Biomedical subjects

N S Wang

Publications and source records attributed to N S Wang.

At least 19 recordsLinked to original sources

PubMed2001

The application of intramolecular radical cyclizations of acylsilanes in the regiospecific formation of cyclic silyl enol ethers.

Acylsilanes with terminal alpha-stannyl bromide or xanthate functionalities are prepared. Alpha-stannyl radicals generated from these acylsilanes undergo intramolecular cyclizations to give cyclic silyl enol ethers regiospecifically. The radical processes involve radical cyclization, Brook rearrangement, and beta-fragmentation in sequence. A tributylstannyl group serves as the radical leaving group. The newly formed sigma-bond and pi-bond are located between the same two carbon atoms. This approach is limited to the formation of five-membered rings. In another route, omega-bromo-alpha-phenylsulfonylacylsilanes are synthesized. The radical cyclizations of these alpha-sulfonylacylsilanes also give cyclic silyl enol ethers. The phenylsulfonyl moiety is the radical leaving group in this system. Furthermore, the newly formed sigma-bond and pi-bond are located at adjacent positions sharing a single carbon atom. The latter approach is effective for both five- and six-membered ring formation.

Journal Article↗

PubMed2001

Transient expression of wild-type or mitochondrially targeted Bcl-2 induces apoptosis, whereas transient expression of endoplasmic reticulum-targeted Bcl-2 is protective against Bax-induced cell death.

Bcl-2 protein family members function either to promote or inhibit programmed cell death. Bcl-2, typically an inhibitor of apoptosis, has also been demonstrated to have pro-apoptotic activity (Cheng, E. H., Kirsch, D. G., Clem, R. J., et al. (1997) Science 278, 1966-1968). The pro-apoptotic activity has been attributed to the cleavage of Bcl-2 by caspase-3, which converts Bcl-2 to a pro-apoptotic molecule. Bcl-2 is a membrane protein that is localized in the endoplasmic reticulum (ER) membrane, the outer mitochondrial membrane, and the nuclear envelope. Here, we demonstrate that transient expression of Bcl-2 at levels comparable to those found in stably transfected cells induces apoptosis in human embryonic kidney 293 cells and in the human breast cell line MDA-MB-468 cells. Furthermore, we have targeted Bcl-2 specifically to either the ER or the outer mitochondrial membrane to test whether induction of apoptosis by Bcl-2 is dependent upon its localization within either of these membranes. Our findings indicate that Bcl-2 specifically targeted to the mitochondria induces cell death, whereas Bcl-2 that is targeted to the ER does not. The expression of Bcl-2 does result in its cleavage to a 20-kDa protein; however, mutation of the caspase-3 cleavage site (D34A) does not inhibit its ability to induce cell death. Additionally, we find that transiently expressed ER-targeted Bcl-2 inhibits cell death induced by Bax overexpression. In conclusion, the ability of Bcl-2 to promote apoptosis is associated with its localization at the mitochondria. Furthermore, the ability of ER-targeted Bcl-2 to protect against Bax-induced apoptosis suggests that the ER localization of Bcl-2 may play an important role in its protective function.

Apoptosis↗

PubMed2001

Reinforcement by orally delivered methadone, cocaine, and methadone-cocaine combinations in rhesus monkeys: are the combinations better reinforcers?

RATIONALE: Polydrug abuse is a problem that has been infrequently examined. In the present study, drug self-administration procedures were used to investigate the reinforcing effects of drug combinations. OBJECTIVES: To determine the absolute and relative response rates maintained by orally delivered methadone, cocaine, and their combinations under sequential and concurrent access. Choice between drug combinations containing different concentrations of cocaine was also determined. METHODS: Oral intake of methadone, cocaine, and their combinations was studied with rhesus monkeys during daily 3-h sessions. Lip contact (the operant response) was reinforced by delivery of liquid contingent upon completion of a fixed-ratio schedule. In one series, the drugs and drug combinations were studied sequentially with the water vehicle concurrently available. In the next series, the drugs and drug combinations were concurrently available. In the third series, pairs of drug combinations containing different concentrations of cocaine were also concurrently available. RESULTS: Methadone, cocaine and their combinations functioned as reinforcers. Under sequential access, response rates for the drug combinations and the component drugs were often similar. However, under concurrent access, response rates for the drug combinations were greater than response rates for the component drugs at the highest FR size for each condition. Also, drug combinations containing higher cocaine concentrations were preferred to combinations containing lower cocaine concentrations. CONCLUSIONS: Combinations of methadone and cocaine have relatively greater reinforcing effects than the component drugs, and these greater reinforcing effects are better detected with concurrent measures than with sequential measures.

