Dextromethorphan potentiates morphine antinociception at the spinal level in rats

PURPOSE: Morphine is an effective analgesic, but adverse effects limit its clinical use in higher doses. The non-opioid antitussive, dextromethorphan (DM), can potentiate the analgesic effect of morphine and decrease the dose of morphine in acute postoperative pain, but the underlying mechanism remains unclear. We previously observed that DM increases the serum concentration of morphine in rats. Therefore, we investigated the effects of drugs administered at the spinal level to exclude possible pharmacokinetic interactions. As DM has widespread binding sites in the central nervous system [such as N-methyl-D-aspartate (NMDA) receptors, sigma receptors and alpha(3)ss(4) nicotinic receptors], we investigated whether the potentiation of morphine antinociception by DM at the spinal level is related to NMDA receptors. METHODS: We used MK-801 as a tool to block the NMDA channel first, and then studied the interaction between intrathecal (i.t.) morphine and DM. The tail-flick test was used to examine the antinociceptive effects of different combinations of morphine and other drugs in rats. RESULTS: DM (2-20 microg) or MK-801 (5-15 microg) showed no significant antinociceptive effect by themselves. The antinociceptive effect of morphine (0.5 microg, i.t.) was significantly enhanced by DM and reached the maximal potentiation (43.7%-50.4%) at doses of 2 to 10 microg. Pretreatment with MK-801 (5 or 10 microg, i.t.) significantly potentiated morphine antinociception by 49.9% or 38.7%, respectively. When rats were pretreated with MK-801, DM could not further enhance morphine antinociception (45.7% vs 50.5% and 43.3%). CONCLUSION: Our results suggest that spinal NMDA receptors play an important role in the effect of DM to potentiate morphine antinociception.     

Nucleotide Sequence of the ADH23 Gene Encoding the Human Alcohol Dehydrogenase β3 Subunit

All nine exons of the ADH2(3) allele, which encodes the human alcohol dehydrogenase beta 3 subunit, have been cloned and sequenced. Comparison of this sequence to the ADH2(1) nucleotide sequence revealed only a single difference that results in an amino acid change, thus proving that the significant kinetic differences between these two isozymes is due to the Cys for Arg substitution at position 369. There are also two silent polymorphisms, and two changes in noncoding regions.     

Liver and lung resection for colorectal metastasis

Aim: To examine the survival benefit of liver and lung resection for colorectal metastasis and the potential prognostic factors that affect patient survival. Methods: All patients who had resection of lung or liver metastasis for colorectal metastasis in Queen Elizabeth Hospital, Hong Kong from 1995 to 2004 were retrospectively reviewed. The overall and disease‐free survival was analysed, in particularly between liver and lung metastasis. All factors that may have affected the survival were entered into Cox's proportional hazards regression model to identify significant variables associated with survival. Results: At 5 years, the overall survival of patients who had resection of lung and liver metastasis was 44% and 38%, respectively; the disease‐free survival was 26% and 24%, respectively. Overall and disease‐free survival of patients with resection of lung metastasis was comparable to those with resection of liver metastasis. The differentiations of primary tumour and time to metastasis were shown to be significant prognostic factors influencing overall survival. Those patients with systemic chemotherapy after resection of colorectal metastasis demonstrated a significantly higher probability of overall survival. Conclusion: Resection of lung and liver metastases from colorectal origin was safe and both procedures improved survival. The use of chemotherapy after resection of metastasis significantly improved the overall survival.     

Use of the Arndt wire-guided endobronchial blocker via nasal for one-lung ventilation in patient with anticipated restricted mouth opening for esophagectomy.

Functional separation of the lungs may be accomplished by several methods. Patient with restricted mouth opening has limited options for one-lung ventilation. We report the use of wire-guided endobronchial blockade, a new tool for achieving one-lung ventilation in a patient with restricted mouth opening requiring nasotracheal, fiberoptic intubation for esophagectomy and reconstruction with gastric tube substitution.     

Treatment of pyoderma gangrenosum

Critical to the proper management of pyoderma gangrenosum are correct diagnosis, identification and treatment of any underlying disorder, and the proper choice of topical and systemic therapy. Many agents are available for the treatment of pyoderma gangrenosum. We review the current therapeutic options, their efficacy and side effects, and we offer some guidelines for their proper selection.     

