Fatal intoxications in Denmark following intake of morphine from opium poppies

Summary In Denmark it is legal to grow opium poppies for the production of poppy seeds and until 1986 for decoration purposes, too. Danish poppy capsules contain 0.3–5 mg morphine per capsule and the content of morphine in opium exuded from the capsules may amount to 24%. This has resulted in misuse as both fresh and dried poppy capsules have been used for the production of content/x3253h740tg5801p/xxlarge8220.gif" alt="ldquo" align="MIDDLE" BORDER="0">opium teacontent/x3253h740tg5801p/xxlarge8221.gif" alt="rdquo" align="MIDDLE" BORDER="0">. During the period 1982–1985, seven casualties occurred among drug addicts in Denmark which were solely or partly caused by these opium poppies.     

Decreased antibody-dependent cellular cytotoxicity in minimal change nephrotic syndrome

Secondary IgG response to a tetanus toxoid booster and in vitro measurement of immunoglobulin synthesis, antibody-dependent cellular cytotoxicity (ADCC) and content/r57q863578668741/xxlarge947.gif" alt="gamma" align="MIDDLE" BORDER="0">-interferon (IFN-content/r57q863578668741/xxlarge947.gif" alt="gamma" align="MIDDLE" BORDER="0">) production were evaluated in 20 healthy controls and in 17 children with minimal change nephrotic syndrome (MCNS), during the acute nephrotic phase and 6 months after remission. Defective responses were observed in all but IFN-content/r57q863578668741/xxlarge947.gif" alt="gamma" align="MIDDLE" BORDER="0"> production during the acute nephrotic phase; these improved with disease remission. There was a significant correlation between decreases in vitro IgG production and ADCC reaction. These data indicate that defective antibody production is associated with decreased ADCC during the acute nephrotic phase of MCNS.     

Only activated but not non-activated presynaptic α2-autoreceptors interfere with neighbouring presynaptic receptor mechanisms

Summary Experiments were carried out in rabbit cerebrocortical slices in order to find out whether the attenuation by presynaptic content/r2318063g024x323/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-autoreceptors of effects mediated by presynaptic opioid content/r2318063g024x323/xxlarge954.gif" alt="kappa" align="BASELINE" BORDER="0">- and adenosine A₁-receptors requires activation of the content/r2318063g024x323/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-receptors. The slices were preincubated with ³H-noradrenaline and then superfused with medium containing desipramine 1 content/r2318063g024x323/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l. They were stimulated electrically either with single pulses or with trains of 32 pulses at 1 Hz.The overflow of tritium elicited by a single pulse amounted to 0.21% of the tritium content of the tissue. It was Ca²⁺-dependent and tetrodotoxin-sensitive and not changed by rauwolscine 1 content/r2318063g024x323/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l or yohimbine 0.3 content/r2318063g024x323/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l. Ethylketocyclazocine (EK; 0.1–10 nmol/l) and R-(–)-N⁶-phenylisopropyladenosine (PIA; 1–1,000 nmol/1) potently inhibited the overflow evoked by a single pulse, and their effects were not changed by yohimbine. — The overflow of tritium elicited by trains of 32 pulses at 1 Hz amounted to 0.92% of the tritium content of the tissue and was increased approximately fourfold by yohimbine 0.3 content/r2318063g024x323/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l. EK and PIA were less potent inhibitors than in the one pulse experiments. Yohimbine greatly enhanced the effects of EK and PIA. The enhancement was even more pronounced when the Ca²⁺ concentration in the medium was reduced in order to obtain a control tritium overflow similar to that evoked by 32 pulses in the absence of yohimbine.The results demonstrate that there is no content/r2318063g024x323/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenergic autoinhibition when noradrenaline release is elicited by a single pulse. Under these conditions, the non-activated presynaptic content/r2318063g024x323/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptor does not interfere with presynaptic opioid content/r2318063g024x323/xxlarge954.gif" alt="kappa" align="BASELINE" BORDER="0">- and adenosine A₁-receptor mechanisms. It is only when the autoreceptor is activated by released noradrenaline that it attenuates neighbouring presynaptic receptor mechanisms, and this attenuation is removed by content/r2318063g024x323/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptor antagonists.Send offprint requests to N. Limberger at the above address     

Characteristics of β-endorphin-induced histamine release from rat serosal mast cells Comparison with neurotensin,dynorphin and compound 48/80

Summary Rat peritoneal mast cells were exposed to the neurohormone and basic opioid peptide content/n561712311808n24/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-endorphin. content/n561712311808n24/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-Endorphin induced a dose-dependent release of histamine from the mast cells. A significant histamine release was found at 5 content/n561712311808n24/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l of content/n561712311808n24/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-endorphin and maximal release (35% of total) at 20 content/n561712311808n24/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">mol/l. The histamine release process was very rapid and terminated within 30 s at 37°C, and in this sense is very similar to the histamine release induced by compound 48/80 or neurotensin. The histamine release was temperature-dependent showing an optimum release around 30°C, and it was independent of available extracellular calcium, but was inhibited in the presence of high extracellular calcium concentrations. Naloxone, only in very high concentrations (10 mmol/l), inhibited the release, and the very same concentration also inhibited the neurotensin — as well as the compound 48/80-induced histamine release. Cromoglycate and benzalkoniumchloride, a 48/80 antagonist, both produced a progressive dose-dependent inhibition of content/n561712311808n24/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-endorphin-, neurotensin- as well as compound 48/80-induced histamine release. Taken together, the findings indicate that the opioid peptide content/n561712311808n24/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-endorphin induces a selective, energy-dependent release of histamine from peritoneal rat mast cells. The pattern of release has much in common with that of compound 48/80 and other basic peptides, such as neurotensin and substance P. In addition this pattern of release is similar to that induced by dynorphin. Send offprint requests to Anita Sydbom at the above address     

