Drugs chlorphentermine

Fig. 1.9 Structures of charge neutral (phosphatidylcholine) and acidic (phosphatidylserine) phospholipids together with the moderately lipophilic and basic drug chlorphentermine. The groupings R1 and R2 refer to the acyl chains of the lipid portions.

The accumulation of fat is a common cellular response to toxic compounds, which is normally reversible. Usually triglycerides accumulate, although sometimes phospholipids accumulate, as occurs after exposure to the drug chlorphentermine (see chap. 2). Steatosis is particularly common in the liver as this organ has a major role in lipid metabolism (Fig. 6.15). The lipid may appear in the cell as many small droplets or as one large droplet. Interference with lipid metabolism can occur at several points ... 

Lullmann H, LuUmann-Rauch R, Wassermann O. Drug-induced phosphohpidoses. II. Tissue distribution of the amphiphihc drug chlorphentermine. CRC Crit Rev Toxicol 1975 4(2) 185-218. 

Figure 3 presents the mean levels of self-infusion for the 14 phenylethyl-amines shown in figure 1. Of all the drugs tested, injection rates were... 

In a summary of the human abuse literature on anorectic phenylethylamines, Griffiths et al. (1979) found there was a good correlation between the results of self-administration studies in animals and information about the subjective effects and abuse in man. Specifically, amphetamine, diethyl-propion, and phenmetrazine have been associated with numerous clinical case reports involving abuse, and these three compounds as well as benz-phetamine and /-ephedrine have shown similar subjective effects in drug abuser populations (Griffiths et al. 1979). In addition, fenfluramine was associated with low incidence of abuse in humans and did not maintain self-injection responding in animals. Chlorphentermine was similarly associated with low incidence of abuse in man, but did not maintain selfinjection uniformly in animals (Griffiths et al. 1979). 

Table 1.1 shows the preferential binding of chlorphentermine to phosphatidylcholine-containing membranes, the phospholipid with overall acidic charge. These systems predict the actual affinity of the compound for the membrane, rather than its ability to cross the membrane. Membrane affinity, and hence tissue affinity, is particularly important in the persistence of drugs within the body, a topic which wiU be covered in Section 4.2. 

It seems that for drugs to cause accumulation of phospholipids, the necessary physicochemical characteristic is the presence of both hydrophilic and lipophilic parts to the molecule, as exemplified by chlorphentermine (see chap. 3) (chap. 5, Fig. 1). They contain a hydrophobic ring structure and a hydrophilic side chain with a positively charged (cationic) amine group. Such molecules are known as cationic amphipathic drugs or CADs. Other drugs, all in use, known to cause phospholipidosis are amiodarone, chloroquine (chap. 5, Fig. 1), tafenoquine, and gentamycin. 

Fig. 4.6 (A and B) Dependence of the drug-induced reduction of the transition temperature (A 7",) on the amount of chlorphentermine and clofibric acid added. The dissociation equilibrium of the drugs was shifted to the indicated forms by adjusting the pH of the liposome suspension to pH 6 and over pH 9 respectively (A). Dose-effect curves of the uncharged forms (pH 10 and pH 4.5, respectively. Dotted line indicates drug amounts at which morphologic alterations occurred in the liposome suspension (B). (Reprinted from Fig. 2 of ref. 96 with permission from Elsevier Science). (C) Liposomal binding of chlorphentermine and clofibric acid depending on the total amount of drug added to the liposome suspension (mean values of triplicate determinations). Maximum deviation from the mean was 10% of the mean. (Reprinted from Fig. 3 of ref. 96 with permission from Elsevier Science)...

Of the other central stimulants, aminorex, doxapram, fenfluramine, and fenfluramine plus phentermine can cause chronic pulmonary hypertension, as can chlorphentermine, phentermine, phenmetrazine, and D-norpseudoephedrine (SED-9, 8). A genetic predisposition may be involved (SED-9,8). Pulmonary hypertension may develop or be diagnosed a long time after the drug has been withdrawn. 

Anorectic drugs act mainly on the satiety centre in the hypothalamus (1). They also have metabohc effects involving fat and carbohydrate metaboUsm. Most of them are structurally related to amfetamine and increase physical activity. Their therapeutic effect tends to abate after some months, and part of this reduction in effect may be due to chemical alterations in the brain. Fenfluramine commonly produces drowsiness in normal doses, but has stimulaut effects in overdosage. Dexamfetamine, phenmetrazine, and benzfetamine all tend to cause euphoria, with a risk of addiction. Euphoria occasionally occurs with amfepramone (diethylpropion), phentermine, and chlorphentermine, but to a much lesser extent. Some adverse effects are due to sympathetic stimulation and gastrointestinal irritation these may necessitate withdrawal but are never serious. There are interactions with monoamine oxidase inhibitors and antihypertensive drugs. 

Pathological changes in the lungs were produced with chlorphentermine in laboratory animals (SED-9, 14). Pulmonary complications might therefore occur in humans, which puts in doubt the wisdom of continuing to recommend chlorphentermine as an anorectic drug until more definitive information is available. 

Class C includes certain drugs related to the amphetamines, such as benzphetamine and chlorphentermine, buprenorphine, diethylpro-pion, mazindol, meprobamate, pemoline, pipradrol and most benzodiazepines. Cannabis and cannabis resin have been rescheduled as class C, but were class B until 2003. 

Figure 4 Design of chlorphentermine-drug conjugates for lung targeting.

Special arrangements apply to the prescribing of drugs of dependence in the UK under the provisions of the Misuse of Drugs Act 1971. Drugs controlled include cocaine, dipipanone, diamorphine (heroin), methadone, morphine, opium, pethidine, phencyclidine, lysergjde (LSD), amphetamines, barbiturates, cannabis, codeine, pholcodine, and certain drugs related to the amphetamines, such as chlorphentermine and diethylpropion. 

The immunomodulatory azaspiranes are novel cationic amphiphilic drugs with beneficial effects in a number of animal models of autoimmune disease and transplantation. Waites et al. (1995) compared W,W-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-propanamine HCl (SK F 105685) and two analogues, SK F 106615 and SK F 103811 with chlor-phentermine and chloroquine for their ability to induce phospholipid accumulation and suppressor cell activity. Oral administration of SK F 105685 and SK F 106615 caused phospholipid accumulation in bronchoalveolar lavaged rat macrophages but to a far lesser extent (three- to fivefold) than chlorphentermine. Neither the immunologically unreactive azaspirane SK F 103811 nor chloroquine affected phospholipid levels. Alveolar macrophages from rats treated with SK F 105685 or SK F 106615 expressed more potent suppressor cell activity than chlorphentermine. Neither SK F 103811 nor chloroquine induced suppressor cell activity. 

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