Search

The peptide CO-NH function was replaced by a trans carbon-carbon double bond or by a CH2-CH2 isostere in enkephalin analogues of DADLE, DCDCE-NH2 or DPDPE. In DADLE the 2-3 and the 3-4 peptide bond was modified, whereas in the cyclic analogues the Gly3-Phe4 bond was replaced by the isosteres Gly psi (E,CH = CH)Phe [5-amino-2-(phenylmethyl)-3(E)-pentenoic acid] or Gly psi (CH2CH2)Phe [5-amino-2-(phenylmethyl)pentanoic acid]. In general, the modification results in a drop in potency which is the largest for the flexible CH2-CH2 replacement. The Gly3 psi (E,CH = CH)Phe4 DCDCE-NH2 analogue retains considerable potency. These results confirm the importance of the peptide function at the 2-3 and 3-4 position in enkephalin analogues for biological potency.

Summary: Purpose: We compared propofol with high-dose barbiturates in the treatment of refractory status epilepticus (RSE) and propose a protocol for the administration of propofol in RSE in adults, correlating propofol's effect with plasma levels. Methods: Sixteen patients with RSE were included; 8 were treated primarily with high-dose barbiturates and 8 were treated primarily with propofol. Results: Both groups of patients had multiple medical problems and a subsequent high mortality. A smaller but not statistically significant fraction of patients had their seizures controlled with propofol (63%) than with high-dose barbiturate therapy (82%). The time from initiation of high-dose barbiturate therapy to attainment of control of RSE was longer (123 min) than the time to attainment of seizure control in the group receiving propofol (2.6 min, p = 0.002). Plasma concentrations of propofol associated with control of SE were 14 μM ± 4 (2.5 μg/ml). Recurrent seizures were common when propofol infusions were suddenly discontinued but not when the infusions were gradually tapered. Conclusions: If used appropriately, propofol infusions can effectively and quickly terminate many but not all episodes of RSE. Propofol is a promising agent for use in treating RSE, but more studies are required to determine its true value in comparison with other agents.

beta-Adrenergic antagonism decreases the size of myocardial infarction and provides myocardial protection during hypothermic arrest for cardiac surgery. However, concern regarding the negative inotropic and chronotropic effects of beta-adrenergic antagonism persisting after cardiopulmonary bypass (CPB) has impeded the use of esmolol for this purpose during cardiac surgery. This is a randomized, double-blind prospective study of the effects of esmolol infused during CPB and the effects of hypothermic CPB on esmolol. Patients scheduled for CPB were randomized to receive intravenous esmolol (300.micrograms.kg-1.min-1 during CPB after a bolus of 2 mg/kg prior to CPB) or placebo. Infusion was stopped at 10 min after release of aortic cross-clamp. Hemodynamics were measured, as well as serum esmolol, catecholamines, lactate, and potassium. Postoperative variables measured included electrocardiographic changes, creatine kinase (CK)-MB fractions, post-CPB dysrhythmias and drugs, hospitalization time and cost, and mortality. Esmolol was administered to 16 patients and placebo to 14. Esmolol levels reached a high of 10.5 +/- 0.9 micrograms/mL during CPB, but decreased to 0.1 +/- 0.02 microgram/mL within 30 min after stopping infusion. Cardiac indices (cardiac index, stroke volume index, left cardiac work index, left ventricular stroke work index, right cardiac work index, and right ventricular stroke work index) were higher in the esmolol group for the first hour post-CPB (P < 0.05). Systemic arterial lactate and coronary sinus lactate were lower in the esmolol group after CPB (P < 0.05), but myocardial lactate extraction was not significantly different between groups. After CPB, hemoglobin was lower in the esmolol group (P < 0.05) due to longer CPB and aortic cross-clamp time (P < 0.05), but oxygen consumption was less than in the control group (P < 0.05). Post-CPB serum potassium was higher in the esmolol group (P < 0.05). Results are confounded by more chronically beta-adrenergically blocked patients randomized to the esmolol group (P < 0.05). Esmolol infused during CPB in this series of patients was associated with high concentrations during CPB but did not result in any adverse clinical effects after CPB.

