Thermodynamics of Solutions I: Benzoic Acid and Acetylsalicylic Acid as Models for Drug Substances and the Prediction of Solubility

Purpose. To investigate the solution process of drug substances (exemplified by benzoic acid, BA, and acetylsalicylic acid, ASA), particularly the interrelation between enthalpic and entropic terms of Gibbs energy, in different solvents. To develop an approach for the estimation of standard solution enthalpies based on a self-consistent thermochemical scale. Method. Two independent methods, solubility experiments (concentrations of saturated solutions) and solution calorimetry (standard solution enthalpies) in aliphatic alcohols and individual organic solvents were used. Correlation between the thermodynamic functions in various solvents were analyzed by standard statistical methods. Multiple regression analysis between H ⁰ _sol values and the parameters of the solvents was run on the Koppel-Palm equation. Results. Based on experimental data, a compensation effect between thermodynamic functions was observed. Correlation was found between H ⁰ _sol (BA) and H ⁰ _sol (ASA) [where the H ⁰ _sol (BA)-values were used as a self-consistent thermochemical scale]. Furthermore, H ⁰ _sol correlated with the Koppel-Palm basicity of the solvents. Conclusions. The model based on solubility and solution experiments might be useful for the prediction of solubility or solvation of drug substances in different media. The regression equation based on the self-consistent thermochemical scale makes it possible to approximate the ability to solvate a drug substance in comparison with structure-relative substances.     

Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans

Purpose. A theoretical method has been devised for prediction of drug absorption after oral administration to humans. Methods. Twenty structurally diverse model drugs, ranging from 0.3 to 100% absorbed, were investigated. The compounds also displayed diversity in physicochemical properties such as lipophilicity, hydrogen bonding potential and molecular size. The dynamic molecular surface properties of the compounds were calculated, taking into account their three-dimensional shape and flexibility. Results. An excellent sigmoidal relationship was established between the absorbed fraction after oral administration to humans (FA) and the dynamic polar molecular surface area (PSA_d) (r² = 0.94). The relationship was stronger than those obtained for more established predictors of drug absorption. Drugs that are completely absorbed (FA > 90%) had a PSA_d 60 ² while drugs that are < 10% absorbed had a PSA_d > 140 ². Conclusions. The results indicate that PS Ad can be used to differentiate poorly absorbed drugs at an early stage of the drug discovery process.     

Cannabis interferes with nest-building behavior in mice

Nest-building, a behavioral model shown to be disrupted by hallucinogens, has never been used to answer questions concerning the psychotomimetic effects of ⁹-THC. Several fractions of cannabis and tobacco pyrolysis products were tested consecutively in the same procedure. The following drugs were injected i.p. under a saline-drug-saline schedule: d-amphetamine (6 mg/kg), pentobarbital (25 mg/kg), ⁹-THC (10 mg/kg, 5 mg/kg, 2.5 mg/kg), the cannabis fractions designated I_s (water soluble products), II_s (nonsoluble, nonvolatile products), III_s (it comprises what is inhaled by a common hashish smoker), and analogous fractions of tobacco pyrolysis products designated III_B (what is inhaled by a common tobacco smoker), II_B and I_B.The effects of ⁹-THC (10 mg/kg), II_s, and III_s were quite similar as far as the disruption of the normal behavioral pattern is concerned. d-Amphetamine, ⁹-THC (5 mg/kg), and II_B disrupted the normal behavioral pattern as well. The similarity of the effects of II_s and III_s was unexpected in view of the different contents of cannabinoids in these fractions. Also unexpected was the similarity of the effects of ⁹-THC (10 mg/kg) and III_s (40 mg/kg containing 7% ⁹-THC) as well as the activity of fraction III_B.     

Simple model to explain effects of plasma protein binding and tissue binding on calculated volumes of distribution,apparent elimination rate constants and clearances

