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Biomedical subjects

Y Pak

Publications and source records attributed to Y Pak.

At least 19 recordsLinked to original sources
PubMed2007

Safety and efficacy of transdermal fentanyl in patients with cancer pain: phase IV, Turkish oncology group trial.

We have performed a prospective evaluation of the efficacy, safety and convenience of the transdermal therapeutic system - fentanyl (TTS-F) in Turkish cancer patients when it was newly available in Turkey. Ninety-nine patients with historically confirmed malignancy and pain entered the study; the mean age was 55.1 (16-58) years. The study duration was 28 days. Transdermal therapeutic system - fentanyl was used in opioid-naïve or pre-treated patients. Most patients reported a decrease in pain severity. Use of rescue medication decreased from day 4 to day 28. The majority of patients rated patch convenience of use as excellent. A total of 22.2% of patients experienced adverse events that were either probably related or very likely to be related to the study drug. The majority of the adverse events mentioned were related to the digestive system. Eighteen serious adverse events were reported by 13 patients. Six events were doubtfully related, and 12 events were not related to the study drug. Four patients died during the trial. None of these deaths was attributed to the study drug. In conclusion, the trial showed that TTS-F is easily managed, effective and will help to enable the appropriate opioid administration to patients who are suffering from cancer pain in Turkey.

Administration, Cutaneous↗
PubMed2004

Experimental lens-sparing optimization in therapeutic orbital irradiation with electron beams.

There has been a number of approaches in the literature for therapeutic malignant and benign orbital irradiation. All techniques intend to deliver a homogenous dose to the orbital and retroorbital target volume while sparing the lens of excessive dose. In this experimental lens-sparing study, 4 MeV and 12 MeV anterior electron irradiation has been used with cerrobend shielding circular blocks of varying diameter and thickness placed on a thin Mylar at the distal tip of the electron applicator to spare the lens. The first phase of the study in water phantom has been designed to determine the shield thickness and diameter constant for 4 MeV and 12 MeV electron beams. After optimizing the lens dose by water phantom, the second phase of our study has been designed to measure doses at lens and other specific localizations in randophantom under same conditions with 4 MeV and 12 MeV electron beams. By this technique lens accumulated 18.56% of prescribed dose and lateral aspects of the lens received 44.59% of the prescribed dose in 4 MeV electron irradiation, whereas this was 13.86% and 44.80%, respectively in 12 MeV electron irradiation. The technique used is found to be an extremely simple and effective technique allowing an easier setup with excellent dose distribution characteristics with lens sparing applicable to orbital irradiation practice.

Electrons↗
PubMed2003

Evaluation of dose homogenization and radiation carcinogenesis risk in total body irradiation for bone marrow transplantation.

The purpose of this study is to report on the dose homogeneity in total body irradiated patients undergoing Bone Marrow Transplantation (BMT), and carcinogenic risk in surviving patients. Between 1987 and 2001, 105 patients received hyperfractionated (6 fractions in 3 days) 12 Gy Total Body Irradiation (TBI) in our institution with lateral opposed fields. All the patients had measurements with thermoluminiscence dosimetry (TLD100) placed on seven bilateral body sites in vivo, controlled by the randophantom measurements to verify reasonable dose homogeneity achievement. The comorbid effects in the whole TBI conditioning group with at least three months post BMT follow-up were noted and surviving patients who had a minimum 5-year and maximum 14-year follow-up (median 7.8 years) have been evaluated for carcinogenic radiation risk on the basis of tissue weighting factors as defined by ICRP 60. Reasonable dose homogeneity by lateral opposed beam TBI has been obtained in all 105 patients in whom lateral TLD100 measurement means were within +5% of the planned doses. Calculated carcinogenesis risk factor was 11.34% for males and 12.40% for females, and no second-cancer has been detected whilst radiation-induced 5 cataracts and 10 interstitial pneumonia comorbidities were noted. Dose homogenization can be well achieved for hyperfractionated lateral-beam TBI with acceptable comorbidities and estimated second-cancer risk is significant but relatively low compared to the risk from the clinical indications for TBI.

Bone Marrow Transplantation↗
PubMed2002

Postoperative radiotherapy for ganglioglioma; report of three cases and review of the literature.