This study tested the hypothesis that compounds which may bind simultaneously to delta and mu receptors may be more potent antinociceptive agents than would be predicted from their binding affinities at individual mu and delta opioid receptors. D-Tca-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 ([D-Tca1]CTAP) (where D-Tca is a cyclic D-tryptophan analogue) was synthesized and evaluated in radioligand competition assays, opioid bioassays, and in an antinociceptive assay (the tail-flick test in mice). Additionally, the metabolic stability of [D-Tca1]CTAP was evaluated in striatal and cerebellar tissue slices. In rat brain in vitro, [D-Tca1]CTAP competed weakly for sites labelled by [3H]D-Phe-Cys-Tyr-D-Trp-Om-Thr-Pen-Thr-NH2 ([3H]CTOP) (mu-ligand), and [3H][D-Pen2,pCl-Phe4,D-Pen5]enkephalin (delta-ligand); [D-Pen2,D-Pen5]enkephalin (DPDPE) (delta-agonist) was 6.5-fold less and 230-fold more potent, respectively, against these ligands. Additionally, in mouse isolated vas deferens and guinea pig isolated ileum smooth muscle preparations, [D-Tca1]CTAP proved to be weak as either a delta (IC50 of approximately 2 microM) or mu (IC508 microM) receptor agonist. Surprisingly, however, i.c.v. [D-Tca1]CTAP produced antinociception with potency similar to DPDPE. The antinociceptive actions of [D-Tca1]CTAP were apparently not due to a metabolite or the release of endogenous opioids, as this compound proved stable in both striatal and cerebellar tissue slices and its antinociceptive actions were not enhanced by the 'enkephalinase' inhibitor thiorphan. The suggestion that [D-Tca1]CTAP might be acting by binding simultaneously to mu and delta receptors to produce its antinociceptive effect is supported by the demonstrated antagonism resulting from mu receptor blockade with either beta-funaltrexamine (beta-FNA) or naloxonazine, or by delta receptor blockade by ICI 174,864 ([N,N-diallyl-Tyr1,Aib2,3,Leu5] enkephalin). Furthermore, the antinociceptive properties of [D-Tca1]CTAP were antagonized by (naltrindole-5'-isothiocyanate) (5'-NTII), an antagonist at the delta 2 opioid receptor subtype, but not by the delta 1 antagonist [D-Ala2,D-Leu5,Cys6]enkephalin (DALCE). Additionally, no antagonism was produced by nor-binaltorphimine (nor-BNI), a kappa antagonist. From these data, [D-Tca1]CTAP appears to bind to mu, and 5'-NTII-sensitive delta 2, opioid receptors, and may represent the first of a class of compounds which may act at an opioid receptor complex via 'self-potentiation'.

An exploratory needs assessment for AIDS education and prevention was conducted at a traumatic brain injury (TBI) rehabilitation facility among 29 clients that also experience coexisting substance abuse disorders. The results suggest that the surveyed clients possessed a moderate level of information about AIDS. Their knowledge level was variable with a major source of misinformation surrounding the use of condoms. The sample members' knowledge was not related to the type or severity of substance abuse, nor was it associated with safer sexual practices. The present results are compared to earlier findings that used an identical survey with a dual disordered population of psychiatrically impaired substance abusers. The results should help in developing an AIDS education and prevention programme for clients with the dual diagnosis of TBI and substance abuse. Clients need up-to-date information that can be comprehended and used. Education will need to be coupled with approaches that present both behavioural and attitudinal change strategies that are best suited to these clients.

A sample of 206 drug users volunteered for a survey questionnaire of AIDS-related risk behaviors. The Risk Behavior Inventory (RBI) was used to elicit self-report information on risk behaviors including drug use, needle use, and sexual practices. Non-IV cocaine users reported less risk behaviors than patients involved in IV drug use. Nevertheless, non-IV users remained substantially at risk for HIV exposure because of sexual practices and sexual interaction with IV drug users. Multiple regression analysis indicated that method of drug administration (IV vs non-IV) was the major contributor of accountable variance in risk behaviors, while other patient variables, such as age, gender, educational level, employment, and marital status, did not contribute significantly to the explained variance.

