OAR@UM Collection:

Pulmonary and general pharmacokinetic studies on racemic ethosuximide using a chiral sensitive GC/MS technique.

2020-11-11T12:18:49Z

Title: Pulmonary and general pharmacokinetic studies on racemic ethosuximide using a chiral sensitive GC/MS technique. Abstract: A modified specific, sensitive and reproducible chiral gas chromatographic method for the resolution and quantification of ethosuximide enantiomers in urine and plasma was developed. The samples were extracted by liquid-liquid extraction, using diethylether and the enantiomers were separated and quantified on a chiral gas chromatographic column. The method involved the use of GC/MS instrumentation for the acquisition of data in the electron impact, selective-ion monitoring mode, collecting ions of mass-to-charge ratio (mlz) exactly equal to 55 and 70 units and which were specific for ethosuximide. The limit of quantitation of the method was 5 µg/ml for urine samples and 10 µg/ml for plasma samples with both enantiomers. The method proved to be linear, precise and reproducible in the 5-300 µg/ml concentration range for urine samples and in the 10-250 µg/ml concentration range for plasma samples. Intraday and interday coefficients of variation were low, while recovery studies were acceptable. The reproducible extraction and quantification techniques were applied in the determination of pulmonary pharmacokinetic parameters of the enantiomers following the intravenous administration of rac-ethosuximide to an intact rabbit model. Following a 6 mg intravenous bolus dose of rac-ethosuximide to New Zealand white rabbits, (S)-ethosuximide had a mean (± standard deviation) pulmonary uptake of 39.15 ± 13.38% and a mean retention of 63.49 ± 8.03%, while (R)-ethosuximide had a mean pulmonary uptake of 24.18 ± 16.93% and a mean retention of 54.51 ± 10.16%. Also, following the first-pass of indocyanine green dye, a nonextractable indicator, through lung tissue, mean transit time was equal to 13.535 ± 0.010 s, cardiac output was equal to 280.67 ± 49.69 mlmin-1 , while central blood volume was equal to 63.31 ± 11.21 ml. The chiral GC/MS method developed was also applied in the determination of general pharrnacokinetic parameters of ethosuximide following the intravenous administration of different doses of the drug to rats. Statistically significant differences were found for half-life and clearance of the enantiomers of ethosuximide (p < 0.05). After a 40 mg intravenous bolus dose of rac-ethosuximide, (S)ethosuximide had a mean (± standard deviation) half-life of 23.5 (± 1.6) h and a clearance of 0.064 (± 0.022) Lh-1kg-1, while (R)-ethosuximide had a mean half-life of 19.4 (± 1.2) h and a clearance of 0.067 (± 0.045) Lh-1kg-1. No statistically significant difference was found for volume of distribution estimated for both enantiomers (2.184 ± 0.791 Lkg-1 for (S)-ethosuximide and 1.843 ± 1.166 Lkg-1 for (R)-ethosuximide) (p > 0.05). Description: M.SC.PHARMACOLOGY

The use of a non-sedating antihistamine in a hyperbaric environment.

2020-11-10T13:48:44Z

Title: The use of a non-sedating antihistamine in a hyperbaric environment. Abstract: Allergic symptoms and asthma have increased considerably over the past years. Pollen counts increase significantly in spring and early summer, causing symptoms involving the ear, nose and throat (ENT). Coincidentally, recreational scuba diving starts to peak at this time. Antihistamines may be taken by a diver to relieve ENT symptoms and prevent serious injury, especially where the diver has no particular wish to stop diving to allow for the infection or allergy to subside. However, antihistamines are associated with dry mouth and drowsiness. An additive effect or even potentiation of nitrogen narcosis, which causes cognitive or motor function decrements, is a reason not to recommend the use if antihistaminic drugs when diving. These recommendations are based on the theoretical pharmacological mechanisms of the drugs, which have not been verified with controlled clinical trails. One must also take into consideration the fact that in a hyperbaric environment, potentiation or attenuation of a drug may be an eventuality. Also, new effects may present themselves. Few studies (Sipinen et al., 1995; Taylor et aI., 2000) designed to test whether antihistamines aggravate nitrogen narcosis, cognitive or motor functions, or the appearance of cardiac arrhythmias have been carried out, and no such research has as yet been performed locally. In fact, the taking of medication and diving is a very contentious issue. There are very few absolute guidelines in this regard. Generally, the use of medication, including over-the-counter (OTC) preparations such as antihistamines, while diving is not recommended. Minimal research has been carried out to determine alterations in pharmacodynamics and pharmacokinetics of medication in man under water or their effect in potentiating conditions like nitrogen narcosis, hyperventilation, hypothermia, and motion sickness. Thus, drawing from the above, and taking into account the increasing popularity of sport diving amongst the Maltese population, conducting a study to assess the effects of the administration of a non-sedating antihistamine (cetirizine) with pressure, provided some insight in this field of medicine which may prove useful to divers, medical practitioners and pharmacists alike. Such a study was aimed at: • evaluating the psychometric effects of antihistamines in a hyperbaric environment • evaluating whether these effects pose an added hazard to the risk of nitrogen narcosis Nitrogen narcosis affects mood, intellectual function, response to stimuli, balance and co-ordination, and the level of consciousness of the diver. It occurs as a diver is exposed to an increasing partial pressure of nitrogen and is of significant danger to the diver because it increase the risk of an accident and decreases the ability of the diver to cope with the emergency. The project involved two separate studies. The first study focused on the evaluation of the effects of administration of antihistamines in 40 randomly selected fully qualified divers. A second study was conducted to elucidate information on drug-taking habits of divers using a questionnaire and involving 80 divers. The first study was a double-blind placebo-controlled type of study. Each subject was given a standard oral dose of an antihistamine or a placebo. After two hours had elapsed, blood was drawn from the subjects for subsequent analysis, and the subjects were subjected to four different psychometric tests under hyperbaria in a multi place hyperbaric chamber. The results thus obtained did not indicate any significant differences in performance between subjects under the effects of cetirizine and subjects that had been given the placebo. For some tests, however, differences were noted in the performance of the subjects with pressure. By means of the questionnaire, one could gain an insight to the drug-taking habits of a selection of local divers. It seems that preparations to relieve sinus congestion feature highly among the medications taken by divers. The interaction of such preparations and the underwater environment is also relatively common in these divers. No correlation was found between diving injuries and the drug-dive interaction. Physical and psychological fitness for diving has some basic requirements. Namely, divers must be able to equalise pressure readily in all body airspaces and divers must not be subject to impairment of consciousness, alertness, or judgement (Walsh, 1979). Thus, it is anticipated that the conclusions drawn from this study will go towards increasing the safety and pleasure of sport diving. Description: M.SC.PHARMACOLOGY