Gangliogliomas are rare tumors of the central nervous system. The definite role of postoperative radiotherapy has not been established. In studying three cases who underwent radiotherapy after subtotal resection, we evaluated the clinical, pathological, radiological features with follow-up of mean 8.1 years. All of three patients were male, and mean age was 22.3 years. All of the cases have temporal lobe lesions and, except for one, they all have seizures. Radiotherapy was given to all patients after surgery. Parallely opposed local fields were used. A total of 54 Gy in 5.5 weeks was given to the mid-plane using a Co-60 tele-therapy device. No recurrence, no new symptoms, and no new neurological deficiency were detected during follow-up.

Adult↗
PubMed2002

Can radiotherapy be a treatment option for elderly women with invasive vulvar carcinoma without radical surgery?

PURPOSE OF THE INVESTIGATION: To evaluate the impact of radiotherapy after limited surgery in vulvar carcinoma. METHODS: Between March 1980 and January 2000, 22 patients older than 60 years and suffering from invasive vulvar carcinoma were treated with limited surgery and radiotherapy at Gülhane Military Medicine Academy. These are the subjects of this review. RESULTS: The median age of the patients was 67 (range 60 to 78 years). Median follow-up was 35 months (range 12 to 60 months). Local recurrence rate was 18%. Median time to local failure was 12 months (range 8 to 14 months). Two patients with local failure also developed lung metastases. Five-year survival rate was 60% and cause-specific survival rate was 69%. No treatment delay or death related to treatment was observed. CONCLUSIONS: Radiotherapy and conservative surgery can be an alternative to radical surgery with less morbidity in elderly patients.

Age Factors↗
PubMed2002

Evaluation of radiation carcinogenesis risk in vertebral hemangioma treated by radiotherapy.

The purpose of this study is to report carcinogenesis risk factor evaluation in vertebral hemangioma patients treated by radiotherapy. Between 1975 and 1995, 29 patients received 20-30 Gy total irradiation dose using conventional fractionation scheme. All the patients had measurements with thermoluminescent dosimeters (TLD 100 ), placed on multiple randophantom sites in vivo within the irradiated volume, to verify irradiation accuracy and calculate carcinogenesis risk factor. Twenty nine still-alive patients who had a minimum 6-year and maximum 26-year follow-up (median 14.34 years) have been evaluated by carcinogenic radiation risk factor on the basis of tissue weighting factors as defined by International Commission on Radiological Protection Publication 60. Reasonable pain relief has been obtained in all 29 patients. Calculated mean carcinogenesis risk factor is 0.6% for single irradiation portals and 0.9% for double irradiation portals in the whole group, whilst no secondary cancer has been detected. Radiotherapy is an effective treatment modality in relieving pain of vertebral hemangioma patients. Estimated secondary cancer risk factor for this benign neoplasm irradiation is not as high as can be feared.

Adult↗
PubMed2001

Recognition of 16S rRNA by ribosomal protein S4 from Bacillus stearothermophilus.

Protein S4 is essential for bacterial small ribosomal subunit assembly and recognizes the 5' domain (approximately 500 nt) of small subunit rRNA. This study characterizes the thermodynamics of forming the S4-5' domain rRNA complex from a thermophile, Bacillus stearothermophilus, and points out unexpected differences from the homologous Escherichia coli complex. Upon incubation of the protein and RNA at temperatures between 35 and 50 degrees C under ribosome reconstitution conditions [350 mM KCl, 8 mM MgCl2, and 30 mM Tris (pH 7.5)], a complex with an association constant of > or = 10(9) M(-1) was observed, more than an order of magnitude tighter than previously found for the homologous E. coli complex under similar conditions. This high-affinity complex was shown to be stoichiometric, in equilibrium, and formed at rates on the order of magnitude expected for diffusion-controlled reactions ( approximately 10(7) M(-1) x s(-1)), though at low temperatures the complex became kinetically trapped. Heterologous binding experiments with E. coli S4 and 5' domain RNA suggest that it is the B. stearothermophilus S4, not the rRNA, that is activated by higher temperatures; the E. coli S4 is able to bind 5' domain rRNA equally well at 0 and 37 degrees C. Tight complex formation requires a low Mg ion concentration (1-2 mM) and is very sensitive to KCl concentration [- partial differential[log(K)]/partial differential(log[KCl]) = 9.3]. The protein has an unusually strong nonspecific binding affinity of 3-5 x 10(6) M(-1), detected as a binding of one or two additional proteins to the target 5' domain RNA or two to three proteins binding a noncognate 23S rRNA fragment of the approximately same size. This binding is not as sensitive to monovalent ion concentration [- partial differential[log(K)]/partial differential(log[KCl]) = 6.3] as specific binding and does not require Mg ion. These findings are consistent with S4 stabilizing a compact form of the rRNA 5' domain.