Ninety-two substance abusers were surveyed about AIDS-related risk behaviors. The questionnaire administered elicited information on demographics, sexual practices, substance abuse, and risk behaviors involving the use of needles. Results indicated an appropriate base of prevention knowledge and patients' efforts to modify vulnerability to HIV exposure. Nevertheless, patients continue to engage in behaviors resulting in HIV exposure and transmission.

A new cyclic opioid peptide of sequence Tyr-D-Pen-Gly-Phe-Cys-Phe (HBP2) was examined in the mouse isolated vas deferens (MVD) bioassay. Studies with receptor-selective opioid antagonists showed the peptide to be highly selective for delta opioid receptors. HBP2 and the standard delta agonist DPDPE were simultaneously compared using the technique of partial irreversible receptor blockade; data were analyzed using the operational model of pharmacologic agonism. HBP2 was approximately 160 times as potent as DPDPE; estimation of the affinity and efficacy of the two peptides revealed that the potency increase was due to a 5.3-fold increase in efficacy, as well as a 37-fold increase affinity. This contrasts with our previous findings with other cyclic enkephalin analogs, in which increased affinity was achieved without a change in apparent efficacy. Analysis of concentration-response curve shape suggested in addition the possibility of heterogeneity in transduction mechanisms for MVD delta receptors.

The conformationally restricted, cyclic disulfide-containing delta opioid receptor selective enkephalin analogue [D-Pen2,D-Pen5] enkephalin (DPDPE) was modified by 2' (CH3) and 3' (I, OCH3, NO2, NH2) ring substitutions and by beta-methyl conformationally constrained beta-methyltyrosine derivatives in the 1 position. The potency and selectivity of these analogues were evaluated by bioassay in the mouse vas deference (MVD, delta receptor assay) and guinea pig ileum (GPI, mu receptor assay) assays and by radioreceptor binding assays in the rat brain using [3H]CTOP (mu ligand) and [3H][p-ClPhe4]DPDPE (delta ligand). The analogues showed highly variable potencies in the binding assays and in the bioassays. Aromatic ring substituents with positive Hammett constants had decreased potency, while substituents with negative Hammett constraints has increased potency for the opioid receptor. The most potent and most selective compound based on the binding was [2'-MeTyr1]DPDPE (IC50 = 0.89 nM and selectivity ratio 1310 in the binding assays). The 6-hydroxy-2-aminotetralin-2-carboxylic acid-containing analogue, [Hat1]DPDPE, also was highly potent and selective in both assays, demonstrating that significant modifications of tyrosine in enkephalins are possible with maintenance of high potency and delta opioid receptor selectivity. Of the beta-methyl-substituted Tyr1 analogues, [(2S,3R)-beta-MeTyr1]DPDPE was the most potent and the delta receptor selective. The results with substitution of beta-MeTyr or Hat instead of Tyr also demonstrate that topographical modification in a conformationally restricted ligand can significantly modulate both potency and receptor selectivity of peptide ligands that have multiple sites of biological activity.

Norepinephrine (NE) and ATP are thought to be neurotransmitters involved with contractions of the mouse vas deferens (MVD) in vitro. The EC50 values of exogenously administered NE and ATP were 5.16 +/- 1.37 and 315.32 +/- 221.18 microM, respectively. Contractions of MVD induced by electrical field stimulation were blocked by alpha,beta-methylene adenosine-5'-triphosphate (purinergic desensitizer) and not by prazosin (alpha 1-adrenoceptor antagonist), suggesting that ATP is the predominant transmitter in this preparation. However, because the EC50 value for ATP was over 100-fold greater than that for NE, we performed isobolographic analysis comparing NE and ATP actions separately and together. Our results demonstrated a synergistic interaction of ATP and NE. At all ratios of ATP:NE examined, exogenous NE enhanced contractile responses to ATP. These data indicate that the co-transmitters, NE and ATP, in the MVD interact postjunctionally in a synergistic manner.

