Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions

Recent surveys suggest that the abuse of drugs, often in combination, is pervasive throughout society. Adverse consequences of drug abuse tend to be attributed to the single drug "most likely" to be responsible. This is frequently seen in fatality cases, particularly those involving opioids. However, it is difficult to determine the specific cause of death when multiple drugs are involved. Although enhanced toxicity of alcohol and other centrally acting drugs with opioids has been well established in animal studies, there is a paucity of data in well-controlled human studies. We evaluated 1014 fatality cases involving oxycodone (OXC) for evidence of enhanced toxicity associated with multiple drug-drug interactions. We previously reported on these cases, and we classified them by a standardized method into groups that distinguished cases unrelated to drug abuse from those related to drug abuse, cases that involved only OXC from cases involving multiple drugs, drug-induced fatalities from drug-related fatalities, and cases in which the specific drug product OxyContin (oxycodone HCl controlled-release) Tablets were identified from cases where OxyContin was not identified. Our working hypothesis was that OXC in combination with other centrally acting drugs is more toxic than OXC alone, evidenced by the finding of lower mean blood concentrations of OXC in multiple-drug-induced deaths compared to single (OXC only)-drug-induced deaths. Assessment of blood levels determined by specific assay methodology (primarily gas chromatography-mass spectrometry) in these cases provided the following mean postmortem concentrations of OXC: multiple-drug-induced deaths, OxyContin identified, 0.93 microg/mL (N = 167); multiple-drug-induced deaths, OxyContin not identified, 0.73 microg/mL (N = 579); single (OXC)-drug-induced deaths, OxyContin identified, 1.55 microg/mL (N = 12); and single (OXC)-drug-induced deaths, OxyContin not identified, 1.70 microg/mL (N = 15). Overall, mean OXC concentration trends were as follows: single (OXC)-drug-induced, drug-abuse deaths > multiple-drug-induced drug-abuse deaths > drug-related drug-abuse deaths approximately deaths unrelated to drug abuse; and deaths in which OxyContin was identified approximately deaths in which OxyContin was not identified, whether the deaths involved oxycodone alone or multiple drugs. Drug abuse patterns in the multiple-drug-induced cases were complex. Over 135 drugs that were considered to be plausibly contributory to enhanced toxicity were identified in body fluids and tissues. Evaluation of mean OXC blood concentrations in cases that contained one, two, three, four, five, and six or more contributory drugs in combination demonstrated consistently lower mean OXC concentrations than those cases in which OXC was the only drug identified. A smaller number of cases were evaluated in the multiple-drug-induced groups in which OXC was paired with a single other contributory drug. The overall mean OXC concentration for these cases was 0.71 microg/mL (N = 90) as compared to 1.64 microg/mL (N = 27) for the cases in the single drug-induced groups. The consistent finding of lower mean OXC blood levels associated with multiple-drug-induced fatalities supports the stated hypothesis that OXC in combination with other centrally active drugs is more toxic than when OXC was the only drug involved. It was concluded that in cases of multiple-drug fatalities, cause of death (COD) should not be attributed to any single drug. Rather, the unique combination of drugs, the pattern of drug use/abuse, and individual factors, such as tolerance to the respiratory depressant effects of opioids, must be taken into account in arriving at a valid COD statement.     