Base Sequence↗
PubMed2001

Structural basis of binding of high-affinity ligands to protein kinase C: prediction of the binding modes through a new molecular dynamics method and evaluation by site-directed mutagenesis.

The structural basis of protein kinase C (PKC) binding to several classes of high-affinity ligands has been investigated through complementary computational and experimental methods. Employing a recently developed q-jumping molecular dynamics (MD) simulation method, which allows us to consider the flexibility of both the ligands and the receptor in docking studies, we predicted the binding models of phorbol-13-acetate, phorbol-12,13-dibutyrate (PDBu), indolactam V (ILV), ingenol-3-benzoate, and thymeleatoxin to PKC. The "predicted" binding model for phorbol-13-acetate is virtually identical to the experimentally determined binding model for this ligand. The predicted binding model for PDBU is the same as that for phorbol-13-acetate in terms of the hydrogen-bonding network and hydrophobic contacts. The predicted binding model for ILV is the same as that obtained in a previous docking study using a Monte Carlo method and is consistent with the structure-activity relationships for this class of ligands. Together with the X-ray structure of phorbol-13-acetate in complex with PKCdelta C1b, the predicted binding models of PDBu, ILV, ingenol-3-benzoate, and thymeleatoxin in complex with PKC showed that the binding of these ligands to PKC is governed by a combination of several highly specific and optimal hydrogen bonds and hydrophobic contacts. However, the hydrogen-bonding network for each class of ligand is somewhat different and the number of hydrogen bonds formed between PKC and these ligands has no correlation with their binding affinities. To provide a direct and quantitative assessment of the contributions of several conserved residues around the binding site to PKC-ligand binding, we have made 11 mutations and measured the binding affinities of the high-affinity PKC ligands to these mutants. The results obtained through site-directed mutagenic analysis support our predicted binding models for these ligands and provide new insights into PKC-ligand binding. Although all the ligands have high affinity for the wild-type PKCdelta C1b, our site-directed mutagenic results showed that ILV is the ligand most sensitive to structural perturbations of the binding site while ingenol-3-benzoate is the least sensitive among the four classes of ligands examined here. Finally, we have employed conventional MD simulations to investigate the structural perturbations caused by each mutation to further examine the role played by each individual residue in PKC-ligand binding. MD simulations revealed that several mutations, including Pro11 --> Gly, Leu21 --> Gly, Leu24 --> Gly, and Gln27 --> Gly, cause a rather large conformational alteration to the PKC binding site and, in some cases, to the overall structure of the protein. The complete abolishment or the significant reduction in PKC-ligand binding observed for these mutants thus reflects the loss of certain direct contacts between the side chain of the mutated residue in PKC and ligands as well as the large conformational alteration to the binding site caused by the mutation.

Crystallography, X-Ray↗
PubMed2000

Role for the C-terminus in agonist-induced mu opioid receptor phosphorylation and desensitization.

Determining which domains and amino acid residues of the mu opioid receptor are phosphorylated is critical for understanding the mechanism of mu opioid receptor phosphorylation. The role of the C-terminus of the receptor was investigated by examining the C-terminally truncated or point-mutated mu opioid receptors in receptor phosphorylation and desensitization. Both wild-type and mutated receptors were stably expressed in Chinese hamster ovary (CHO) cells. The receptor expression was confirmed by receptor radioligand binding and immunoblottting. After exposure to 5 microM of DAMGO, phosphorylation of the C-terminally truncated receptor and the mutant receptor T394A was reduced to 40 and 10% of that of the wild-type receptor, respectively. Mutation effects on agonist-induced desensitization were studied using adenylyl cyclase inhibition assays. The C-terminally truncated receptor and mutant receptor T394A both showed complete loss of DAMGO-induced desensitization, while the mutant T/S-7A receptor only lost part of its ability to desensitize. Taken together, these results suggest that the C-terminus of the mu opioid receptor participates in receptor phosphorylation and desensitization with threonine 394, a crucial residue for both features. DAMGO-induced mu opioid receptor phosphorylation and desensitization are associated and appear to involve both the mu opioid receptor C-terminus and other domains of the receptor.

