Syndromic management of genital ulcer disease.
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Developing Countries↗
Biomedical subjects
M W Adler
Publications and source records attributed to M W Adler.
Interaction between opioid agonists and neurotensin on thermoregulation in the rat. I. Body temperature.
To examine the role of neurotensin in opioid-induced thermo-regulation, Tyr-Pro-N-MePhe-D-Pro-NH2 (PL-017, 1.86 nmol i.c.v.), neurotensin (NT, 0.0747-2.98 nmol i.c.v.), ([trans-(+/-)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide+ ++]) (U50,488H; U50, 10-40 mg/kg s.c.), dynorphin A1-17 (DY, 4.65 nmol i.c.v.) and DPDPE (4.65 nmol i.c.v.) were injected alone or in combination with NT into unrestrained, male S-D rats. At 20 +/- 2 degrees C ambient, body temperature (Tb) was measured for 3 hr after injection. PL-017 induced dose-dependent hyperthermia; NT, DY and U50 produced dose-related hypothermia. NT (0.0747 nmol) had no effect on PL-017-induced hyperthermia; higher doses of PL-017/NT antagonized the hyperthermia and increased the peak and duration of the hypothermia. Pretreatment with cyclic D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 0.74 nmol i.c.v.) blocked the enhanced PL-017/NT-induced hypothermia but had no effect on NT-induced hypothermia. DY/NT reduced Tb dose dependently but the effect did not differ significantly from NT alone. U50 (20 or 40 mg/kg)/NT increased the peak and duration of the hypothermic response. Naloxone pretreatment (10 mg/kg s.c.) blocked the effect of U50 alone and in combination with NT, as did the peripheral opioid antagonist, naloxone methiodide (100 mg/kg s.c.). Nor-binaltorphimine (25 nmol i.c.v.) partially blocked the effect of U50 on Tb and had no effect on NT or U50/NT. DPDPE did not alter Tb alone or in combination with NT. The data presented provide information on the role of NT in opioid-induced thermoregulation.
Animals↗
Human subject issues in drug abuse research. College on Problems of Drug Dependence.
Administration of drugs of abuse to human volunteers is an important and valuable clinical research procedure. The College on Problems of Drug Dependence recognizes the value and importance of such research and affirms its position that, with proper care, such research can be conducted safely and ethically. This report describes some of the procedures commonly used in human research with drugs of abuse and addresses some of the issues to be considered by researchers and by review committees to insure that such research has an acceptable risk/benefit ratio.
Ethics Committees, Research↗
Inhibition of interleukin-1 and tumor necrosis factor-alpha synthesis following treatment of macrophages with the kappa opioid agonist U50, 488H.
Previous reports from this laboratory, and others, have shown that exogenous mu and kappa opioids modulate both cellular and humoral immune responses. Our earlier work has suggested that accessory cells may serve as a target for the direct effects of kappa opioid compounds. In the present study, the function of the macrophage cell line P388D1 was modulated by the kappa-selective opioid agoinst U50,488H (trans-3,4-dichloro-N-methyl-N-[7-(1- pyrrolidinyl)cyclohexyl]benzene-acetamide methanesulfonate). Lipopolysaccharide-induced interleukin (IL)-1 and tumor necrosis factor-alpha production were inhibited after the administration of nanomolar concentrations of U50,488H. Furthermore, inhibition of IL-1 produced by the P388D1 cell line was reversed by both the classical opioid antagonist naloxone and by the kappa opioid receptor antagonist norbinaltorphimine. Examination of IL-1 mRNA levels in P388D1 by northern blot analysis showed that the inhibition mediated by U50, 488H apparently occurred at the level of transcription. On the other hand, U50,488H failed to modulate the production of IL-6 by this macrophage-like cell line. In addition, U50,488H failed to modulate the production of either IL-1 or tumor necrosis factor-alpha from the macrophage-like cell line RAW 264.7, an indication that subpopulations of macrophages exist with different sensitivities to opioids. These results are consistent with a growing body of data which suggests that a component of the inhibition mediated by opioid compounds involves a reduction in the production of cytokines.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Mouse strain differences in immunosuppression by opioids in vitro.