The pharmacokinetics of doxifluridine and 5-fluorouracil after single intravenous infusions of doxifluridine to patients with colorectal cancer

Summary The disposition kinetics of a new 5-fluorouracil prodrug, 5content/k246108623462064/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-deoxy-5-fluorouridine (5content/k246108623462064/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">dFUR, doxifluridine), were investigated in six patients with colorectal carcinoma. Each patient randomly received two single intravenous doses of 5content/k246108623462064/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">dFUR (2 and 4 g · m^–2) on separate days.Plasma concentrations of 5content/k246108623462064/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">dFUR fell rapidly with terminal half-lives ranging from 16.1 to 27.7 min. A disproportionate increase in the area under the curve with increasing dose was seen in most patients. Doubling the dose resulted in a 40% decrease in nonrenal clearance (0.60 to 0.37 l · min^–1) but no apparent change in renal clearance (0.32 to 0.29 l · min^–1) or steady-state apparent volume of distribution (19.8 to 20.4 l).The mechanism for dose-dependence of 5content/k246108623462064/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">dFUR appears to be primarily due to nonlinear elimination associated with nonrenal processes rather than nonlinear plasma protein or tissue binding.     

Lymphocyte β-adrenergic receptor binding in panic disorder

Lymphocyte beta adrenergic receptor binding using [¹²⁵I]CNP was determined in patients with panic disorder (N=4) or agoraphobia with panic attacks (N=17) and age- and sex-matched healthy subjects (N=22). The patients showed a significantly lower number of content/wu4260l3781wn4j4/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenergic receptor binding sites and a significantly higher affinity of binding than healthy subjects. A past or present history of major depression in the patients did not alter these findings. These results are consistent with a growing body of knowledge implicating noradrenergic dysfunction in the pathophysiology of panic anxiety.     

Synthesis,Physicochemical Properties,and Cytotoxicity of a Series of 5′-Ester Prodrugs of 5-Iodo-2′-deoxyuridine

Five aliphatic 5content/l6444461378u1m1u/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-esters of 5-iodo-2content/l6444461378u1m1u/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">deoxyuridine (IDU) were synthesized via an acid chloride alcoholysis reaction. The solubility in pH 7.4 phosphate buffer, lipophilicity as determined by partition experiments in octanol/pH 7.4 buffer, and cytotoxicity of these potential prodrugs were evaluated. The esters showed a 43- to 250-fold increase in lipophilicity and a 1.6- to 14-fold decrease in aqueous solubility relative to IDU. At a concentration of 50 µM, all esters showed reduced cytotoxicity toward uninfected Vero cells relative to IDU.     

A Biotin–Avidin-Based Enzyme Immunoassay for βh-Endorphin

An avidin–biotin enzyme-linked immunosorbent assay (ELISA) is described for content/h1v517777n768x1l/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">_h-endorphin (content/h1v517777n768x1l/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">_h-EP). Microtiter plates coated with commercially available antibodies were used together with content/h1v517777n768x1l/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">_h-EP tracer derivatives that were biotinylated in positions 24, 28, and 29 via a C₆ spacer arm. Nonspecific binding of biotinylated derivatives to the microtiter plates was blocked with a mixture of 1% casein and 10% ethanolamine in 0.1 M NaHCO₃. A sequential saturation procedure using a high-affinity antiserum in combination with an avidin–alkaline phosphatase complex matched the sensitivity of reported radioimmunoassays (RIAs), with a detection limit of 0.5 fmol/assay. The intra- and interassay coefficients of variation were 5 and 12%, respectively. Results obtained by ELISA and RIA showed good correlations (r = 0.95). The content/h1v517777n768x1l/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-EP concentration in extracted rat plasma after high-performance liquid chromatographic (HPLC) fractionation was determined by this method to be 1600 fmol/ml.     

Cotinine determination by immunoassays may be influenced by other nicotine metabolites

Polyclonal rabbit anticotinine antiserum, which can be used for biomonitoring nicotine uptake by the determination of cotinine in body fluids, was checked by a competitive ELISA for its cross-reactivity with nine nicotine metabolites. The highest percentage of relative crossreactivity (about 30%) was observed with trans-3content/w1202211463l54w5/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-hydroxycotinine, a metabolite which is known to be excreted in 3-fold higher amounts than cotinine in the urine of human smokers. Therefore, it is possible that cotinine determinations performed by immunochemical methods — especially in urine — may yield overestimated cotinine concentrations.     

Induction of light hydrocarbon nephropathy by p-dichlorobenzene

In order to clarify the etiology of a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats, the nephrotoxicity of p-dichlorobenzene (p-DCB) was investigated in a subchronic study. Groups of ten male and ten female Fischer 344 rats were dosed by gavage with 0 (controls), 75, 150, 300 or 600 mg p-DCB/kg/day in corn oil. Half of the animals were sacrificed after 4 weeks and the remainder after 13 weeks. Increased urinary LDH and epithelial cell excretion and exacerbation of hyaline droplet accumulation in the cytoplasm of renal cortical cells were observed in male rats over the entire dose range investigated. Tubular single cell necrosis, dilated tubules with granular cast formation in the outer zone of the medulla, were evident in male rats after 4 and 13 weeks of treatment with doses of 150–600 mg/kg/day. In female rats there was no indication of a nephrotoxic action of p-DCB. The effects on the kidney, both in their morphological characteristics and the fact that they occur exclusively in male animals, correspond to the light hydrocarbon nephropathy observed as a result of short-term treatment with a number of aliphatic and cyclic hydrocarbons. The development of cortical renal tumors seems to be associated with this kind of kidney damage which is unique to male rats. The literature on this subject generally regards these renal effects as not predictive for man.