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The few benefits and the hazards of compound preparations and polypharmacy have been discussed. Examples of some well known interactions and their mode/site of action have been recorded. The study of drug interaction is an expanding field with an increasing appreciation of pharmacokinetics and pharmacogenetics.

Controlled clinical trials dealing with the first antimycobacterial treatment, published between 1948 and 1971, have been methodologically compared. Three comparable groups have been formed (US-Japan

The effects of high-dose ascorbic acid on warfarin-induced hypoprothrombinemia and clotting factor activity kinetics were studied in healthy dogs. The biologic half-life and rates of synthesis of these factors were unaffected by ascorbic acid. No changes were noted in the prothrombin times of animals chronically treated with anticoagulants or in the concentration of factors II and factors VII X complex in these dogs. These investigations do not support a postulated significant drug interaction between warfarin and ascorbic acid.

The data reported demonstrate a synergistic response between the alkylating agents nitrogen mustard, cyclophosphamide, and thio-TEPA, and the barbiturate sodium pentobarbital. The synergistic toxicity

Open any current medical journal and one is reminded that the coadministration of two or more drugs can either cause deleterious effects or lead to ineffective therapy. Those concerned with drug therapy are increasingly aware of this phenomenon but are confronted with the problem that a patient may be taking three, four, and, on occasion, even more drugs simultaneously. The computer will aid in the storage and retrieval of such information and act as a useful early warning signal, but prudent multiple drug therapy, if deemed necessary, can only be achieved with a better understanding of the nature and quantitative aspects of drug interactions. A drug interaction might broadly be defined as any reaction between one drug and another substance within or out of the body. In this review, the definition is restricted to events occurring within living systems with major emphasis on the alteration by one drug on the rate and extent of absorption, distribution, metabolism, and excretion of another. Prescott (1969) has called these “pharmacokinetic interactions” to distinguish them from the numerous interactions between drugs at their sites of action (Morrelli, 1970). This distinction is somewhat arbitrary as any or all possibilities can occur in vivo. The interaction may be direct, such as the competitive inhibition of drug metabolism and the displacement of a drug from binding sites, or it may be indirect. One example of the latter is the decreased renal clearance of acids, whose renal clearance is sensitive to urinary pH, produced when the urine is rendered alkaline using either the carbonic anhydrase inhibitor, acetazolamide, or sodium bicarbonate.

When one considers the complex interaction of antiarrhythmic drugs, either among the various groups or in the presence of altered electrolytes, the number of possible antagonistic and synergistic actions becomes almost infinite. This overview has attempted to amalgamate present information concerning drug and electrolyte interactions. Fortunately, in the clinical setting one is usually operating within the physiologic range for serum electrolytes, and many of these alterations shown in laboratory studies may not be pertinent. It should be remembered, however, that when serum electrolyte derangements are present, the usual or expected effects of antiarrhythmic drugs may be masked, leading to erroneous therapy or to the conclusion that the therapy is either inadequate or useless. This summary also points out that marked beneficial effects can be achieved, particularly by the use of digitalis and propranolol, in slowing AV conduction in the presence of supraventricular arrhythmias and that low potassium completely nullifies the action of the quinidine-like or Group 1 agents. The antagonism of bretylium to quinidine-like agents should alert the clinician to the possibility that the administration of Group 1 drugs in the wake of Group 3 or possibly other antiarrhythmic drugs may either nullify or aggravate certain pharmacologic actions. Although it is true that quinidine, lidocaine, and procainamide can be used with increased efficacy in the presence of propranolol, the opposite may be true when they are used in the presence of bretylium. Precise monitoring of serum electrolytes would appear essential before and during antiarrhythmic drug therapy.

Routine laboratory investigations carried out in 94 cases with acute spinal cord injury indicated moderate to severe deficiency within the extrinsic prothrombin activator system in 82.2 per cent of the patients. The clotting defect could be shown to be related to subnormal levels of vitamin K dependent plasma factors VII and X. There were 25 drop-outs in this study due to drug interference, irregular administration of vitamin K, intercurrent disease, etc. In the remaining group of 36 patients, none of the common etiological factors of acquired hypoprothrombinemia could be incriminated—such as poor intestinal resorption due to lack of bile salts, hepato-biliary disease, broad-spectrum oral antibiotherapy, drug interaction, hyperpyrexia, prolonged parenteral feeding, etc. In nine (25 per cent) of the cases total correction of factors VII and X was achieved after oral administration of vitamin K; in two (5.5 per cent) partial correction was similarly attained; in the remaining group of 25 (69.5 per cent) who proved to be resistant to oral vitamin K all but two normalised their factors after intravenous administration of the vitamin. These observations support the hypothesis that in acute spinal cord injury intestinal uptake of lipo-soluble substances may temporarily be impaired.