Peptide E is a μ-selective opioid peptide derived from proenkephalin A which contains [Met 5 ]-enkephalin at the amino end and [Leu 5 ]-enkephalin at the carboxyl end. Peptide E is further processed both centrally and peripherally to a [Leu 5 ]-enkephalincontaining fragment which was investigated to determine if processing leads to alterations in receptor selectivity. Peptide E-(15–25) inhibited electrically stimulated contractions in both the mouse vas deferens, longitudinal muscle, myenteric (IC 50 = 459 nmol/ L), and guinea pig ileum (IC 50 = 2630 nmol/L), indicating a sixfold δ-receptor selectivity. When administered intracerebroventricularly to mice, peptide E-(15–25) also produced potent analgesia which was completely antagonized by naloxone pretreatment, but the peptide had no effect on intestinal transit as measured by the radiochromium geometric center method. This is consistent with earlier findings that intracerebroventricular δ-opioid-selective agents are analgesic but do not inhibit intestinal transit. In vitro radioligand binding assays were performed using male Sprague-Dawley rat whole brain homogenates. The IC 50 for peptide E against [ 3 H]naloxone was 1.8 nmol/L compared with the δ-opioid ligand, [ 3 H] [d-Pen 2 , d-Pen 5 ]-enkephalin of 38.8 nmol/L. The IC 50 for peptide E-(15–25) against [ 3 H]naloxone was 497 nmol/L, but for [ 3 H] [d-Pen 2 , d-Pen 5 ]-enkephalin it was 50.6 nmol/L. Therefore, peptide E loses μ-opioid receptor affinity (1.8–497 nmol/L) after proteolytic processing and the loss of the amino terminal tyrosine but maintains a high δ-opioid affinity (38.8–50.6 nmol/L). These studies demonstrate that enzymatic peptide processing of peptide E to peptide E-(15–25) leads to a shift from μ to δ-receptor selectivity and a different spectrum of biological effects on gut motility.

Several peptides of diverse structure, reported to possess high affinity and selectivity for the delta opioid receptor, were studied using the mouse isolated vas deferens preparation to determine the effect of peptidase inhibition on their apparent potency. The peptides evaluated included [Leu5] enkephalin, the cyclic enkephalin analogs [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Pen2,p-F-Phe4,D-Pen5]enkephalin (F-DPDPE), the linear enkephalin analogs [D-Ala2,D-Leu5]enkephalin (DADLE) and [D-Ser2(O-tBu), Leu5,Thr6]enkephalin (DSTBULET), and the naturally occurring amphibian peptides Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 (dermenkephalin), Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 (deltorphin I) and Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 (deltorphin II). Concentration-response curves were determined for each peptide in the absence and presence of a combination of the peptidase-inhibiting agents bacitracin, bestatin, and captopril. A wide range of potencies was observed, both in the control state and in the presence of peptidase inhibition. The synthetic enkephalin analogs demonstrated small increases in potency with peptidase inhibition (no increase in the case of DPDPE), whereas the naturally occurring peptides were markedly increased in potency, up to as much as 123-fold for dermenkephalin. In the presence of peptidase inhibition, deltorphin II was the most potent peptide tested (IC50 = 1.13 x 10(-10) molar), and as such is the most potent delta opioid agonist reported to date. Stability to metabolism must be considered in the design and evaluation of in vitro experiments using peptides of this type.