Characterization of a lysosomal serine carboxypeptidase from Trypanosoma cruzi

Trypanosoma cruzi, the flagellate protozoan which is the causative agent of the American trypanosomiasis, Chagas disease has carboxypeptidase activity. The enzyme has been purified to protein homogeneity, and shown to be a lysosomal monomeric glycoprotein with a molecular mass of about 54kDa. The enzyme has an optimum acidic pH (4.5 with furyl acryloyl-Phe-Phe as substrate), is highly specific for hydrophobic C-terminal amino acid residues, and is strongly inhibited by 3,4-dichloroisocoumarin (IC(50) value 0.3 microM). The enzyme is encoded by a number of genes arrayed in head-to-tail tandems; one of these genes has been cloned and sequenced. Sequence comparisons indicate that the enzyme belongs to the C group of serine carboxypeptidases, within the S10 serine peptidase family, and shows the higher similarity to plant and yeast enzymes. The residues involved in catalysis and most of those involved in substrate binding are conserved in the T. cruzi enzyme as well as 8 out of 10 Cys residues known to be involved in disulfide bridges in the yeast enzyme. This is the first report of an S10 family enzyme in trypanosomatids. The presence of serine carboxypeptidases is not restricted to T. cruzi, being possibly a general character of trypanosomatids.     

Changes in brain serotonin turnover,body and head shakes in kainic acid-treated rats

Kainic acid induces seizures and neurotoxicity in rats, produces changes in brain serotonin (5-HT), dopamine and noradrenaline metabolites among other changes in neurotransmitters. In this work, we investigated the changes in 5-HT turnover in brain regions from 84 rats intraperitoneally injected with kainic acid and a specific behavioural change, the body and head shakes, exerted by this neurotoxin in the presence of 5-HT receptor antagonists. Kainic acid produced an increase in 5-hydroxyindoleacetic acid levels in frontal cortex (212%; 180%), striatum (177%; 116%), amygdala (202%; 337%) and hippocampus (43%; 70 %) at 2 and 24 hr as compared with controls, respectively. Serotonin turnover was increased in amygdala (157%) and frontal cortex (169%) at 2 hr; whereas 24 hr after kainic acid administration, increases were observed in amygdala (207%), and frontal cortex (178%). Kainic acid also produced an increase in the frequency of head and body shakes when administered alone or together with pargyline, a monoamine oxidase inhibitor; whereas the administration of 5-HT receptor antagonists such as ketanserin and methiothepin, decreased this behaviour 54% and 50% as compared with kainic acid alone, respectively. These results suggest an active participation of 5-HT neurotransmission on the excitotoxic action of kainic acid in the brain.     

Early primary immune response against erythrocytes: a case report

BACKGROUND: Primary immune response against red blood cell (RBC) antigens often takes weeks or months to be detected. In previous reports, for children receiving multiple units of blood components, ranging from five to 81 units, the elapsed time between the first RBC transfusion and antibody detection ranged from 18 to 78 days. Cytomegalovirus (CMV) is sometimes associated with immunohaematologic findings and may modulate immune response. CASE REPORT: A 24-week-old male infant with interstitial pneumonia and hepatitis because of CMV developed an RBC auto antibody and two RBC alloantibodies: anti-Jka, detected in tube 11 days after a single RBC transfusion, and anti-K, detected only in papain gel test 18 days later. CONCLUSION: As anti-Jka is not a naturally occurring antibody, this is the most rapid primary immune response against an RBC antigen after a single RBC transfusion ever described, in the youngest child ever described.     

Auditory function in guinea pigs treated with netilmicin and other aminoglycoside antibiotics

Summary The following aminoglycoside antibiotics netilmicin, sisomicin, gentamicin, and kanamycin were submitted to a comparative study of their ototoxicity using both reflexological (Preyer's pinnareflex) and electrophysiological (near and far field) methods. The daily s.c. administration of sisomicin, gentamicin, and kanamycin for 21 days provoked a dose-related impairment of the cochlear function, detected with all the employed techniques. On the other hand, a very low ototoxic effect of netilmicin was demonstrated with electrophysiological but not with the reflexological evaluation.The reliability of the methods used in these experiments is also compared.     

Leisure-time physical activity and secondary conditions in women with physical disabilities

Purpose:?To examine the relationship between secondary conditions and leisure-time physical activity participation (LTPA) in women with physical disabilities.

Method:?A survey was conducted in a metropolitan urban USA area of women (n?=?170) with physical disabilities including MS, CP, polio, arthritis, TBI, and CVA among others and aged 21?–?65 years. Outcome measures were LTPA, secondary conditions (numbers and severity), and functional status.