Administration, Oral↗

PubMed2000

Simplified rat intubation using a new oropharyngeal intubation wedge.

Our new oropharyngeal intubation wedge made from a plastic 3-ml syringe has been used successfully for the expansion of the oropharyngeal cavity and visualization of vocal cords for endotracheal intubation in the rat. All the animals we used tolerated the intubation and ventilation procedures in a series of experiments. After the proper setting of the respirator, vital signs were maintained within normal range. The postmortem examination and measurements in the upper airway confirmed that the endotracheal tube was properly sited and also demonstrated the precise size of the device that should be used. The main advantages of this method include low cost, simplicity, and reliability. Furthermore, because no expensive, elaborate, difficult-to-operate, or hard-to-get special equipment is needed, this technique can be used in every laboratory.

Animals↗

PubMed1999

Orally delivered methadone as a reinforcer: Effects of the opioid antagonist naloxone.

The effects of the opioid antagonist naloxone were studied with three monkeys under a mutually exclusive fixed-interval 15 s (FI 15 s) schedule of reinforcement. Under this schedule, at the end of each interval, the monkey could obtain one liquid delivery from either the spout that delivered methadone (0.8 mg/ml) or the spout that delivered vehicle (deionized water). Naloxone doses from 0.0125 to 0.2 mg/kg (IM daily 10 min prior to the session) were studied in an ascending then descending order. In the ascending series, low naloxone doses produced increases of methadone deliveries in the first hour of the session for three monkeys and increases over the entire 3-h session for two of the three monkeys. At higher doses naloxone decreased methadone deliveries in all three monkeys. Naloxone's effects were usually greater during the descending dose series than during the ascending series. These findings suggest that a history of naloxone injections is one determinant of response to the drug. Vehicle maintained responding was generally low and not changed by naloxone in a systematic way. The time course of methadone deliveries showed that naloxone's effects were greatest in the first hour of the session and were a direct function of dose. These experiments demonstrate that oral methadone reinforced behavior is sensitive to naloxone pretreatment and that the effects of naloxone are a direct function of dose.

Administration, Oral↗

PubMed1999

Compliance and functional residual capacity after staple versus combined staple/holmium laser lung volume reduction surgery in a rabbit emphysema model.

BACKGROUND: There is some evidence to suggest that laser exposure, when added to standard staple reduction techniques, may result in improved physiologic response to lung volume reduction surgery (LVRS). In this study, we compared physiologic responses of staple LVRS with combined staple/laser in a rabbit emphysema model. METHODS: Ninety-three New Zealand White rabbits underwent emphysema induction with aerosolized elastase 4 weeks before surgery and were killed 1 week after surgery. Treatment groups were bilateral moderate volume staple LVRS (< or =3 g, n = 39), combined moderate volume staple (< or =3 g)/holmium laser LVRS (n = 18), large-volume staple LVRS (> or =3 g, n = 27), or sham surgery (n = 9). RESULTS: Decrease in postoperative static respiratory system compliance by combined moderate-volume staple/laser treatment (1.22 cc/cm H2O) was similar to large-volume staple resection (1.40 cc/cm H2O, p = 0.39), and superior to moderate staple resection (0.82 cc/cm H2O, p = 0.01) or sham surgery (0.09 cc/cm H2O, p = 0.0001). Functional residual capacity decrease was greater after combined moderate staple/laser resection (6.46 cc) than large-volume staple resection (4.52 cc, p = 0.33), moderate-volume staple resection (4.59 cc, p = 0.43), or sham surgery (4.10 cc, p = 0.29). Perioperative mortality was highest after laser/staple LVRS (22%, 4/18). CONCLUSIONS: In this rabbit model, combined staple/ holmium laser reduction for emphysema results in significant improvement in compliance and trends toward improvement in functional residual capacity above staple reduction alone, but with higher mortality.