Pharmaceutical overdose in Malta : with special reference to paracetamol.

2020-11-10T05:29:03Z

Title: Pharmaceutical overdose in Malta : with special reference to paracetamol. Abstract: Paracetamol has been in clinical use for some forty years, it is widely used prescription and over the counter analgesic. World wide the annual consumption exceeds 25,000 tons. In the last decade, international published data has shown a substantial increase in the number of self-poisoning patients being referred to district poison units. In Malta, data has never been compiled to date either about paracetamol overdose or about overdose with pharmaceutical preparations in general. Thus, the position of paracetamol overdose with respect to the general pharmaceutical overdose picture was uknown. Knowledge about the formation and toxicity of paracetamol metabolite has been known for some years. In fact treatment of paracetamol overdose focuses on blocking the formation of this toxic metabolite, N-acetyl parabenzoquinoneimine. Peak plasma levels, which are usually reached within 30 – 60 minutes after ingestion of a normal dose, are delayed for up to four hours. Glutathione conjugation, which plays an important part in the detoxification of paracetamol, is a saturable process and when 70% of the available cellular glutathione is depleted, more of the toxic metabolite is formed. This then causes hepatocellular damage. The guidelines which have been issued about the treatment procedure are reviewed. The aim of this research was to seek information regarding the general picture of pharmaceutical overdose cases in Malta and how paracetamol fits into this picture. The retrieval of information was extremely complex and arduous as it involved a retrospective compilation of information, collating of data from various division within the Health Department, such as the Health Information Unit. The Toxicology Laboratory, the Emergency Laboratory, the Admissions and Emergency (A & E) department at the general hospital, the Government Pharmaceutical Services section and the administrative section of the Health Department and correlating and analysing this fragmented noncomputerised data. Data was obtained for overdose cases for seven years between 1995 and 2001. The main types of drugs responsible for drug overdose deaths in Malta were narcotics and psychodysleptics (39.2 %), anti-epileptic,sedative-hypnotic, anti-parkinsonian drugs and psychotropics (20.3 %), some gases and vapours (18.9 %), alcohol (8.1 %), anti-pyretics, anti-rheumatics and non-opoid analgesics (4.1 %) and other and unspecified drugs (9.3 %). The majority of the drug overdose victims (70.3 %) were between 20 and 49 years of age and 78.4 % were male. Most of the patients who were admitted to hospital because of drug overdose (66.7 %) were between 15 and 44 years while the male to female ratio of admissions is approximately 1: 1. From the data collected paracetamol overdose in Malta appears to be less common when compared to the data available from other countries such as UK where 42 % of all overdoses in Oxford in 1990 were due to paracetamol. In addition the consumption of some of the other drugs used commonly for overdose such as diazepam and bromazepam was calculated by means of the DDD methodology in an attempt to explain whether the different trends in overdose in Malta could be due to different consumption patterns for these drugs in Malta. The data collected was completely novel and in spite of the limitations which exist due to limited computerisation of the data in Malta, a general picture has emerged regarding pharmaceutical over dose in Malta including paracetamol overdose. Description: M.SC.PHARMACOLOGY