Transforming Growth Factor-β1 Induces Apoptosis through Down-Regulation of c-mycGene and Overexpression of p27Protein in Cervical Carcinoma

Transforming growth factor-β1 (TGF-β1) is known to be a potent growth inhibitor for many cell types, including most epithelial cells. In skin keratinocytes, TGF-β1 has been shown to inhibit growth and to rapidly reduce c-mycexpression. However, the molecular mechanism of TGF-β1 action on cell growth of cervical carcinoma has not yet been elucidated. We thus assessed the effect of TGF-β1 on the growth of cervical carcinoma cell lines. Two cervical squamous carcinoma cell lines, CUMC-3 and CUMC-6, were incubated with varying concentrations of TGF-β1, and growth inhibition was evaluated with tetrazolium-based colorimetric assay. After culture in TGF-β1 for 24 h, inhibition of growth was detected in a dose-dependent manner at concentrations of 0.1–10 ng/ml in both cell lines. This effect of TGF-β1 on cultured carcinoma cells was associated with apoptotic process including oligonucleosomal ladder DNA and apoptotic body formations. Northern blot analysis revealed c-mycmRNA expression was suppressed by 10 ng/ml of TGF-β1 following 3 h of treatment in both cell lines. Western blot analysis showed that the level of p27^Kip1protein was increased after TGF-β1 treatment in both cell lines. These results suggest that the mechanisms by which TGF-β1 inhibits the growth of cervical carcinoma are complex and may include effects on down-regulation of c-mycgene, and overexpression of p27^Kip1protein.     

Cholera Toxin B-Mediated Targeting of Lipid Vesicles Containing Ganglioside GM1 to Mucosal Epithelial Cells

Purpose. To determine whether the non-toxic pentameric B subunit of Cholera toxin (CTB) binding to ganglioside GM1 on both the lipid vesicles and epithelial cells may provide a means to target lipid vesicles to mucosal cells expressing surface GM1. Methods. Sonicated lipid vesicles containing ganglioside GM1 were prepared. Inter-vesicle cross-linking due to pentameric CTB binding to these GM1 vesicles was determined with a sub-micron particle analyzer. Association of CTB to GM1 vesicles was analyzed with continuous sucrose gradient centrifugation. CTB-mediated binding of GM1 vesicles to human mucosal epithelial cells (Caco-2 and HT-29), mucous membranes of mouse trachea, and nasal tissues were detected with fluorescent labeled vesicles. Results. An increase in lipid particle size due to binding of CTB to lipid vesicles and inter-vesicles cross-linking was detected. At a 30-to-1 mole ratio of membrane-bound GMl-to-CTB, optimum increase in GM1 vesicle aggregation, was detected. Under such conditions, all the added CTB molecules were associated with GM1 vesicles. Time course analysis showed that inter-vesicles cross linking by CTB was detectable within 10 min. and reached a maximum value at 60 min. CTB associated GM1-vesicles bind to mucosal epithelial cells HT-29 and Caco-2 with similar affinity [K_d = 7.8 × 10^–4 M lipid (Caco-2) and 7.6 × 10^–4 M lipid (HT-29)]. GM1 mediated binding specificity was demonstrated by blocking with anti-GMl antibody and the insignificant degree of CTB-associated GM1 vesicle binding to GM1 deficient C6 cells. Conclusions. The CTB-mediated GM1 binding to multiple membrane surfaces provides selective localization of GM1 vesicles to GM1 expressing mucosal cells and tissues. The strategy may be useful in localizing drugs and proteins to gut and respiratory tract mucosa.     

Post-transplantation diabetes is better controlled after conversion from prednisone to deflazacort: a prospective trial in renal transplants