An in vitro assay was used to compare the effect of opioids on antibody production by splenocytes from C3HeB/FeJ, C57BL/6J, C57BL/6ByJ and B6C3F1/J mice immunized with sheep red blood cells (SRBC). Spleen cells were removed from mice that had been injected 2 wk prior with SRBC. These mice received no opioids in vivo. Dissociated spleen cells taken from each of the mouse strains were exposed to morphine with or without naloxone, or to U50,488H with or without norbinaltorphimine (nor-BNI), for 5 days in a Mishell-Dutton culture, with added SRBC as antigen. Immune responsiveness was assessed by the number of plaque-forming cells (PFC) per culture. The results showed a profound difference in the effects of the opioids on the spleen cells of the four mouse strains. Spleen cells of C3HeB/FeJ mice were suppressed approximately 50% in the number of PFC both by morphine (10(-5) to 10(-8) M) and by U50,488H (10(-5) to 10(-11) M). Suppression was blocked by pretreatment with naloxone or norbinaltorphimine, respectively. In contrast, spleen cells taken from C57BL/6J mice were not suppressed by either opioid, at doses ranging from 10(-5) to 10(-11) M. Spleen cells of B6C3F1/J mice were suppressed by U50,488H, but not morphine. Cells of C57BL/6ByJ mice gave inconsistent results in experiments measuring suppression by morphine, and U50,488H. Overall, these studies confirm our previous work showing that opioids directly affect the function of cells of the immune system via classical opioid receptors. In addition, the results show that mouse strain is a major variable in evaluating the immunomodulatory effects of opioids.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Intracerebroventricular treatment with an antisense oligodeoxynucleotide to kappa-opioid receptors inhibited kappa-agonist-induced analgesia in rats.
In vivo treatment with an antisense (AS) phosphorothioate oligodeoxynucleotide (oligo) to the rat kappa-opioid receptor selectively inhibited kappa-mediated analgesia in the rat cold-water tail-flick test. Intracerebroventricular (i.c.v.) AS oligo significantly inhibited the analgesic effect of i.c.v. spiradoline, but not that of mu- or delta-opioid agonists. The dose-effect curve for s.c. spiradoline was shifted to the right after AS, but not missense or sense oligo treatment. Thus, AS oligos provide another technique with which to selectively manipulate opioid receptors and further support the role of non-mu opioid receptors in mediating analgesia in rats.
Analgesia↗
Both T cells and macrophages are targets of kappa-opioid-induced immunosuppression.
We have previously shown that antibody responses are inhibited following administration of kappa-opioid agonists. We found that the inhibition was blocked by either naloxone or the kappa-selective antagonist norbinaltorphimine. This inhibitory activity is apparent after short-term treatment with the kappa-opioid agonist. In an attempt to identify the cell populations which serve as the target for this immunosuppressive effect, we have carried out cell fractionation analyses to generate isolated T cells and macrophages. Using multiple cell fractionation methods, we have determined that short-term treatment of either T cells or macrophages with the kappa-opioid agonist U50,488H results in significant inhibition of in vitro antibody responses. We also find that the inhibition of both T cell and macrophage activity can be blocked by naloxone. These studies demonstrate that resting T cells and macrophages express kappa-opioid receptors and exhibit significant opioid responsiveness prior to activation by antigen.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
A study of the physiological mechanisms contributing to neurotensin-induced hypothermia.
Although central administration of neurotensin is known to produce marked hypothermia in the rat, there are no studies which have investigated the effects of neurotensin on oxygen consumption and heat exchange, the physiological mechanisms which are the principal contributors to changes in body temperature. We report a significant correlation between dose and the duration and degree of post-injection heat loss following central administration of neurotensin. Oxygen consumption does not appear to be affected by neurotensin. We suggest that it is this dose-dependent, post-injection heat loss which is responsible for neurotensin-induced hypothermia. Furthermore, the hypothermia does not appear to reflect a change in set point.
Animals↗
Receptor selectivity of icv morphine in the rat cold water tail-flick test.