Adenylyl Cyclases↗
PubMed2000

A successful and simplified filgrastim primed single apheresis method without large volume apheresis for peripheral blood stem cell collection.

BACKGROUND: There is a tendency to use only one apheresis collection to reduce the morbidity and the cost of peripheral blood stem cell collection. We studied whether rapid and complete engraftment could be achieved by single apheresis by using only Filgrastim without large volume apheresis in previously treated patients. METHODS: Engraftment of single apheresis in 25 patients was compared with those of multiple apheresis in 26 patients; 52% of patients in the single apheresis group and 62% of patients in the multiple apheresis group were heavily pretreated. All patients received 10-15 microg/kg/day of Filgrastim starting on day 14 after 3-4 cycles of induction chemotherapy. Apheresis was performed using Cobe Spectra on day 4, 5 or 6 in the single apheresis group and every other day in the multiple apheresis group after day 3. RESULTS: The median collection volume was 250 ml (250-300 ml) in the single apheresis group and 750 ml (200-1500 ml) in the multiple apheresis group. The median CD34(+) cell number was not significantly different in the two groups (11.79 vs. 9.38x10(6)/kg). The median times to achieve leukocytes > or =1x10(9)/l and platelets > or =50x10(9)/l counts were 10 days (8-21 days) and 15 days (9-38 days) in the single apheresis group vs 11 days (8-23 days) and 20 days (10-32 days) in the multiple apheresis group, respectively (p<0.05). Antibiotic use was less in the single apheresis group than the multiple apheresis group (9 vs. 12 days, p<0.05). CONCLUSION: Adequate numbers of peripheral stem cells were harvested by G-CSF in a single apheresis without large volume apheresis even in heavily pretreated patients. Rapid and complete engraftment occurred in all patients and it was faster in single than multiple apheresis.

Adult↗
PubMed2000

Evaluation of a minimal experimental design for determination of enzyme kinetic parameters and inhibition mechanism.

The advent of combinatorial chemistry has led to a deluge of new chemical entities whose metabolic pathways need to be determined. A significant issue involves determination of the ability of new agents to inhibit the metabolism of existing drugs as well as its own susceptibility for altered metabolism. There is need to estimate the enzyme inhibition parameters and mechanism or mechanisms of inhibition with minimal experimental effort. We examined a minimal experimental design for obtaining reliable estimates of K(i) (and V(max) and K(m)). Simulations have been applied to a variety of experimental scenarios. The least experimentally demanding case involved three substrate concentrations, [S], for the control and one substrate-inhibitor pair, [S]-[I]. The control and inhibitor data (with 20% coefficient of variance random error) were simultaneously fit to the full nonlinear competitive inhibition equation [simultaneous nonlinear regression (SNLR)]. Excellent estimates of the correct kinetic parameters were obtained. This approach is clearly limited by the a prior assumption of mechanism. Further simulations determined whether SNLR would permit assessment of the inhibition mechanism (competitive or noncompetitive). The minimal design examined three [S] (control) and three [S]-[I] pairs. This design was successful in identifying the correct model for 98 of 100 data sets (20% coefficient of variance random error). SNLR analysis of metabolite formation rate versus [S] permits a dramatic reduction in experimental effort while providing reliable estimates of K(i), K(m), and V(max) along with an estimation of the mechanism of inhibition. The accuracy of the parameter estimates will be affected by the experimental variability of the system under investigation.

Enzyme Inhibitors↗
PubMed2000

Comparison of granulocyte-colony, stimulating factor and granulocyte macrophage-colony stimulating factor in the treatment of chemotherapy extravasation ulcers.

The results of perilesional granulocyte macrophage-colony stimulating factor and granulocyte-colony stimulating factor application in a patient with chemotherapy extravasation ulcers are reported. A 64-year-old patient with recurrent ovarian carcinoma was admitted to our department in February 1999. In June 1998, six cycles of chemotherapy were applied to the patient after surgery. At the first cycle, two ulcers appeared on both lower arms related to doxorubicin extravasation despite all interventions. When the patient was admitted to in our department, we observed an ulcer on the distal part of the right lower arm with a dimension of 1.5x2 cm and another on the proximal portion of the left lower arm with a dimension of 2.5x3 cm. Of those ulcers, the bigger and deeper one on the left was treated with weekly 400 mcg granulocyte macrophage-colony stimulating factor subcutaneously for three weeks. The lesion completely disappeared in the fourth week. The other ulcer that was left for control on the right arm was treated with weekly 48 M.U. granulocyte-colony stimulating factor for four weeks. This ulcer did not reduce in size. As a result granulocyte-colony stimulating factor did not affect the healing of chemotherapy extravasation ulcers, as did granulocyte macrophage-stimulating factor.