It is well known that long-term use of steroids plays a decisive role in the development of glucose intolerance and diabetes mellitus (DM). Deflazacort, an oxazoline derivative of prednisolone, has been introduced as a potential substitute for conventional steroids in order to ameliorate glucose intolerance. We initiated a randomized study of conversion from prednisone to deflazacort in kidney transplantation (Tx) recipients presenting with pre-Tx or post-Tx DM to ascertain whether or not the switch to deflazacort would ameliorate the diabetic state. Forty-two recipients in the conversion group were compared with 40 patients on prednisone (the control group) in a prospective manner. The dose reduction of insulin or oral blood glucose-lowering agents, the adequacy of glucose control, and the development of side effects were the criteria for evaluating outcome. In the conversion group, patients were switched to deflazacort at a dose ratio of 6 mg deflazacort to 5 mg prednisone. During the mean follow-up period of 13.2 months, neither graft dysfunction nor acute rejection developed in the conversion group. Improvement in blood glucose control in the conversion group was noted. When the conversion group was stratified into pre- or post-Tx DM, promising effects were clearly evident in the post-Tx DM patients. More than 50 % dose reduction of blood glucose-lowering agents was possible in 42.3 % of post-Tx DM patients. In conclusion, it was readily possible to control blood glucose better in post-Tx DM recipients without seriously affecting the immunosuppressive activity after conversion to deflazacort. Received: 20 August 1996 Received after revision: 25 November 1996 Accepted: 6 December 1996     

Down-regulation of muscarinic receptors in the striatum of organophosphate-treated swine

Subacute (daily) administration of diisopropylfluorophosphate (DFP) to male swine (Yorkshire white) resulted in a 97% inhibition of cholinesterase and a decrease of [3H]quinuclidinyl benzilate [( 3H]QNB) binding sites in homogenates of striata by approximately 50% after 14 days. The maximal density of receptors (Bmax) decreased from 2.1 +/- 0.3 to 1.0 +/- 0.2 pmole/mg protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding (control: 52.6 +/- 10.7 pM; 7-day: 57 +/- 2.8 pM). Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL = 115 +/- 62 microM (55 +/- 3%) and KiH = 1.8 +/- 0.7 microM (45 +/- 3%), respectively, for the low- and high-affinity states. Seven-Day treatment with DFP reduced the percentage of high-affinity receptors to 22 +/- 8.6%, but affected neither the low- nor the high-affinity Kd (100 +/- 20 and 2 +/- 0.6 microM). With the addition of Mg2+, striatal homogenates had low- and high-affinity receptors in the proportion of approximately 1 to 1. In the presence of Gpp(NH)p + Mg2+ the ratio of high- to low-affinity receptors was 3:1 in homogenates of control tissue (to 26 +/- 5%). This treatment had no effect on this ratio in homogenates of tissue from 7-day DFP-treated swine (3:1) since it was already 3:1. Pirenzepine displacement of [3H]QNB binding was best described by a two-binding site model, with Ki values of 38 +/- 14 and 201 +/- 78 nM, which represent 74 and 26% of the binding sites, respectively. The high affinity Kd value was unchanged following 7 days of DFP treatment (24 +/- 5 nM). There appears to be little change in the displacement curves for pirenzepine inhibition of [3H]QNB binding. This suggests that about 75% of the receptors are of the M1 subtype. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the proportion of agonist affinity states which is related to the interaction of the guanine nucleotide binding protein and the muscarinic receptor.     

Ocular Pharmacokinetics and Pharmacodynamics of Phenylephrine and Phenylephrine Oxazolidine in Rabbit Eyes

The aqueous humor concentration of phenylephrine and its corresponding mydriatic response were measured over time in New Zealand albino rabbit eyes following a 10-µl topical instillation of a phenylephrine HC1 viscous solution (10%) or a phenylephrine oxazolidine (prodrug) suspension in sesame oil (1 and 10%). The bioavailability of a 1% prodrug suspension in the rabbit eye (AUC of aqueous humor concentration vs time) was 30% lower than that of a 10% phenylephrine solution (P < 0.1) with the exception that the peak time occurred 34 min earlier with the prodrug. A 10% prodrug suspension increased the aqueous humor bioavailability approximately eightfold but improved the mydriatic activity (AUC of mydriasis vs time) only fourfold. The pharmacokinetic parameters, apparent absorption, and elimination rate constants, of phenylephrine and the prodrug were determined from aqueous humor concentration–time and mydriasis–time profiles. The study showed that the kinetic parameters of phenylephrine estimated from its mydriasis profile do not accurately reflect the kinetics of drug distribution in the iris. These parameters also varied with the instillation of phenylephrine solution or prodrug suspensions. A mydriatic tolerance of the pupil response was apparent after the topical instillation of phenylephrine solution. The mydriatic tolerance may be due to the decrease in receptor number in the iris dilator muscle.