The cold water tail-flick test in the rat is somewhat unique in that it is sensitive to the analgesic effects of delta- and kappa- in addition to mu-opioid agonists. The present study was designed to test whether a component of morphine-induced analgesia in this test might be mediated by delta- or kappa-opioid receptors. Morphine was administered icv in combination with the non-selective opioid antagonist naloxone (NLX), as well as the mu-, delta- and kappa-selective antagonists, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr (CTAP), naltrindole (NTI) and norbinaltorphimine (norBNI), respectively. Morphine induced analgesia in a dose related manner. Administration of NLX (1-10 micrograms) or CTAP (1 microgram) antagonized morphine in a competitive fashion. Neither NTI (1-10 micrograms) nor norBNI (0.1 microgram) had any effect on the morphine dose-effect curve. Thus, morphine appeared to be a selective mu agonist in the cold water tail-flick test, at least by the icv route.
Animals↗
Survey of undergraduate teaching in genitourinary medicine in Britain.
OBJECTIVE: To determine whether the time allocated for undergraduate teaching of genitourinary medicine has changed since 1984 and to determine the impact of HIV/AIDS on the teaching of the specialty. METHODS: A self completion questionnaire was sent to the consultant in charge of each department of genitourinary medicine attached to a UK medical school. RESULTS: Replies were received from all twenty seven medical schools. Most schools (24/27) offer a course of lectures accompanied by clinical teaching; however, one medical school does not include teaching of genitourinary medicine in the undergraduate curriculum at all and two others are unable to offer all students clinical tuition. The mean time devoted to lectures is 6.7 hours (range 0-15 hours) made up of 4.8 hours of genitourinary medicine lectures and 1.9 hours of lectures on HIV/AIDS. The mean time allocated for clinic-based teaching of each student is 9.2 hours (range 0-27 hours). On average the time allocated for lecturing and clinical teaching of the speciality has decreased since 1984 although there is considerable variation between schools (time for clinical teaching and lecturing combined ranges from 0-41.0 hours). CONCLUSIONS: The findings of this survey suggest there is considerable variation in both the quantity and quality of undergraduate teaching of genitourinary medicine provided throughout the UK.
Acquired Immunodeficiency Syndrome↗
Effect of ambient temperature on the ability of mu-, kappa- and delta-selective opioid agonists to modulate thermoregulatory mechanisms in the rat.
Tyr-Pro-N-MePhe-D-Pro-NH2 (1.86 nmol), dynorphin A1-17 (4.65 nmol) and DPDPE (4.64 nmol), which are selective for mu-, kappa- and delta- opioid receptors, respectively, were injected into the right lateral ventricle of unrestrained male Sprague-Dawley rats. At ambient temperatures of 30 degrees C and 5 degrees C, brain surface temperature (Tb), oxygen consumption (VO2) and heat exchange (Q) were measured for 3 hr after injection in a gradient-layer calorimeter. Tyr-Pro-N-MePhe-D-Pro-NH2 at 30 degrees C caused significant hyperthermia (1.39 +/- 0.48 degree C) with onset occurring 15 to 30 min after injection and lasting 60 min after injection. Increased Tb was due to a significant decrease in Q (-1.31 +/- 0.31 cal/g/hr) and to a 60 to 75% increase in VO2 compared with saline controls. Thirty-min pretreatment with cyclic D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (0.74 nmol), a mu-selective antagonist, blocked the changes. At 30 degrees C, neither dynorphin A1-17 nor DPDPE significantly altered Tb, Q or VO2. At 5 degrees C ambient, Tyr-Pro-N-MePhe-D-Pro-NH2 decreased VO2, resulting in hypothermia (-1.01 degree +/- 0.46 degree C). Q was significantly reduced during the same period. Postinjection thermoregulatory responses to i.c.v. injection of dynorphin A1-17 at 5 degrees C varied widely from animal to animal, and lethality (33%, within 60 min after injection) became a significant factor.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
Opioids, receptors, and immunity.
The results achieved by those seeking to determine whether opioids and other drugs of abuse can affect immunity are quite astonishing given the short period of time that research has focused on this area. Despite the fact that there is no longer any question that opioids produce a variety of effects on the immune system, the extent and significance of these changes in the drug-abusing population remains to be determined. Whether or not the findings in mice and in in vitro preparations can be extrapolated to man is not yet known. Of major significance is the question of whether the endogenous opioid system is involved in immunoregulation. Given the multitude of drugs taken by drug abusers and the varying patterns of drug administration, the significance of the findings in the literature is still an open question. However, it is only by continuing studies such as those discussed at this meeting that we will find the answers.
Animals↗
Immunosuppressive effects of morphine on immune responses in mice.