Animals↗

PubMed1999

The glandular component in congenital cystic adenomatoid malformation of the lung.

Although severe congenital cystic changes (CCC) of the lung may be fatal, less severe forms may regress or vanish spontaneously. With recent advances in sonography, asymptomatic CCC are increasingly found. Whether all CCC should be promptly excised, or not, is uncertain. Congenital cystic changes conceptually are bronchopulmonary foregut malformations (BPFM) with a predilection for malignant degeneration. Among all BPFM, congenital cystic adenomatoid malformation (CCAM) is most common. We therefore searched for evidence of early malignant transformation in five surgically excised and three autopsy lungs with CCAM. By light microscopy, CCAM resembled poorly formed and dilated bronchi, bronchioles and respiratory air spaces. Four lungs had multiple nodular aggregates of mucus producing cells; the glandular component (GC). By scanning electron microscopy, GC appeared as multiple micropolyps, resembling neuroepithelial bodies. By transmission electron microscopy, GC had a surface proliferation of cells with granules of the mucous type and a basal increase in cells with owl-eyed neuroendocrine granules. The glandular component in CCAM appeared similar to the mucous cells in hyperplastic polyps of the colon and a type of mucus producing bronchioloalveolar carcinoma. Our findings support the hypothesis that CCAM is caused by dysregulated paracrine growth of mature cells and extracellular matrices and that GC could have the potential for malignant transformation. Further clinical and laboratory studies of BPFM are needed for the appropriate management of congenital cystic changes.

Autopsy↗

PubMed1998

Anatomy of the pleura.

The lung and heart, the vital organs, have to be protected and also have to move and change volume continuously to function. For the best protection and function of the lung, the thorax is shaped almost like a bellows with the diaphragm as the moving part. Furthermore, the outer surface of the lung and the inner surface of the protective thoracic cage are covered by an elastic, serous, and lubricating membrane to form the pleural cavity. This is almost like inserting a sealed-wet and stretchable-plastic bag between the lung and the thoracic wall and diaphragm to decrease friction. The lubrication is accomplished by the facing mesothelial cells that have bushy-surface microvilli enmeshing hyaluronic acid-rich glycoproteins. The amount of fluid in the pleural cavity is regulated by the hydrostatic-osmotic pressure relationship and pleuro-lymphatic drainage. Excess fluid, large particles, and cells in the pleural cavity are removed through preformed stomas assisted by respiratory movements. The stoma is found only in the anterior lower thoracic wall and diaphragm and is like the drain of a sink. Finally, clinical and subclinical injuries of the pleura appear to occur often. Reactive mesothelial cells constantly repair the damages and keep the pleural cavity open. Without mesothelial cells, the lung cannot function properly and the pleural cavity will be quickly obliterated by fibrosis.

Animals↗

PubMed1998

Segmental necrosis of small bronchi after prolonged intakes of Sauropus androgynus in Taiwan.

Since 1994 an endemic of chronic obstructive pulmonary disease (COPD) has developed in Taiwan after a prevalent use of a body-weight-reducing vegetable, Sauropus androgynus (SA). All conventional treatments for COPD, including steroids and bronchodilators, had been ineffective. Studies of limited lung biopsy specimens from these patients revealed bronchiolitis obliterans. A few patients died, but many developed protracted chronic respiratory failure. Because of the chronic debilitation and ineffective conventional treatments, single lung transplants were performed as the last resort in four patients. The excised lungs revealed focal fibromuscular sclerosis and obliteration of bronchial arteries in the wall of large bronchi 4 to 5 mm in diameter with segmental necrosis of bronchi 2 to 4 mm in diameter. Bronchi immediately proximal to the necrotic zone showed fibrosis and atrophy of cartilage, bronchial glands, and smooth muscle cells; bronchioles immediately distal showed obstruction or dilatation. Most bronchi larger than 5 mm, pulmonary vessels, small bronchioles, and alveoli were little altered. The pathologic changes were most consistent with segmental ischemic necrosis of bronchi at the water-shed zone of bronchial and pulmonary circulation. The specific etiologic agent and detail of pathogenesis of this SA-related COPD needs further investigation.