Antineoplastic Agents↗
PubMed1999

Agonist-induced, G protein-dependent and -independent down-regulation of the mu opioid receptor. The receptor is a direct substrate for protein-tyrosine kinase.

The mu opioid receptor (MOR) has been shown to desensitize after 1 h of exposure to the opioid peptide, [D-Ala(2), N-MePhe(4), Gly-ol(5)]enkephalin (DAMGO), largely by the loss of receptors from the cell surface and receptor down-regulation. We have previously shown that the Thr(394) in the carboxyl tail is essential for agonist-induced early desensitization, presumably by serving as a primary phosphorylation site for G protein-coupled receptor kinase. Using a T394A mutant receptor, we determined that Thr(394) was also responsible for mu opioid receptor down-regulation. The T394A mutant receptor displayed 50% reduction of receptor down-regulation (14.8%) compared with wild type receptor (34%) upon 1 h of exposure to DAMGO. Agonist-induced T394A receptor down-regulation was unaffected by pertussis toxin treatment, indicating involvement of a mechanism independent of G protein function. Interestingly, pertussis toxin-insensitive T394A receptor down-regulation was completely inhibited by a tyrosine kinase inhibitor, genistein. Tyrosine kinase inhibition blocked wild type MOR down-regulation by 50%, and the genistein-resistant wild type MOR down-regulation was completely pertussis toxin-sensitive. Following DAMGO stimulation, MOR was shown to be phosphorylated at tyrosine residue(s), indicating that the receptor was a direct substrate for tyrosine kinase action. Mutagenesis of the four intracellular tyrosine residues resulted in complete inhibition of the G protein-insensitive MOR internalization. Therefore, agonist-induced MOR down-regulation appears to be mediated by two distinct cellular signal transduction pathways. One is G protein-dependent and GRK-dependent, which can be abolished by pertussis toxin treatment of wild type MOR or by mutagenesis of Thr(394). The other novel pathway is G protein-independent but tyrosine kinase-dependent, blocked by genistein treatment, and one in which Thr(394) has no regulatory role but phosphorylation of tyrosine residues appears essential.

Amino Acid Sequence↗
PubMed1998

In vivo chiro-inositol metabolism in the rat: a defect in chiro-inositol synthesis from myo-inositol and an increased incorporation of chiro-[3H]inositol into phospholipid in the Goto-Kakizaki (G.K) rat.

We report our comparative studies of myo- and chiro-[3H]inositol distribution in control nondiabetic Wistar and spontaneous nonobese insulin-resistant Type II diabetic G.K. rat tissues following 78-h labeling period. From various tissue extracts, free inositols, inositol phosphates, and inositol phospholipids were isolated and analyzed. Our findings demonstrate (1) a significant difference in the metabolism of myo- and chiro-inositol in normal Wistar and G.K. rats, (2) a severe defect in conversion of myo-[3H]inositol to chiro-[3H]inositol at the inositol phospholipid level of insulin-sensitive tissues of the G.K. rat, (3) an increased incorporation of myo-[3H]inositol into purified inositol phospholipids of the G.K. rat consistent with a decreased conversion to chiro-[3H]inositol, (4) the presumed presence of a pathway which incorporates chiro-[3H]inositol into inositol phospholipids, and which is overactive in the G.K. rat compared to the Wistar rat, and (5) no or minimal conversion of chiro-[3H]inositol to myo-[3H]inositol.

Animals↗
PubMed1997

Agonist-induced desensitization of the mu opioid receptor is determined by threonine 394 preceded by acidic amino acids in the COOH-terminal tail.