Results:?Respondents experienced 11.99 (?±?6.05) secondary conditions in the past year, self-rated their severity as ‘moderate problems’, and reported moderate levels of functional impairment. LTPA participation (excluding calisthenics/exercise) was reported to be 2.90 (?±?5.12) times/week with 39.4% reporting no participation. After controlling for the interaction between severity of secondary conditions and functional status, the secondary conditions of physical deconditioning and isolation were significantly and inversely related to LTPA participation (r?=???0.164, p?=?0.036; r?=???0.156, p?=?0.045, respectively).

Conclusion:?Reported secondary conditions of physical deconditioning and isolation are inversely related to the ability of moderately impaired women with physical disabilities to participate in LTPA when functional status was controlled and should be considered in efforts to increase involvement in this health promoting behaviour.     

Effect of whole brain radiation on local cerebral glucose utilization in the rat

We assessed, by means of the [14C]-2-deoxy-D-glucose autoradiography method, the effect of whole-brain x-radiation on local cerebral glucose utilization in the rat brain. Animals were exposed to conventional fractionation (200 +/- 4 cGy/day, 5 days/week; total dose, 4000 cGy). Metabolic experiments were made 2 to 3 weeks after completion of the radiation exposure. In comparison with control and sham-irradiated animals, cerebral metabolic activity was diffusely decreased after irradiation. Statistically significant decreases in metabolic activity were observed in 13 of 27 brain regions studied. In general, the brain areas with the highest basal metabolic rates showed the greatest percentage of decrease in glucose utilization. The concept that radiation suppresses glucose utilization before any morphological change takes place in the cell structures was the basis of this study. Metabolic alterations after irradiation may explain the syndrome of early delayed deterioration observed in humans after whole-brain radiotherapy. These studies have applications to observations made with the [18F]-fluorodeoxyglucose method in conjunction with positron emission tomographic scans in patients receiving radiation therapy for intracranial malignancies. The data reported here also have potential clinical implications for the evaluation of a risk/benefit ratio for radiotherapy in patients with benign neurosurgical diseases or children undergoing prophylactic treatment of the central nervous system.     

Safety of therapeutic beta-blockade in patients with coexisting bronchospastic airway disease and coronary artery disease

Atherosclerotic coronary artery disease and bronchospastic airway disease frequently coexist in older patients. There are substantial data suggesting reduced mortality with the use of beta-adrenergic blocking drugs in patients with symptomatic coronary artery disease, especially patients who have postmyocardial infarction and/or severe coronary artery disease associated with left ventricular dysfunction. Conversely, the use of beta-adrenergic blocking drugs (even selective beta(1)-adrenergic blocking drugs) has the potential of exacerbating bronchospasm. This prospective registry evaluates the safety of use of selective beta(1)-adrenergic blocking drugs in patients with symptomatic coronary artery disease and bronchospastic airway disease. A total of 835 consecutive patients with symptomatic coronary artery disease were prospectively evaluated for coexisting coronary and bronchospastic airway disease. Of these, 30 patients (mean age: 61 +/- 14 years) met the qualifying inclusion criteria. All these study patients except 1 (29/30 [96%]) reached therapeutic beta-blockade (resting heart rate <70 beats per minute). The 1 patient who discontinued use of beta-adrenergic blocking drugs as a result of lifestyle-limiting bronchospasm had no serious adverse outcome. No hospitalizations were required because of worsening bronchospasm. Ten percent of patients reported increased requirement of inhaled beta(2)-agonist use. The patients were followed for 15 +/- 9 months. One patient died of stroke at 22 weeks of follow-up. In conclusion, use of selective beta(1)-adrenergic blocking drugs at a therapeutic dose is safe (as long as careful clinical follow-up is available) and should be considered in all patients with coexisting symptomatic coronary artery disease and bronchospastic airway disease.