Adult↗

PubMed1998

Comparisons of pleurodesis induced by talc with or without thymol iodide in rabbits.

STUDY OBJECTIVE: At the present time, talc administered either as a slurry or an aerosol is a popular agent for producing pleurodesis. Some investigators use iodized talc while others use plain talc. The purpose of the present study was to determine if iodized talc slurry produced a better pleurodesis in animals than did plain talc. DESIGN: New Zealand white male rabbits were randomly assigned to receive talc slurry, 200 mg/kg, with or without the addition of 50 mg iodide intrapleurally. Approximately 10 rabbits in each group were killed 1, 2, 4, 7, 14, and 28 days after the injection. The amount and character of pleural fluid, the degree of pleural adhesions, and the microscopic changes were compared in the two different groups. RESULTS: The pleural fluid findings, the gross adhesion score for the pleura, and the microscopic changes in the visceral pleura were essentially identical for the rabbits that received iodized talc and those that received plain talc. The injection of both plain talc and iodized talc produced a normoglycemic exudative pleural effusion that had, for the most part, disappeared by the fourth day postinjection. The amount of pleural fluid at 48 h was 3.3+/-0.6 mL in the plain talc and 2.2+/-0.5 mL in the iodized talc group. At 28 days, the mean degree of gross pleurodesis in the talc group was 2.6+/-0.2 compared with 2.3+/-0.2 in the iodized group, while the mean degree of microscopic fibrosis was 1.4+/-0.3 in the plain talc group compared with 2.0+/-0.3 in the iodized talc group. CONCLUSION: From this study, we conclude that the addition of 50 mg of iodide does not improve the results with talc slurry pleurodesis in rabbits.

Animals↗

PubMed1997

Comparison of Ho:YAG versus Nd:YAG thoracoscopic laser treatment of pulmonary bullae in a rabbit model.

OBJECTIVE: To determine the relative efficacy and morbidity of Ho:YAG versus Nd:YAG laser treatment of bullous lung disease in an animal model. SUMMARY BACKGROUND DATA: Laser coagulation procedures for treatment of emphysematous pulmonary bullae and heterogeneous emphysema continue to evolve. The role of lasers in lung volume reduction surgery remains controversial due to issues of relative efficacy and morbidity. The Nd:YAG laser is most commonly used for these procedures. We hypothesized that the shallower penetration of the Ho:YAG laser may be better suited for laser bullae coagulation and emphysema lung volume reduction with increased efficacy and reduced lung injury. METHODS: Thirty New Zealand White rabbits (15 normal rabbits; 15 with bullous lung disease) were evaluated with Ho:YAG compared to Nd:YAG laser exposures. Bullae were coagulated by either Ho:YAG or Nd:YAG treatment. In all animals (bullous-induced and normals), unaffected lung tissue in the upper lobes and contralateral lungs were treated with 5 spot exposures of Nd:YAG and Ho:YAG, each to assess depth of lung injury. Animals were sacrificed at Days 0, 7, and 21 and their lungs were examined histologically. RESULTS: Ho:YAG and Nd:YAG exposures caused equivalent lung injury to normal lung tissue. In the acute phase, parenchymal necrosis depth was similar for both Ho:YAG and Nd:YAG (850 +/- 273 microns vs. 900 +/- 270 microns respectively, p = 0.7). By Day 7, lung necrosis depth was 925 +/- 133 microns Ho:YAG vs. 1225 +/- 235 microns Nd:YAG (p = 0.33), and lung fibrosis depth was 300 +/- 134 microns Ho:YAG vs. 558 +/- 127 microns Nd:YAG (p = 0.11). By Day 21, pulmonary parenchymal necrosis was not seen. Pleural fibrosis depth was maximal at Day 21, reaching 250 +/- 102 microns for Ho:YAG vs. 300 +/- 156 microns Nd:YAG (P = 0.88). Pleural necrosis depth was 67 +/- 42 microns Ho:YAG vs 48 +/- 34 microns Nd:YAG (p = 0.42) on Day 7 and resolved by Day 21. During surgical coagulation procedures, the Ho:YAG laser was dramatically more efficient in coagulating bullae. The Ho:YAG laser required less exposure at equivalent power and resulted in immediate desiccation of bullae, in sharp contrast to the Nd:YAG laser. CONCLUSIONS: Because the Ho:YAG was more effective and did not result in more acute lung injury than the standard Nd:YAG laser in this study, Ho:YAG lasers may have improved potential for laser treatment of bullae or lung volume reduction surgery (LVRS) compared to Nd:YAG lasers.