To account for some of the more important aspects of drug interaction we shall consider a model which can also account for certain general properties of the action of a single drug. A simple model in which there may be enzymatic detoxification of a drug is studied theoretically. The relation between time for appearance of an effect due to the drug and the size of the dose is found to contain the same parameters as the relation between the effectiveness of paired doses and the interval of time between doses. A similar situation holds when the drug is given at a constant rate.

A common practice in the medical science is the prescription of multiple drugs at a time, which may sometimes be neither safe nor effective and may be deleterious. The present study was aimed to evaluate such a combination of diltiazem with ibuprofen and naproxen. The invitro interaction of diltiazem with ibuprofen and naproxen has been studied at room temperature and at different pH in the aqueous medium by spectroscopic and conductometric methods, and the invivo study was done in the rabbit by measuring blood pressure using a mercury manometer. It has been found that diltiazem formed stable 1 : 1 complexes with ibuprofen and naproxen along with some intermediates. The Ardon’s spectrophotometric method was employed to confirm the formation of 1 : 1 complex and for the calculation of the stability constants. The invivo study was carried out to evaluate the influence of ibuprofen and naproxen on the antihypertensive activity of diltiazem in the rabbit. Concurrent administration of ibuprofen and naproxen with diltizem did not make any significant change in the antihypertensive activity of diltiazem. It is thus inferred that co-administration of diltiazem with ibuprofen and naproxen may be considered as safe and effective. Key words: Drug interaction, complexation, co-administration, diltiazem, naproxen, ibuprofen, stability constant Dhaka Univ. J. Pharm. Sci. Vol.5(1-2) 2006 The full text is of this article is available at the Dhaka Univ. J. Pharm. Sci. website

The toxic effects of adrenaline, isoprenaline, and terbutaline have been determined in mice after pretreatment of the animals with isoprenaline, terbutaline, and saline solution (control). Pretreatment with isoprenaline and terbutaline was without any significant effect on the mortality (LD 50) due to isoprenaline and terbutaline. The sensitivity to adrenaline, however, was considerably increased after pretreatment with isoprenaline but only slightly after terbutaline.

As a biological phenomenon the interaction between drugs may be viewed in ‘explanatory’ or ‘empirical’ terms. In clinical psychopharmacology the former is rarely possible: two examples are cited, one concerning amphetamine and reserpine, the other desmethyl-imipramine and tetrabenazine. Among centrally acting substances, empirical studies of the interaction between alcohol and the barbiturates have been pursued intensively by several methods in clinic and laboratory. Both general considerations and recent work on the effects of amphetamine-barbiturate combinations suggest caution in the medical use of mixtures of psychotropic drugs. Adverse reactions caused by interaction between psychotropic drugs and other substances have still to be studied systematically as a potential hazard.

The problems of comparing several anaesthetics are reviewed with particular reference to the effects of premedication, the intrinsic activity of drugs and their affinity for certain tissues and the effect of multiple drug interaction. The physiological and pathological states of those patients who are used as subjects of such studies are essential factors to be clearly determined. The effects of acute tolerance, cumulation and tachyphylaxis were also cited as factors to be considered.

A variety of drugs including anticholinergics, antihistamines, MAO inhibitors, miscellaneous stimulants and depressants (“tranquilizers”), and imipramine-like compounds were tested in rats conditioned to respond in the Sidman, continuous avoidance procedure. Several doses of each drug were tested to determine the minimum effective dose that increased (stimulated) or decreased (depressed) the rate of lever pressing. Behaviorally inactive doses of each drug were then tested in three drug interaction experiments: 1) amphetamine potentiation, 2) cocaine potentiation, 3) stimulation with a nondepressant dose of tetrabenazine. Pretreatment with imipramine-like compounds or cocaine produced stimulation in all three drug interaction experiments. Promethazine, tyramine, guanethidine, as well as a few anticholinergics, and MAO inhibitors potentiated amphetamine and cocaine, but did not stimulate with tetrabenazine. Chlorpromazine, azacyclonol, methylphenidate, phenindamine, and promazine were inactive in the three drug interaction tests. Imipramine-like drugs differed qualitatively from all other agents tested in that they had no systematic effects when given alone, but consistently produced stimulation when combined with a small, nondepressant dose of tetrabenazine. A comparison of the present behavioral data with previous biochemical findings indicates that imipramine induces a stimulant (or antidepressant) effect by increasing the reactivity of central mechanisms to the action of “free” norepinephrine.