To identify the structural determinants necessary for mu opioid receptor desensitization, we serially ablated potential phosphorylation sites in the carboxyl tail of the receptor and examined their effects on [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO)-induced desensitization. First, we replaced Thr394 with alanine (T394A) and stably expressed this mutant receptor in Chinese hamster ovary cells. The T394A receptor did not desensitize after 1 h of treatment with DAMGO, indicating that Thr394 is required for agonist-induced early desensitization. To test whether Thr394 was the only residue necessary, we investigated the importance of 7 potential phosphorylation sites between residues 363 and 383, which were all replaced by alanines with the Thr394 maintained. This mutant (AT) showed partial loss of desensitization (30%), which was attributable to the Ala mutation at Thr383, since complete desensitization was achieved by restoring Thr383 (ATT). These results suggest that Thr394 is the primary recognition site for G protein-coupled receptor kinases, but Thr383 is also required for complete agonist-induced desensitization. The specificity of Thr394 as the primary initiation site appears to be dependent on the preceding acidic amino acid stretch, because in a mutant in which glutamic acid residues at 388, 391, and 393 were replaced by glutamines (EQ), agonist-induced desensitization was completely abolished, identical to the T394A mutant.

Alanine↗
PubMed1996

Characterization of the properties of cocaine in blood: blood clearance, blood to plasma ratio, and plasma protein binding.

As part of a study to examine cocaine disposition and interaction with ethanol, it was necessary to characterize various properties of cocaine in the blood of the experimental animal. All studies were conducted using blood from healthy adult male Sprague-Dawley rats. Cocaine was incubated in whole blood at 37 degrees C at concentrations of 500-4000 ng/mL. The apparent first-order rate constant for cocaine loss was independent of concentration. Blood clearance, calculated assuming blood volume to be 64 mL/kg, was estimated to be 0.056 +/- 0.003 mL/(min.kg); a value considerably smaller than estimates of systemic clearance. The addition of NaF increased the rate of loss to form benzoylecgonine, as a result of increased chemical degradation and as a consequence of increased pH (to pH 8.0 over 30 h). This NaF-enhanced degradation was abolished when NaF was added to blood buffered to pH 7.4. Ethanol had no influence on cocaine degradation, and there was no evidence of cocaethylene (ethylcocaine) formation. Blood to plasma ratios determined in spiked and authentic samples were constant (0.94-1.05 and 0.99-1.03, respectively) and independent of concentration (100-1500 ng/mL) and pH (7.2-7.6). This ratio was not influenced by NaF or ethanol. The unbound fraction (fu) of cocaine determined in spiked plasma varied from 0.62 to 0.63 over the concentration range (75-2025 ng/mL). Ethanol had no effect on binding. The values for fu determined from authentic blood samples taken from rats dosed intravenously with cocaine (10 mg/kg) ranged from 0.67 to 0.69 (over the concentration range 300-1500 ng/mL). Cocaine plasma protein binding was independent of concentration but depended upon plasma pH (fu, 0.765 and 0.486, at pHs 7.0 and 7.8, respectively.

Animals↗
PubMed1996

Agonist-induced functional desensitization of the mu-opioid receptor is mediated by loss of membrane receptors rather than uncoupling from G protein.

The effects of acute exposure of the opioid peptide [D-Ala2,N-MePhe4, Gly-ol5]enkephalin (DAMGO) on the mu-opioid receptor were examined in Chinese hamster ovary (CHO) K-1 and baby hamster kidney stable transfectants. In the CHO cell line, acute 1-hr treatment with DAMGO decreased the density of receptors without affecting the affinity or proportion of agonist-detected sites and attenuated the ability of the agonist to inhibit forskolin-stimulated cAMP accumulation. In contrast, similar 1-hr treatment of baby hamster kidney cells did not affect receptor density or agonist ability to inhibit cAMP accumulation, but longer duration of agonist exposure resulted in a reduction in membrane receptor, identical to the CHO cells. These results suggested that for the mu-opioid receptor, alteration in receptor density was the major determinant for the observed agonist-induced desensitization. Consistent with this notion, the ratio of the DAMGO concentration yielding half-maximal occupation of the mu receptor to that yielding half-maximal functional response was < 1. This suggests the necessity for a high mu receptor occupancy rate for maximal functional response, so that any loss of cell surface opioid-binding sites was a critical determinant in reducing the maximal response. This hypothesis was further supported by the observation that irreversible inactivation of fixed proportions of opioid-binding sites with beta-chlorn-altrexamine demonstrated that there were few spare receptors, which is in contrast to what has been reported for other G protein-coupled receptors, including the delta-opioid receptor. Taken together, these data suggest that the opioid agonist DAMGO has a high affinity for the mu receptor but must occupy > 70% of the available receptors to generate the maximal second messenger-linked response.

Analgesics↗