Summary A simple pharmacokinetic model, incorporating linear plasma protein binding, linear tissue binding, and first order elimination of free (unbound) drug, was studied. If Cl_p is the plasma clearance, V_f is the true volume of distribution of free drug, is the apparent elimination rate constant, is the fraction of the drug which is free in plasma, f is the fraction of the drug which is free in the entire body, k_f is the intrinsic elimination rate constant for free drug, and A _TB ^o is the initial amount of drug which is bound to tissues, then the model indicates that the following relationships hold: (1) Cl_p = V_f k_f; (2) = f k_f; and V_dext = (/f) V_f. Only , and not f, can be measuredexperimentally. Dividing Cl_p by provides an estimate of the intrinsic clearance of free drug, V_fk_f. A plot of V_dext versus has an intercept equal to V_f, and the ratio of the slope/intercept is an estimate of A _TB ^o /A _f ^o , where A _f ^o is the initial amount of free drug (equal to V_f times initial concentration of free drug in plasma). Thus, an estimate of A _TB ^o may be obtained. Dividing the intrinsic clearance by V_f provides an estimate of k_f. Thus, theoretically, estimates of V_f, k_f, A _TB ^o and f may be obtained. The variables are not separated when is plottedversus , and curvature of such plots is expected; no useful information is obtained from such plots.Partly supported by Public Health Service Grant 5-P-11-GM 1559 and partly by Grant 1RO1AAOO683-O1A1 from the National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland.     

Hydrogen Bonding and Electrostatic Interaction Contributions to the Interaction of a Cationic Drug with Polyaspartic Acid

Purpose. To determine the mechanism and identify forces of interactionbetween polyaspartic acid and diminazene (a model drug). Such knowledgeis essential for the design of polymeric drug delivery systemsthat are based on molecular self-assembly into complexes or micellartype systems. Methods. Complex formation was studied by isothermal titrationmicrocalorimetry and the McGhee von Hippel model was applied toobtain K _obs, H _obs, and n _obs. The calorimetry data were compared withboth an optical density study and the amount of free/complexed drug. Results. The diminazene-polyaspartic acid interaction is enthalpicallydriven, whereby one diminazene molecule interacts with two monomersof polyaspartic acid. The dependence of K _obs on saltconcentrationreveals a contribution of electrostatic interactions. However, applyingManning's counter ion condensation theory shows that the major drivingforce for the complex formation is hydrogen bonding, with interfacialwater molecules remaining buried within the complex. Themodelling of the pH dependence of K _obs and H _obsdemonstrates thatthe ionization of carboxylic groups of polyaspartic acid is a prerequisitefor the interaction. Conclusions. Complex formation between diminazene and polyasparticacid is driven by both electrostatic interactions and hydrogen bonding,with the latter being the dominating force. Although electrostaticinteractions are not the major driving force, ionization of the drug andpolymer is essential for complex formation.     

Pharmacokinetics and transplacental distribution of fentanyl in epidural anesthesia for normal pregnant women

BACKGROUND: Fentanyl is an opioid drug widely used as a co-adjuvant in abdominal delivery, a fact that justifies its pharmacokinetic study under these conditions. OBJECTIVE: Our objective was to investigate the pharmacokinetics and placental transfer of fentanyl in parturients whose pregnancies were resolved by cesarian section with epidural anesthesia. PATIENTS and METHODS: Ten clinically normal parturients who delivered at term received 5 ml of 2% lidocaine hydrochloride without a vasoconstrictor for skin and subcutaneous blockade, followed by epidural injection of 2 ml fentanyl citrate (0.05 mg/ml), 15 ml 0.5% bupivacaine hydrochloride with 1:200,000 epinephrine, and 10 ml 2% lidocaine hydrochloride without a vasoconstrictor. Maternal blood samples were collected at various times after injection (1–840 min), and the fentanyl plasma concentrations were determined by gas chromatography-mass spectrometry. Pharmacokinetic analysis was performed using the bi- or tricompartmental model. The fetal/maternal ratio of the plasma fentanyl was determined at birth. RESULTS: The values of the pharmacokinetic parameters were: t_&frac; = 13.5 min, t_1/2 = 192.5 min, t_1/2 = 620 min, AUC^0- = 137.404 ng.min per millilter, C_l/f = 464.984 ml/min, V_d/f = 299.974 l, C_l/f/kg = 6.875 ml/min per kilogram, and V_d/f/kg = 4.441 l/kg. The latency between drug administration and birth was 28.5 min, with a maternal and fetal plasma concentration of 0.310 and 0.245 ng/ml, respectively, at a median fetal/maternal ratio of 0.892. CONCLUSION: The study demonstrated a rapid passage of fentanyl from the epidural space to maternal blood and a significant transplacental transfer of maternal fentanyl of about 90%, which should serve as an alert to obstetricians.     