Animals↗

PubMed1997

The effects of early chest tube placement on empyema resolution.

STUDY OBJECTIVES: The objective of this study was to determine the impact of the timing of chest tube insertion on outcome for the treatment of empyema, using a new animal model of empyema. DESIGN: A prospective, controlled randomized, blinded design was used. SETTING: The study was conducted in an animal research laboratory. PATIENTS OR PARTICIPANTS: Sixty-six 2- to 3-kg rabbits were used in this study. INTERVENTIONS: After induction of empyema, the rabbits were divided into four groups. Fourteen rabbits had chest tubes placed at 24 h after empyema induction. Seventeen rabbits had chest tubes placed at 48 h and 14 rabbits had chest tubes placed at 72 h after empyema induction. Twenty-one rabbits served as control rabbits and had no chest tubes placed. MEASUREMENTS AND RESULTS: Ten days after induction of empyema, the rabbits were killed. The pleural spaces of each rabbit were examined and a gross score, pleural peel score, and a microscopic score were calculated for each rabbit. The median gross score, mean pleural peel score, and median microscopic scores were significantly higher in the rabbits that underwent late chest tube placement (72 h) relative to those that underwent early chest tube placement (24 or 48 h). CONCLUSIONS: This study supports previous expert opinion statements and conclusions from retrospective analyses that early chest tube placement (relative to delayed chest tube placement) is beneficial for the treatment of empyema.

Animals↗

PubMed1996

Animal model for thoracoscopic laser ablation of emphysematous pulmonary bullae.

BACKGROUND AND OBJECTIVE: Thoracoscopic laser techniques have been described for treatment of pulmonary bullae. Clinical application of this procedure has proliferated despite limited data regarding efficacy or optimal techniques. The objective of this study was to develop an animal model for investigating laser treatment of bullous lung disease. STUDY DESIGN/MATERIALS AND METHODS: Sixty-two New Zealand White rabbits (3-5 kg) were injected intravenously with 0.35 cc sterile-filtered Sephadex G-100 beads (1 g/100 cc suspension). Three hours later, rabbits were anesthetized, intubated, and 10 cc 0.7% heat-treated or 1% untreated carrageenan solution was instilled endotracheally into a catheter wedged in a mainstem bronchus. RESULTS: Bullae formed over 4-6 weeks in 33% of the animals treated with 0.7% heat-treated carrageenan, and 90% of animals receiving 1% untreated carrageenan (P < 0.005) as demonstrated by serial thoracoscopy. Thoracoscopy was performed at 6-8 weeks using 5 mm trocars under general anesthesia and mechanical ventilatory support. Animals developed pulmonary bullae ranging in size from 0.5 to 2 cm. Bullae were ablated under thoracoscopic visualization using a CO2 laser with a 4 mm OD rigid probe and short focal length in a defocused mode, or an Nd:YAG laser with a 0.4 mm diameter flexible fiberoptic probe. Animals recovered quickly following thoracoscopy. CONCLUSION: We have successfully developed an animal model for thoracoscopic laser ablation of emphysematous pulmonary bullae. This animal model should be useful in investigating treatment of bullous lung disease in humans.

Animals↗

PubMed1996

Comparison of continuous versus pulsed CO2 and Nd:YAG laser-induced pulmonary parenchymal lung injury in a rabbit model.