The need for behavioral change of risky sexual practices has been of the highest priority since the onset of the AIDS epidemic. The major focus of education for safe sex has been emphasis on condom use. We surveyed 124 individuals applying to treatment for various chemical dependencies and 60 individuals applying for non-chemical-dependency medical treatment on various aspects of condom knowledge, history of use, and attitudes. Respondents reported that AIDS has motivated them to increase their use of condoms, however, only 13.9% always use them. Education is needed in the areas of increasing protection. Along with the use of a condom, the need for a reservoir tip and the risks associated with multiple sex partners should be stressed.This report contains the findings of a survey designed to investigate the knowledge of condoms, history of use, and attitudes among chemically attitudes among chemically addicted populations. The study took place in the Division of Alcohol and Drug Dependence of the SUNY Health Science Center at Brooklyn, Department of Psychiatry, Kings Country Addictive Disease Hospitals. Researchers interviewed 124 individuals seeking treatment for chemical dependency, as well as 60 individuals applying for non-chemical dependency treatment to serve as controls. 25% of those interviewed reported intravenous injection as their primary route of drug administration, 25% reported smoking crack of sniffing cocaine, 17.4% cited alcohol abuse. The remaining 32.6% made up the control group. In a few instances, drug users scored better than the controls on condom knowledge, but overall, the survey found no significant differences in the level of knowledge about AIDS and condoms use among the drug, alcohol, and control groups. As expected, the survey found that those individuals who have a history of condom use scored higher on the knowledge quiz than those with less experience. Very few individuals in any of the groups mentioned monogamy as a strategy for risk reduction, or mentioned multiple sex partners as high-risk activity. While sensitivity and embarrassment did not play a significant role in condom use frequency, 26.1% of those interviewed agreed with the statement "If my partner doesn't mention using a condom neither will I." 32% of males and 57.1% of females reported having has a sex partner refuse to use a condom. These findings, the report explains, suggest the need to address sexually risky behavior within the chemically addicted populations.

We have designed and synthesized several cyclic disulfide-containing peptide analogues of dynorphin A (Dyn A) which are conformationally constrained in the putative "address" segment of the opioid ligand. Several of these Dyn A analogues exhibit unexpected selectivities for the kappa and mu opioid receptors(s) of the central vs peripheral nervous systems. Thus, incorporation of conformational constraint in the putative "address" segment of Dyn A analogues has resulted in the kappa/mu opioid receptor ligands [Cys5,Cys11]Dyn A1-11-NH2 (1) and [Cys5,Cys11,D-Ala8]Dyn A1-11-NH2 (2), which possess high kappa and mu opioid receptor affinities centrally (guinea pig brain, GPB), but only weak activity at peripheral kappa and mu opioid receptors (guinea pig ileum, GPI). On the other hand, [Cys8,Cys13]Dyn A1-13-NH2 and [D-Cys8,D-Cys13]Dyn A1-13-NH2 (5) display high kappa potencies and selectivities at the peripheral (GPI) but not at the central (GPB) kappa opioid receptor. The lack of correlation between the pharmacological profiles observed in smooth muscle and in the brain binding assays suggests the existence of different subtypes of the kappa and mu opioid receptors in the brain and peripheral nervous systems.

This study examined the six-month and one-year treatment statuses of 118 patients admitted to an abstinence-oriented, outpatient facility serving dually diordered adults. Findings revealed that persons who have been underserved by the mental health and substance abuse fields can be engaged in treatment and will respond favorably to it. Overall, demographic characteristics, admission diagnoses, and past treatment history did not predict treatment outcomes. Rather, patients who participated more fully in treatment had better recoveries than did those who did not engage in treatment. In addition, patients who complied and responded to treatment during their first six months in treatment were more likely to comply and respond to treatment during the second six months of treatment. These results should encourage other clinicians to develop innovative services that meet the needs of dually disordered adults.

The conformationally restricted, cyclic disulfide-containing enkephalin analogue [D-Pen2,D-Pen5]enkephalin (DPDPE) was modified by halogenation (F, Cl, Br, I) of the phenylalanine-4 residue in the para position. The potency and selectivity of these analogues for the delta opioid receptor was greater than that of the parent peptide. The analogues possessed greater potency and affinity for the delta receptors than DPDPE in the mouse vas deferens assay and in radioreceptor assays (against [3H]DPDPE), respectively. [p-ClPhe4]DPDPE was the most selective in the radioligand binding assays (IC50(mu)/IC50(delta) = 574), being about 5-fold more delta opioid receptor selective than DPDPE in this assay, whereas [p-IPhe4]DPDPE was the most selective in the classical bioassay systems using the mouse vas deferens and guinea pig ileum assays (IC50(GPI)/IC50(MVD) = 17,374), making it nearly 9-fold more selective than DPDPE in direct comparisons using the same assay conditions.