Influence of polymorphism on the surface energetics of salmeterol xinafoate crystallized from supercritical fluids

Purpose. To characterize the surface thermodynamic properties of two polymorphic forms (I and II) of salmeterol xinafoate (SX) prepared from supercritical fluids and a commercial micronized SX (form I) sample (MSX). Methods. Inverse gas chromatographic analysis was conducted on the SX samples at 30, 40, 50, and 60°C using the following probes at infinite dilution: nonpolar probes (NPs; alkane C5-C9 series); and polar probes (PPs; i.e., dichloromethane, chloroform, acetone, ethyl acetate, diethyl ether, and tetrahydrofuran). Surface thermodynamic parameters of adsorption and Hansen solubility parameters were calculated from the retention times of the probes. Results. The free energies of adsorption (-G_A) of the three samples obtained at various temperatures follow this order: SX-II > MSX SX-I for the NPs; and SX-II > MSX > SX-I for the PPs. For both NPs and PPs, SX-II exhibits a less negative enthalpy of adsorption (H_A) and a much less negative entropy of adsorption (S_A) than MSX and SX-I, suggesting that the high -G_A of SX-II is contributed by a considerably reduced entropy loss. The dispersive component of surface free energy (_s ^D) is the highest for MSX but the lowest for SX-II at all temperatures studied, whereas the specific component of surface free energy of adsorption (-G_A ^SP) is higher for SX-II than for SX-I. That SX-II displays the highest -G_A for the NP but the lowest _s ^D of all the SX samples may be explained by the additional -G_A change associated with an increased mobility of the probe molecules on the less stable and more disordered SX-II surface. The acid and base parameters, K_A and K_D, that were derived from H_A ^SP reveal significant differences in the relative acid and base properties among the samples. The calculated Hansen solubility parameters (_D, _P, and _H) indicate that the surface of SX-II is the most polar and most energetic of all the three samples in terms of specific interactions (mostly hydrogen bonding). Conclusions. The metastable SX-II polymorph possesses a higher surface free energy, higher surface entropy, and a more polar surface than the stable SX-I polymorph.     

Complexation of Nifedipine with Substituted Phenolic Ligands

The bioavailability of nifedipine in man is highly variable. This may be partly due to its poor aqueous solubility (5–6 µg/ml over pH 2.2–10.0, as determined in this laboratory). We initiated this study to examine the enhancement of aqueous nifedipine solubility via complexation. A series of substituted aromatic ligands was studied to identify those structural features important for complexation with nifedipine. The studies were performed at 25°C employing the solubility technique, using pH 2.2 or 7.0 buffers at an ionic strength of 0.25 M. The apparent equilibrium complexation constants for the 1:1 and/or 1:2 complexes were determined, where appropriate. A linear free-energy approach was used to relate K _1:1 with Hammett's sigma () and fractional partition coefficient () parameters. The following correlation was obtained: log (K _l:l/K _o = 0.31 + 0.l0 + 0.36 (r ² = 0.86, P < 0.003, N = 9), where K _o is the complexation constant for phenol. Statistical analyses showed that was more important than in affecting nifedipine complexation. The exact location of this interaction on the nifedipine molecule is undefined at present.     

Effect of nicotine and tacrine on acetylcholine release from rat cerebral cortical slices

Summary The effect of nicotine (1–10 M) and tacrine (9-amino-1,2,3,4-tetrahydroacridine; THA) on stimulation evoked release of [³H]acetylcholine from the rat brain slice preparation preincubated with [³H]choline was investigated.In these preparations, nicotine enhanced while tacrine inhibited evoked [³H]acetylcholine release. These effects were blocked by (+)tubocurarine (1 M) and atropine (0.1 M) respectively. In the presence of idazoxan (0.3 M) plus atropine (0.1 M), nicotine (3 M) continued to enhance evoked [³H]acetylcholine release while the inhibitory effect of tacrine (1 M) on evoked [³H]acetylcholine release was reversed to an enhancement. Under these circumstances the effects of both nicotine and tacrine were blocked by (+)tubocurarine (1 M).These findings demonstrate that tacrine can both inhibit or enhance [³H]acetylcholine release, most likely through its activity as a cholinesterase inhibitor. Under normal circumstances following tacrine the predominant effect of the elevated levels of acetylcholine will be activation of inhibitory presynaptic muscarine receptors on cholinergic nerves and an inhibition of evoked [³H]acetylcholine release. Under conditions where both presynaptic inhibitory muscarine and ₂-adrenoceptors are blocked, the elevated levels of acetylcholine produced by tacrine will lead to the activation of facilitatory presynaptic nicotine cholinoceptors on cholinergic nerves and an enhancement of evoked [³H]acetylcholine release. Send offprint requests to R. Loiacono at the above address     

