Pharmacological and toxicological evaluation of the locally abused glue "Kolla" in rats

This work was devoted to study the physicochemical properties as well as the neuropharmacological and toxicological effects of the local glue "Kolla" which is commonly and widely abused by street children in Egypt. Chemical analysis showed that the main volatile solvent ingredient of "Kolla" is toluene and, thus, it was used as a reference toxic solvent in this study. Three different concentrations of each inhalant, glue and toluene, were investigated. Single inhalation [30 min] of both "Kolla" [1000, 4000 ppm] and toluene [5610, 22576 ppm] potentiated the sleeping time of pentobarbital. In their higher concentrations, "Kolla" [8000 ppm] and toluene [45153 ppm] antagonized the hypnotic action of pentobarbital. Single inhalation [30 min] of the tested substances produced motor incoordination and decreased locomotor activity of rats. The higher concentration of toluene [45153 ppm] increased this activity. Repeated daily inhalation [30 min/day for 10 days] of "Kolla" and toluene in the 3 tested concentrations increased locomotor activity of rats. Levels of Malondialdehyde [MDA.] in cortex and cerebellum increased after repeated inhalation of glue and toluene. Also, glutamate level in hippocampus increased after repeated inhalation of the two toxic inhalants. Extraction of liver, kidney and heart after 10 days of daily repeated inhalation showed some histopathological changes

Possible pharmacodynamic interactions between the CNS stimulant [Nikethamide] and analgesic drugs in experimental animals

Recently, there has been striking increase in research on drug combinations that enhance analgesia in clinical populations as well as in experimental animals. These studies involve combinations of drugs that have been viewed, as effective analgesics in their own right, such as opioids and nonsteroidal anti-inflammatory drugs, and drugs that have not traditionally been viewed as analgesics. The purpose of this study was to investigate the possible pharmacodynamic interactions between a CNS stimulant [nikethamide] and opioid [morphine] and non-opioid [paracetamol] drugs. Also, this study assessed the rationale of these interactions in terms of efficacy and safety by using different models of analgesic and behavioral tests. Albino mice and rates were used, as experimental animals. The analgesic effect of drugs and their combination was evaluated using [hot-plate] [54 °C], [tail clip] and [writhing] [acetic acid, 1%. i.p.] tests. The behavioral effects of the drugs and their combinations were also determined. Nikethamide significantly diminished the analgesic effect of morphine [1-10 mg/kg, i.p.] in all tests [antagonism] and enhanced the analgesic effect of paracetamol [50-400 mg/kg. i.p.] in all tests [additive]. Coadministration of nikethamide [100 mg/kg, i.p.] with morphine [2.71 mg/kg, ED[50]] significantly decreased locomotor activity and impaired the acquisition on conditioned avoidance responses but did not affect motor coordination to any significant extent. On the other hand, coadministration of nikethamide [100 mg/kg, i.p.] with paracetamol [117.94 mg/kg, i.p, ED[50]] significantly increased locomolor activity and improved the acquisition on conditioned avoidance responses but did not affect motor coordination to any significant extent. We can conclude that the systemic coadministration of nikethamide significantely antagonized the analgesic effect of morphine and such combination was accompanied by increased side effects. In contrast, nikethamide significantly enhanced, the analgesic effect of paracetamol in an additive fashion and this combination was not accompanied by increased side effects

Serum level monitoring of digoxin in cardiac patients attending Assiut University Hospitals: utility in therapy optimizations.