BACKGROUND AND OBJECTIVE: Laser techniques have recently been described for treatment of patients with emphysema and bullous lung disease. Laser exposure of the pulmonary parenchyma during these procedures is complicated by laser-induced lung injury with substantial associated morbidity. Animal investigations are needed to develop methods that reduce lung injury. We hypothesized that the depth of injury could be reduced by pulsing laser exposures, with the goal of limiting thermal effects to more superficial tissue levels. In this study, we compared acute and chronic histologic injury resulting from pulsed- versus continuous-mode CO2 and Nd:YAG laser pulmonary parenchymal exposures in rabbits. STUDY DESIGN/MATERIALS AND METHODS: A total of 40 New Zealand White (NZW) rabbits underwent thoracotomy followed by exposure with CO2 laser (n = 10 continuous vs. n = 10 pulsed at 250 Hz with duty cycle 0.15 ms) or ND:YAG laser (n = 10 continuous vs. n = 10 pulsed at 10 Hz with duty cycle 0.10 sec) to the visceral pleural surface using 1 minute of laser exposure (5 watts, defocused to 70 W/cm2 power density) to the exposed lung surface. Rabbits were sacrificed at 4 and 21 days post-injury, and lungs were examined histologically. RESULTS: CO2 and Nd:YAG laser treatment resulted in substantial pulmonary parenchymal injury. While CO2 laser-induced damage was distinct from Nd:YAG histologically, pulsed-mode laser exposures did not reduce lung injury for either laser. Acute edema occurred to depths of 1180 +/- 338 microns for continuous-mode CO2 laser exposures compared to 1,340 +/- 430 microns in pulsed mode (p = .77). For Nd:YAG laser exposure, acute edema depth was 750 +/- 748 microns continuous versus 1120 +/- 367 microns pulsed mode (p = .65). Chronic lung fibrosis depth was 450 +/- 164 microns for CO2 continuous mode compared to 575 +/- 170 microns in pulsed mode (p = .61). Lung fibrosis depth for Nd:YAG was 550 +/- 96 microns, continuous versus 484 +/- 180 microns pulsed mode (p = .76). CONCLUSION: The similarity in injury between pulsed- and continuous-mode exposures suggests that thermal relaxation times are long relative to the selected pulse frequencies in intact living rabbit lungs. Alternatively, brief high-energy pulsations may increase focal temperatures with a tendency to increase injury depth relative to the penetration of the laser light. Thus, pulsed laser modes in these settings appear to be ineffective in reducing laser-induced lung injury in clinical settings.

Animals↗

PubMed1996

Multicentric epithelioid angiosarcoma of the bone. Pitfalls in clinical and morphological diagnosis.

Epithelioid angiosarcoma of the bone represents a challenging diagnosis by bone marrow biopsy. We present a case of a multicentric high grade angiosarcoma of the bone with epithelioid features. On the basis of the clinical presentation, the radiological findings, and the appearance of loosely clustered tumor cells detected in the initial bone marrow biopsy, the main differential diagnoses considered were a poorly differentiated non-secretory multiple myeloma and metastatic carcinoma. Subsequent morphologic, immunohistochemical and electron microscopic examination of tissue samples clarified the nature of the tumor as epithelioid angiosarcoma. We discuss potential pitfalls in clinical and morphological diagnosis. The strong reactivity of the tumor cells with the nonspecific but ubiquitous mesenchymal marker vimentin in similar cases should direct early attention to the rare malignant bone tumor, epithelioid angiosarcoma, with subsequent confirmation of this diagnosis with specific immunohistochemical endothelial cell markers and/or electron microscopy.

Aged↗

PubMed1996

Comparison of mitoxantrone and tetracycline as pleural sclerosing agents in rabbits.