Verapamil clearance is reduced during halothane administration. This study evaluated relative contributions of reduced hepatic flow rate and hepatic metabolizing enzyme inhibition by halothane as a cause of reduced verapamil clearance. An isolated perfused rat liver model was utilized in which flow rate could be fixed during halothane administration. Perfusions were performed on five to six livers under each of the following conditions: (a) control--40 mL/min flow rate with no anesthetic exposure; (b) 1.5% halothane--40 mL/min; (c) 2.25% halothane--40 mL/min; (d) reduced flow--20 mL/min with no anesthetic exposure; and (e) reduced flow with 1.5% halothane--20 mL/min. Halothane caused dose-dependent decreases in both total hepatic and intrinsic clearance rates (P less than 0.05). With no anesthetic exposure, a flow reduction of 50% (20 mL/min) also gave a large reduction (P less than 0.05) in hepatic clearance of verapamil compared with the control condition (40 mL/min). The addition of 1.5% halothane to the reduced flow condition was not associated with further reduction in hepatic clearance rate. Results of this study suggest that although both reduced hepatic perfusion and hepatic enzymatic inhibition by halothane administration are associated with decreased verapamil clearance, a greater proportion of this decrease appears to be due to reductions in hepatic flow. The present results may apply to other drugs used in anesthesia that have high hepatic extraction ratios; thus, clearance of these drugs may be more dependent on hepatic blood flow than on hepatic enzyme activity.

The Defense Mechanism Inventory (DMI) and The Risk Behavior Inventory (RBI) were administered to substance abusers hospitalized on a drug detoxification service. The groups were categorized on the basis of self-reported IV versus non-IV substance abuse. Significant between- group differences were obtained on the DMI and RBI. The non-IV group responded less often than the IV group with the Turning Against Object (TAO) response option, resulting in higher scores when Turning Against Self (TAS), Reversal (REV), Principalization (PRN) and Projection (PRO) were summed into a single score. Significant within-group differences were obtained for DMI response levels and defenses. Both groups relied less on TAO at the thought level and more on PRN and REV as primary defenses. The IV group reported twice as many risk behaviors as the non-IV group and risked HIV exposure through needle use and sexual transmission modes. Consideration was given to the role of principalization and denial within the addicted individual's defense structure and the relationship of these defenses to HIV-related risk behavior.

A new transdermal drug-delivery system that administers the synthetic opioid fentanyl through intact skin was evaluated for 24 hours postoperatively in eight patients who had undergone orthopedic surgery. Plasma samples were obtained over a 72-hour period for pharmacokinetic analysis in five patients. The patients were also evaluated intensively for adequacy of analgesia, frequency of nausea and sedation, and occurrence of ventilatory depression. A median lag time of 2.25 hours after application of the transdermal system was observed before the appearance of fentanyl in the blood. Median peak concentration and time to peak were 1.0 ng/ml and 22 hours, respectively. The apparent elimination of fentanyl after transdermal administration is prolonged relative to previously reported values. Absorption analysis indicates zero-order fentanyl administration, and in addition, suggests deposition of drug in an epidermal site, with the resultant prolonged absorption process giving the appearance of slow elimination. No significant toxicities were observed. Four patients required no additional analgesia. No consistent correlations among fentanyl concentration and any clinical values were observed. Transdermal administration of fentanyl appears to be a viable alternative to conventional routes of narcotic administration and warrants further study.

A nonreactive, observational research method was used to measure AIDS information-seeking behavior of patients on four drug and alcohol inpatient units at a large public hospital in New York City. Results showed only 23 inquiries from 271 male and female patients over a six-week interval. Possible explanations and implications of these results are discussed.