Implantation of a 75-mg morphine sulfate pellet subcutaneously into mice of different strains and sexes caused profound immunosuppression of their spleen cell primary in vitro antibody responses to sheep red blood cells. No sex differences were observed. In mice of the C3H lineage, naltrexone blocked the immunosuppression. In mice in the C57BL/6J lineage, naltrexone was ineffective in blocking the effects of morphine and was itself suppressive. In beige C57BL/6J bgJ/bgJ mice, placebo pellets were also suppressive. The mechanism of the morphine-induced immunosuppression was investigated in C3HeB/FeJ mice. Addition of normal splenic macrophages to in vitro cultures restored immune responses, as did IL-1, IL-6 and IFN-gamma, suggesting that morphine-induced immunosuppression is due to a deficit in macrophage function. Morphine pellet implantation induced splenic atrophy. Whether suppression is attributable to decreased macrophage numbers or to decreased functional capacity of individual macrophages is currently under investigation.
Animals↗
Morphine treatment in vitro or in vivo decreases phagocytic functions of murine macrophages.
Studies were performed to compare in vitro and in vivo effects of morphine on the phagocytic function of murine peritoneal macrophages. Macrophage monolayers were incubated with Candida albicans for 30 min in the absence of autologous serum. Morphine added in vitro was found to decrease both the phagocytic activity (percent of phagocytic cells) and the phagocytic index (average number of ingested yeasts per cell) in a concentration-dependent manner, with maximal effects of 26% and 41%, respectively, at 10(-6) M. When morphine was administered in vivo via an implanted 75-mg pellet, there was a 22% decrease in phagocytic activity and a 40% decrease in the phagocytic index. Naltrexone completely blocked the effects of morphine both in vitro and in vivo. The results suggest that morphine is capable of interacting directly with opioid receptors on macrophages, resulting in a decrease in phagocytic function.
Animals↗
Effects of in vivo morphine treatment on antibody responses in C57BL/6 bgJ/bgJ (beige) mice.
C57BL/6J bgJ/bgJ (beige) mice are less sensitive than other strains to the analgesic effects of morphine, although they have normal numbers of mu receptors. In the present study, beige mice and their normal littermates (beige+) were treated in vivo with morphine or the opioid antagonist, naltrexone and their primary in vitro antibody responses were assessed. Morphine treatment caused splenic atrophy and suppressed the primary in vitro antibody response in beige and beige+ mice. However, these effects were not blocked by naltrexone co-treatment. In these mouse strains, naltrexone decreased spleen size and antibody responses by itself, which may mask its ability to antagonize morphine. In beige mice, placebo pellet implantation suppressed the primary in vitro antibody response. Morphine did not cause a further suppression of the antibody response in beige mice compared to placebo. Because of this anomalous response to placebo treatment, the immunosuppressive effects of morphine on the antibody response/10(7) cells can not be attributed to a specific drug effect in this strain. However, when antibody responses were expressed on a per spleen basis, the overall capacity to respond to antigenic challenge was suppressed by morphine treatment.
Animals↗
Identification and characterization of [125I]arginine vasopressin binding sites on human peripheral blood mononuclear cells.
Arginine vasopressin (AVP) is a nonapeptide that has been shown to be released from the posterior pituitary during stress. Although noted primarily for its hemodynamic and homeostatic properties, AVP also appears to have an effect on the immune system. It may modulate cellular immunity via its enhancement of the autologous mixed lymphocyte response (AMLR), an effect which we have demonstrated to occur over a wide dose range with a maximum at 10(-7) M. In this study, we examined the binding of [125I]AVP, and AVP analogues to human peripheral blood mononuclear cells (PBMC). AVP inhibited [125I]AVP (0.2 nM) binding on PBMC in a dose-dependent manner with maximal inhibition being reached at 10(-8) M. Specific [125I]AVP binding, as defined as that which could be displaced by 1 x 10(-6) M AVP, was saturable, time-dependent, and linear to cell concentration. Specific binding reached saturation at approximately 1000 pM in 45 minutes. From Scatchard analysis of saturation experiments it appeared to be a homogeneous population of binding sites with KD of approximately 0.5 nM and Bmax of approximately 7.6 fmole/8 x 10(6) cells, corresponding to approximately 527 binding sites/cell. There was a good correlation between AVP binding and cell number. AVP failed to dissociate completely from its binding sites in 60 minutes, perhaps because of the formation of a high-affinity ligand-binding site complex. From competitive binding studies with various AVP antagonists and analogues, it was found that the AVP binding site appeared to be V1-like. AVP binding occurred predominantly on B-cells and macrophages. Having provided evidence for the existence of specific, high affinity, and saturable V1-like AVP binding sites, we suggest a potential modulatory role for AVP in the communication between the neuroendocrine and immune systems.