Complex Formation Between The Anionic Polymer (PAA) and a Cationic Drug (Procaine HC1): Characterization by Microcalorimetric Studies

Purpose. Due to the importance of drug-polymer interactions in, inter alia, drug loading/release, supramolecular assemblies and DNA delivery for gene therapy, the aim of this study was therefore to establish the mechanism of interaction between a model polymer (Polyacrylic acid, PAA) and a model drug (procaine HCl). Methods. This was performed by studying the effect of salt (KCl) concentration on their heat released values using Isothermal Titration Microcalorimetry (ITM). The integrated released heat data were computer fitted to a one class binding model and the thermodynamic parameters (K_obs, H, and N) were determined. Results. As the KC1 concentration was increased, K_obs decreased thus establishing the salt dependence of the interaction. The linear variation of G_obs with S_obs indicated that their interaction was entropically driven. The stoichiometry of the interaction was calculated to be one procaine molecule per monomer of PAA. Dissection of the total observed free energy at each KC1 concentration indicated that the contribution of the non-electrostatic attractions to the interaction of PAA with procaine HC1 was greater than those of the electrostatic attractions. Conclusions. We have shown that the interaction between PAA and procaine HC1 is dependent upon the presence of counterions (monovalent ions) and is mainly entropically driven. The calculated stoichiometry indicated that one procaine HC1 molecule neutralised one carboxylic acid group on PAA. Although electrostatic interactions were necessary for initiating complex formation, the non-electrostatic forces were dominant in stabilising the PAA-procaine HC1 complex.     

Generalization of the discriminative stimulus properties of x0394; 9 in rats

Rats were trained in a water maze to discriminate between IP injections of 3 mg/kg ⁹- (⁹⁽¹¹⁾-THC) and its vehicle. Both ⁸- and ⁹⁽¹¹⁾ were generalized to the training drug. In contrast to our observations in rhesus monkeys, where ⁹-THC is at least 100 times less potent than ⁹-THC, ⁹⁽¹¹⁾ was found to be only seven times less potent in the rat. Relative potencies, expressed as the dosage at which 50% of the animals gave drug responses (ED₅₀) were 1.8 mg/kg and 12.2 mg/kg for ⁹-THC and ⁹⁽¹¹⁾ respectively. Twenty-four hours after receiving 7×ED₅₀=12 mg/kg ⁹ the tests showed intermediate results when conducted with the training dosage; 4×ED₅₀=50 mg/kg ⁹-THC 48 h prior to the training dosage of 3 mg/kg ⁹-THC completely blocked drug-appropriate responses. Coinjection of ED₅₀ dosages of ⁹- and ⁹⁽¹¹⁾-THC led to 90% drug responses, demonstrating the additivity of the cannabis-like effect of both cannabinoids. Differences in the individual sensitivity of the rats to the tested cannabinoids were observed. Findings are interpreted in terms of the receptor mechanism for cannabis-like activity.This paper is dedicated to the memory of Dr. M. Binder who died on February 15, 1984     

Immobilized Artificial Membrane (lAM)-HPLC for Partition Studies of Neutral and Ionized Acids and Bases in Comparison with the Liposomal Partition System

Purpose. To study the partitioning of model acids ((RS)-warfarin and salicylic acid), and bases (lidocaine, (RS)-propranolol and diazepam), with immobilized artificial membrane (lAM)-HPLC, as compared to partitioning in the standardized phosphatidylcholine liposome/buffer system. Methods. The pH-dependent apparent partition coefficients D were calculated from capacity factors (k_IAM) obtained by IAM-HPLC, using a 11-carboxylundecylphosphocholine column. For lipophilic compounds k_IAM, values were determined with organic modifiers and extrapolation to 100% water phase (k_IAMw) was optimized. Temperature dependence was explored (23 to 45° C), and Gibbs free energy (G), partial molar enthalpy (H) and change in entropy (S) were calculated. Equilibrium dialysis was used for the partitioning studies with the liposome/buffer system. Results. For extrapolation of k_IAMw, linear plots were obtained both with the respective dielectric constants and the mole fractions of the organic modifier. All tested compounds showed a similar pH-D diagram in both systems; however, significant differences were reproducibly found in the pH range of 5 to 8. In all cases, G and H were negative, whereas S values were negative for acids and positive for bases. Conclusions. In both partitioning systems, D values decreased significantly with the change from the neutral to the charged ionization state of the solute. The differences found under physiological conditions, i.e. around pH 7.4, were attributed to nonspecific interactions of the drug with the silica surface of the IAM column.     

