTRUCTION

Acute myeloid leukemia was diagnosed in an infant with fever and pancytopenia. Intestinal obstruction was present at diagnosis and laparotomy performed after failure of conservative management demonstrated leukemic infiltration of the resected terminal ileum. Fever and intestinal obstruction persisted, necessitating a second ileal resection, which revealed invasive aspergillosis. Subsequent retrospective analysis identified occasional fungal hyphae in the initial resection specimen. With the combination of intensive chemotherapy and aggressive prolonged antifungal therapy the child survived. Invasive aspergillosis may unusually present at nonpulmonary sites at initial presentation of acute leukemia. Microbiological or histological diagnosis is needed to guide aggressive appropriate management.     

Rickets in Nigerian children: response to calcium supplementation.

In a previous study of rachitic children in Jos, Nigeria we concluded that inadequate dietary intake of calcium was the primary contributing factor to the development of their rickets. The objective of the present study was to determine the effect of calcium supplementation in 10 children with radiographically and biochemically proven rickets from the same geographical area. Rachitic children were provided with calcium supplements of 1000 mg/day for a period of 3 months. Serum and urine samples were obtained at baseline and at 24 hours, 1 week, 4 weeks, and 12 weeks after initiation of supplementation. Serum calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured at each time point. Dietary recalls obtained at two separate times were used to estimate usual daily intakes of calcium and phosphorus. Ten non-rachitic age-matched controls from the same geographical area were recruited for comparison. Nine of 10 rachitic subjects had radiographic evidence of healing after 3 months of calcium therapy. Although serum calcium concentrations returned to control levels, other biochemical data indicated that the rickets of these subjects may have been multifactorial in aetiology, pointing to a possible defect in the synthesis of 25-hydroxyvitamin D.     

Leukotrienes potentiate the effects of epinephrine and thrombin on human platelet aggregation

A cooperation between leukocytes and platelets relative to metabolism of arachidonic acid has been observed in animal studies. To determine potential stimulatory effects of leukotrienes (LTs) on human platelets, LTs were incubated with platelet rich plasma followed by addition of subthreshold concentration of aggregatory stimulus. LTs (LTE4 LTD4 LTC4) alone had no direct effect on platelet aggregation, but potentiated the effects of subthreshold concentrations of epinephrine and thrombin and caused complete platelet aggregation. This potentiation was similar in citrated or heparinized blood and was unaffected by exogenous CaCl2. LTs did not induce secondary wave of aggregation in aspirin or selective TXA2-synthetase blocker OKY-046-treated platelets. In addition, LTs stimulated TXA2 biosynthesis by platelets in the presence of subaggregatory concentrations of epinephrine, but not when platelets had been pretreated with OKY-046. These data indicate that LTs potentiate epinephrine-induced platelet aggregation by modulating TXA2 synthetase activity.