The effects of combinations of diazepam (5 and 10 mg) and alcohol (0.5 and 0.8 g/kg) on skills related to driving were studied in 200 volunteer students. A choice reaction test and two co-ordination tests were employed, one of which was carried out at a fixed speed, and in the other the speed was chosen by the subject himself. — On their own these drugs either did not affect or even slightly improved the skills measured, but their various combinations definitely impaired the subjects' performances. This effect was greatest before the peak levels of blood alcohol were reached. — The combination of these drugs is considered dangerous for driving. The practical effect of taking one of these drugs on its own is more difficult to assess.

In the absence of scheduled shocks cyclazocine (2.5 mg/kg) severely depressed avoidance responding. No behavioural excitation was observed. Behavioural excitation is observed after cyclazocine (2.5 mg/kg) injection, in the presence of scheduled shocks. The excitatory phase associated with the drug is dependent on the presence of the aversive stimulus. Thus, behaviour/drug interaction is dependent on environmental factors. The interaction of stress on psychotomimetic drug-action allows one to formulate a mechanism whereby environmental stress can play a crucial role in the genesis and underlying mechanism of schizophrenia.

1. The administration of either iproniazid or tranylcypromine to mice potentiates the acute toxicity of pethidine, morphine, pentazocine and phenazocine.2. Blood levels of pentazocine in mice pretreated with tranylcypromine do not differ from the levels in animals not receiving the monoamine oxidase (MAO) inhibitor.3. There is no correlation between changes in brain and liver MAO activity and the increased pethidine toxicity.4. A comparison is made between the change in pethidine toxicity and the changes in the concentration of cerebral noradrenaline, dopamine and 5-hydroxytryptamine following the injection of tranylcypromine.5. It is concluded that the increased toxicity of potent analgesics in combination with MAO inhibitors is not due to a decelerated metabolism of the analgesic drug, but is related to an increased concentration of cerebral 5-hydroxytryptamine. A critical level of this monoamine, in the brain, may be necessary before the drug interaction will take place.

The toxicity of caffeine, theophylline and theobromine was increased by the monoamine oxidase inhibitors pargyline, iproniazid, tranylcypramine and β-phenylisopropylhydrazine in the rat. The hypokinesia, ptosis and hypothermia following caffeine were replaced by agitation, disorientation and hyperthermia following caffeine plus pargyline. Antiserotonergic drugs were more effective than symphatholytic drugs in preventing alterations in temperature, homeostasis and the lethal consequences of the drug interaction. Serotonin may play a role in the pharmacologic action of caffeine.

The characteristics of difference spectra induced by a series of barbiturates in a rat liver microsomal system are presented. This data is related to the structures, duration of pharmacological action and metabolic fate of the compounds. The inhibition of the pharmacological action of tremorine and the potentiation of hexobarbital sleeping time in mice by concommitant administration of SKF525A or “Inderal” ∗ (propranolol) is also correlated with the characteristics of the difference spectra of these compounds. A partial correlation between difference spectra and species differences in metabolism is also demonstrated.

SummaryLorazepam (Wy 4036; 7-chloro-5-[o-chlorophenyl]-3-hydroxy-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one) is a new minor tranquillizer of the benzodiazepine class. Compared with a number of other benzodiazepines, lorazepam was the most potent agent tested in a variety of potentially predictive anti-anxiety tests: i.e. treadmill avoidance studies, fighting mice and conditioned suppression learning tests. In addition, lorazepam exhibited potent anticonvulsant activity against metrazol convulsions and electroshock seizures.Motor inco-ordination or ataxia was a prominent feature of the benzodiazepine drugs, but the separation of 'effective' and depressive doses of lorazepam, in the above tests, suggested there is likely to be a wide separation of anti-anxiety and sedative doses in man.The demonstration that lorazepam was the most effective benzodiazepine tested in suppressing fear-conditioning in rats means that the drug is likely to cause amnesia for unpleasant, essentially painful experiences. This action ...

Dogs were given nortriptyline followed six or ten hours later by various doses of hydrocortisone. The rate of disappearance of nortriptyline from plasma decreased in the presence of the steroid. The plasma disappearance of nortriptyline was also studied using the isolated perfused rat liver. Hydrocortisone and testosterone markedly decreased the rate of disappearance of the drug from the perfusion medium.

Interaction between prostaglandin E1 and norepinephrine relative to effects on ocular pressure and pupil size was studied in albino rabbits in which unilateral cervical sympathetic ganglionectomy was performed. The operated animals, at the time of prostaglandin-norepinephrine interaction studies, were pretreated with phenoxybenzamine prior to each study. That dose of norepinephrine which was ineffective in altering ocular effects of prostaglandin in unoperated animals was now effective in antagonizing the ocular effects of prostaglandin in ganglionectomized animals. Supersensitivity of norepinephrine relative to these drug interaction studies was thus demonstrated.