Biorelevant Dissolution Testing to Predict the Plasma Profile of Lipophilic Drugs After Oral Administration

Purpose. To quantitatively compare in vitro dissolution data in biorelevant and compendial media, to investigate whether in vitro differences are reflected in the simulated plasma profile and to specify under which circumstances prediction of the plasma profile of orally administered lipophilic drugs can be achieved. Methods. Previously published dissolution data from seven products of four lipophilic drugs were compared using the first order model, the RRSBW distribution, and a model based on the Noyes-Whitney theory. Simulated plasma profiles were then obtained using a model-dependent approach. Simulated and observed plasma profiles were compared with the difference factor, f ₁. Results. No model consistently provided the best fit to the in vitrodata, which varied significantly with medium composition. Prediction of the plasma profile was possible (9.6 f ₁ 34.2) in seven out of eleven cases. Conclusions. Although prediction of the plasma profile of lipophilic drugs solely on the basis of in vitro data remains an ambitious target, this study shows that the plasma profile of a lipophilic drug can be predicted with appropriate in vitro dissolution data, provided that the absolute bioavailability of the drug is known and the drug has dissolution limited absorption.     

P1-purinoceptor-mediated modulation of neural noradrenaline and ATP release in guinea-pig vas deferens

The effect of P₁-purinoceptor activation on contractions, release of noradrenaline and release of ATP elicited by electrical field stimulation (210 pulses, 7 Hz) was studied in the superfused vas deferens of the guinea pig. Release of noradrenaline was assessed as overflow of total tritium after preincubation with [³H]-noradrenaline. ATP was measured by means of the luciferinluciferase technique.Electrical stimulation elicited reproducible contraction, tritium overflow and ATP overflow. In the absence of other drugs, adenosine (10–100 M) did not change evoked contractions but reduced the evoked overflow of tritium and ATP. In subsequent experiments ₁-adrenoceptors were blocked by prazosin, P₂-purinoceptors by suramin and ₂-adrenoceptors by rauwolscine. No or almost no contraction remained under these conditions. The evoked overflow of tritium was 505% and the evoked overflow of ATP 34% of that observed in the absence of prazosin, suramin and rauwolscine. Adenosine (1–100 M) again reduced the evoked overflow of tritium and ATP, and so did the A₁-selective agonist 2-chloro-N⁶-cyclopentyladenosine (CCPA; 0.032–0.32 M). Adenosine and CCPA decreased the evoked overflow of ATP to a greater extent than the evoked overflow of tritrium.It is concluded that neural release of both postganglionic sympathetic cotransmitters, noradrenaline and ATP, is decreased upon activation of prejunctional P₁- (A₁-) purinoceptors in guinea-pig vas deferens. The A₁-receptor-mediated inhibition of the release of ATP is more marked than the inhibition of the release of noradrenaline, a pattern opposite to the inhibition produced by activation of prejunctional ₂-autoreceptors. Correspondence to: B. Driessen at the above address     

Discriminative effects of combinations of Δ9-Tetrahydrocannabinol and pentobarbital in pigeons

The purpose of the present study is to examine potentially additive effects of pentobarbital and ⁹-Tetrahydrocannabinol ⁹-THC using a drug discrimination paradigm. Three groups of pigeons were trained to discriminate between the effects induced by i.m. administrations of either (a) 0.25 mg/kg ⁹-THC and vehicle, (b) 4 mg/kg pentobarbital and saline, and (c) ⁹-THC and pentobarbital. Test probes under extinction conditions produced orderly dose generalization gradients among the drug-vs nondrug-trained animals. ED₅₀ for pentobarbital was 1.60 mg/kg and ED₅₀ for ⁹-THC was 0.10 mg/kg. Tests in birds discriminating between pentobarbital and ⁹-THC suggested a sharpening of the drug cue effects; tests with the vehicles resulted in approximately a random key selection (33%–66%) while tests with combinations of the two training drugs suggested that ⁹-THC was the more salient cue in this group. Tests with combinations of various doses of pentobarbital and ⁹-THC in the drug-vs nondrug-trained birds did not increase responding on the respective drug-training associated key. Thus the cue effects of pentobarbital and ⁹-THC were not summational under these experimental conditions. In conclusion, rather low doses of pentobarbital and ⁹-THC are effective as discriminative cues in pigeons and the cues thus induced are different. Combinations of the two drugs are not necessarily summational, and the pentobarbital vs the ⁹-THC discriminations augmented the discriminable effects of the two drugs. In addition, the analeptic drug, bemegride, antagonizes the pentobarbital (4 mg/kg) stimulus in the group trained to discriminate between this barbiturate and saline, which agrees with earlier drug antagonism data obtained among mammals (gerbils and rats), required to discriminate between barbiturates and the nondrug condition.     