Bleomycin is the antineoplastic agent used most commonly for the treatment of malignant pleural effusion. It is absorbed rapidly from the pleural space and does not elicit pleurodesis in the normal rabbit pleura. Mitoxantrone is a new antineoplastic that differs from bleomycin in that it binds to membranes. Accordingly it might remain in the pleural space for a longer period and produce a pleurodesis. The objective of this project was to determine whether mitoxantrone is an effective sclerosant in an experimental model in rabbits. The following medications were instilled intrapleurally in anesthetized male rabbits: 35 mg/kg tetracycline or 0.5, 1.0, or 2.0 mg/kg mitoxantrone. The animals were killed at 28 days and the pleural spaces assessed grossly for pleurodesis and microscopically for fibrosis and inflammation. The mean degree of gross pleurodesis did not differ significantly in the rabbits that received tetracycline (3.8 +/- 0.4) and in the rabbits that received 2 mg/kg mitoxantrone (3.2 +/- 1.3). The degree of pleural and lung inflammation was significantly greater after mitoxantrone than after tetracycline, both ipsilaterally and contralaterally. The mortality after the highest dose of mitoxantrone was 50%. From this study we conclude that the intrapleural administration of mitoxantrone in rabbits can produce a pleurodesis. The histologic picture after mitoxantrone administration differs markedly from that after tetracycline injection. After mitoxantrone injection there are many more inflammatory cells present on the side that received the injection, and there is much more fibrosis and inflammation in the contralateral pleura and lung. The model of pleural fibrosis following intrapleural mitoxantrone may be useful for the study of pleural fibrosis.

Animals↗

PubMed1996

Orally delivered methadone as a reinforcer in rhesus monkeys.

Methadone usually is taken orally for drug abuse treatment in humans but oral methadone self-administration by laboratory animals has not been investigated extensively. The present study examines acquisition and maintenance of oral methadone maintained responding in four adult male rhesus monkeys. Drug solution was available from one liquid delivery system and water from a second system during daily 3-h sessions. Locations of liquids were reversed each session, and liquid (0.65 ml per delivery) was delivered according to a fixed-ratio reinforcement schedule. Initially a test for the reinforcing effects of 0.00625-0.4 mg/ml methadone solutions was carried out but a consistent preference for drug over water was not seen. To establish methadone as a reinforcer, a fading procedure was used in which responding was first maintained by solutions of methadone (0.00625-0.4 mg/ml) combined with ethanol (0.0325-2.0% w/v). Subsequently, the concentration of the ethanol in the combination was gradually reduced to zero. Methadone-maintained responding (0.4 mg/ml) persisted when ethanol was no longer present. To confirm that the drug was serving as a reinforcer, the dose was varied: (a) by changing the volume delivered while the concentration was held constant and (b) by changing the concentration of the methadone while the volume per delivery was held constant. Over a wide range of doses, deliveries of methadone solution usually exceeded deliveries of concurrently available water. Orderly relationships were observed among methadone dose, response rate, and drug intake. The study of oral self-administration of opioid drugs by nonhuman primates may be a useful strategy for the development and evaluation of new drug substitution or replacement therapies.

Administration, Oral↗

PubMed1996

Orally delivered methadone as a reinforcer for rhesus monkeys: the relationship between drug concentration and choice.

The relative reinforcing effects of orally delivered methadone were studied in five male rhesus monkeys. Drug deliveries were available under either a fixed-ratio (FR) or a fixed-interval (FI) schedule. Three concentrations of methadone, low (0.05 mg/ml), intermediate (0.2 mg/ml), and high (0.8 mg/ml) were delivered in 0.65 ml volumes. In the first experiment, monkeys were presented with a choice paradigm. Under independent FR schedules responding led to a delivery of either a methadone solution or the water vehicle. For each concentration, deliveries of a methadone solution maintained higher response rates than did deliveries of water. In the second experiment, methadone concentrations were tested in pairs in the following sequence: high vs. low, high vs. intermediate, intermediate vs. low, high vs. intermediate (retest), and high vs. low (retest). The retest of the last two pairs was designed to counterbalance the test sequence, so that order effects, if they existed, could be detected. Regardless of the schedule, the higher concentration of the methadone pair maintained a greater response rate than did the lower concentration. The present results are consistent with the generalization based on other studies that over a broad range of concentrations and across pharmacological classes, reinforcement schedules, and routes of administration, reinforcing effects increase with increases in drug concentration.

Animals↗