Amino Acid Sequence↗
Pyrogenic doses of intracerebroventricular interleukin-1 did not induce analgesia in the rat hot-plate or cold-water tail-flick tests.
There are a few reports in the literature that cytokines can induce analgesia (5, 6, 18). The present study sought to characterize the analgesic effects of intracerebroventricularly (icv) administered interleukin-1 (IL-1) and interferon-alpha (IFN-alpha) in rats. In the cold-water tail-flick test (CWT), latency to tail withdrawal from a -3 degrees C liquid was timed; in the hot-plate test (HP), latency to a rear paw lick or a jump from a 55 degrees C surface was measured. In some experiments, core body temperature was also monitored with a rectal thermistor. In the CWT, human recombinant (hr) IFN-alpha induced a small, statistically significant effect at just one dose (15,000 U icv), but no dose of hr-IL-1 alpha (250-1000 U icv) or hr-IL-1 beta (125-2000 U icv) induced a significant effect at any time point. On the other hand, dose-related increases in body temperature were observed after icv injection of both IL-1 alpha and IL-1 beta. The largest hyperthermic effect was a 1.7 (+/- 0.15) degrees C rise 120 min after administration of 1000 U IL-1 beta. In a second analgesic assay, the HP, IL-1 beta was ineffective as well. Since IL-1 alone did not induce analgesia, we tested its capacity to potentiate morphine analgesia. Morphine (5.0 and 10 micrograms, icv) induced analgesia in the CWT (32.7 and 61.8% maximum analgesia, respectively); however, there was no significant effect of IL-1 beta on morphine-induced analgesia. In summary, we failed to find an analgesic effect of IL-1, alone or in combination with morphine, at doses which clearly had a physiological effect; this is in contrast to the reports cited above.
Analgesia↗
Patterns of hospital care for patients with HIV infection and AIDS.
OBJECTIVE: The aims were to describe the use of inpatient resources by patients with HIV infection and patients with AIDS; to examine trends in service use over time; and to provide data for planners concerned with service provision for HIV infection. SETTING: An inner London health district reporting 9% of AIDS cases nationally. DESIGN: Data on survival times and inpatient and day care use of resources were derived from existing patient records or collected prospectively between 1983 (when the first case of AIDS was diagnosed in the district) and 31 March 1990. SUBJECTS: A total of 488 HIV positive patients of whom 396 had been diagnosed as having AIDS were studied. MEASUREMENTS AND MAIN RESULTS: Inpatient days consumed per annum; trends in the number of bed days per person year with AIDS; the lifetime inpatient use per AIDS patient; and the influence of survival on service use estimates were determined. Altogether 16.4% of a total 17,785 hospital inpatient days were attributable to HIV positive patients who did not fulfil the criteria for AIDS. For patients with AIDS, there was an initial increase in the intensity of inpatient use in 1987 when a dedicated HIV ward was opened. After 1988, however, inpatient use fell to 30.8 bed days per person year with AIDS. Patients diagnosed after April 1987 had noticeably longer survival times than those diagnosed earlier (a median of 17-18 months compared with a median of 10-11 months). From 214 lifetime service use records, it was estimated that patients with short survival (less than six months) would consume 36 days of inpatient care, while those expected to survive longer would consume approximately twice that number of days, irrespective of how much longer they survived. CONCLUSIONS: The data indicate less intensive use of inpatient care by AIDS patients over time, and hence the apparent ability to manage an increasing AIDS patient workload without a comparable increase in occupied bed days. Increases in the size of that workload and changes in the survival profile of patients, together with a relatively constant rate of service demand by longer survivors, however, will continue to place increasing strains on finite inpatient resources. Further research is needed to establish the extent to which the greater use of outpatient and community services can offset this.
Acquired Immunodeficiency Syndrome↗