This study addressed the utility of digoxin level monitoring in the optimization of drug therapy. The results revealed toxic serum levels [> ng/ml] only in 91 of the 147 suspected cases. Among 61 patients with inadequate response, low concentrations [<0.7 ng/ml] were noticed. Similarly, in ten patients with non-compliance, very low subtherapeutic levels were observed even to the nil level in 50% of the cases. Accordingly, therapeutic failure of digoxin resulting from under dosage or non-compliance could be detected by TDM that helped in appropriate intervention and in the achievement of optimum clinical outcome. On the other hand, the TDM in clinically controlled cardiac patients indicated that the target concentration of digoxin required to the control heart failure and/or supraventricular arrhythmias could range from 0.7 ng/ml to 2.0 ng/ml. These data indicated that the international therapeutic range [0.7-2.0 ng/ml] of digoxin could be also applied to Upper Egypt cardiac patients. In addition, this study demonstrated the importance of proper sampling time and measurement of serum potassium and creatinine in the interpretation of digoxin level data

Modulation of the antiepileptic activity of sodium valproate by lithium chloride against pentylene-tetrazole and strychnine-indced seizures in mice.

In this study, the influence of lithium chloride [LiCl] in a dose of 10 mg/kg on the anticonvulsant activity of sodium valproate [VAL] in doses of 200 or 600 mg/kg was valuated against both pentylenetetrazol [PTZ; 100 mg/kg] and strychnine [ST; 1 mg/kg]-induced seizures and mortality. The results revealed that the ip administration of VAL alone was effective against seizures and mortality induced by both PTZ and ST. Significant increases in the onset of seizures and the MST as well as the percent of mice protected from death were recorded. In contrast, the administration of LiCl alone significantly reduced the onset of seizures and offered no protection against death caused by the same convulsive agents, PTZ and ST. Compared with valproate- treated mice, combination of lithium chloride and valproate led to a reduction in the MST of mice and an increase in the percent of protection of animals treated with PTZ and an increase in the MST of mice as well as the percent of protection in the ST- treated group of mice. Also, the results revealed that the combined administration of LiCl and VAL into mice subjected to the test convulsive agents resulted in reduced serum and brain concentration of electrolytes in FTZ-treated animals. Also, significant lowering only in the brain Na+, K+ and Cd2+ contents was observed in mice treated with ST

Effect of a new triazinoaminopiperidine derivative [S9788] on the binding of vinceistine to and 1-acid glycoprotein: implication in multidrug resistance phenomena

Multidrug resistance [MDR] was circumvented by a large number of compounds including verapamil and a newly synthesized triazinoaminopiperidine derivative S9788 [Servier 9788]. S9788 was found to overcome multidrug resistance both in vitro and in vivo. The mode of action of these chemosensitizers is thought to involve interaction on P-glycoprotein, a membrane-bound efflux transport protein for cytotoxic drugs. On the other hand, verapamil binds strongly to alpha 1-acid glycoprotein [AGP] in serum or solutions and AGP can modulate the chemosensitizing action of verapamil in MDR in vitro. The interaction of S9788 with [3H] vincristine was measured at binding sites on alpha 1-acid glycoprotein in vitro using equilibrium dialysis [Dianorm] and clinically relevant concentrations of ligands and protein

Effect of propofol on perception of pain in mice: study on the mechanism of action

Propofol is an intravenous anesthetic used clinically. The latencies of pain threshold of different subhypnotic doses [12.5, 25 and 50 mg kg-1] of propofol administrated intraperitoneally [ip] into mice were measured by using hot plate method technique. The possible mechanism of pain control by propofol was also investigated through blocking beta- endorphin receptors and measuring serum level of beta-endorphin. Morphine [1.5 mg kg-1, ip] was used as reference of reduction of pain sensation. The results showed that propofol in doses of 25 and 50 mg kg-1 increased significantly the latency of pain threshold, but the lower dose [12.5 mg kg-1] failed to produce any significant change. This indicated that propofol reduced pain sensation and this effect is dose-dependent. It was also observed that propofol prevents hyperalgesia produced by prostaglandin [PGE2] [0.5 mg kg-1, ip]. For investigating the mechanism of action of propofol, pretreatment with naloxone [1.0 mg kg-1, ip] abolished significantly the antinociceptive action of propofol. Furthermore, serum level of beta- endorphin was increased significantly after propofol injection particularly at the peak time of propofol action. Serum level of corticosterone was also increased significantly at the time of beta- endorphin release