Endothelins induce prostacyclin release in both vascular and non-vascular tissue

The effects of an iv. administration of endothelin-1, –2 and –3 (0.25–3 nmol kg^–1) or their corresponding proendothelins (1–20 nmol kg^–1) on blood pressure and 6 keto-prostaglandin F₁ (6 keto-PGF₁) release in the anaesthetized ganglion-blocked rat were evaluated. The same peptides were tested for their ability to release 6 keto-PGF_1a from the rat vas deferens in vitro. Endothelins and proendothelins showed a transient hypotensive effect followed by a potent, long lasting vasopressor response. Blood pressure increase induced by endothelins was found to be dose-dependently correlated with 6 keto-PGF₁ plasma level increases. On the other hand proendothelins produced similar pressor responses, but their effect on 6 keto-PGF₁ plasma levels was much less intense at equipressor doses. The effects of endothelins on arterial pressure and 6 keto-PGF₁ release were phosphoramidon-insensitive, while the activities of proendothelins were reduced by phosphoramidon (10 mg kg^–1 i.v.). Both endothelins (5–15 nmol/l) and proendothelins (100–300 nmol/l) were able to increase to a similar extent 6 keto-PGF₁ levels in the rat vas deferens incubation buffer. The releasing activity of endothelins was not modified by the pretreatment with phosphoramidon (50 mol/l). This pretreatment strongly inhibited proendothelin-1 and –2 effects, but not that of proendothelin-3. In conclusion, the results presented in this study indicate that all tested peptides induce 6 keto-PGF₁ release in both vascular and non vascular tissue; all three proendothelins are activated by the same phosphoramidon-sensitive endothelin converting enzyme in our in vivo model, while proendothelin-3 may be processed by a different enzyme(s) in the rat vas deferens, in vitro. They also suggest a different localization of the sites where the peptides are activated and/or exert pressor activity and the sites where they induce 6 keto-PGF₁ release. Finally, prostacyclin release could have a general counter-regulatory activity on effects of endothelin peptides.Company related with A. Menarini Pharmaceuticals, Italy     

Cytotoxic triterpenoid saponins from Vaccaria segetalis

By the guidance of bioassay, one new cytotoxic triterpenoid saponin, 3-O-[β-d-galactopyranosyl-(1 → 2)-β-d-glucuronopyranosyl] quillaic acid 28-O-β-d-glucopyranosyl-(1 → 3)-β-d-xylopyranosyl-(1 → 4)-α-l-rhamnopyranosyl-(1 → 2)-[β-d-fucopyranosyl-(1 → 4)]-β-d-fucopyranoside (1), and five known cytotoxic triterpenoid saponins, vaccaroside E (2), vaccaroside G (3), vaccaroside B (4), segetoside H (5) and segetoside I (6), were isolated from Vaccaria segetalis. Their structures were established on the basis of ESI-MS, IR, extensive NMR (¹H NMR, ¹³C NMR, TOCSY, ¹H–¹H COSY, DEPT, HMQC, HMBC and ROESY) analyses, chemical degradation, and by comparing with previously reported data. Compounds 1–6 showed moderate cytotoxic activities against LNcap, P-388 and A-549 cell lines with IC₅₀ values in the range 0.1–12.9 μM.     

Effects of chronic exposure to Δ9-tetrahydrocannabinol on delayed matching-to-sample in chimpanzees

Three groups of four chimpanzees were trained on a 20-sec delayed matching-to-sample task and then were exposed to a 152 day chronic drug regimen. Two of the chimpanzees in each group were drug naive. The other two chimpanzees in each group had experienced 45 doses of ⁹-tetrahydrocannabinol ( ⁹-THC) four months prior to the present experiment. One group of animals served as nondrug controls. A second control group received an oral dose of 1.0 mg ⁹-THC per kilogram of body weight following each matching-to-sample session. The experimental group was given the same dose of ⁹-THC prior to each daily session. The initial administrations of the drug before but not after each session produced a significant decrease in matching-to-sample accuracy. During the course of the chronic drug regimen, animals in the experimental group recovered very slowly from this initial impairment in matching-to-sample performance. The extent to which the experimental animals recovered seemed to depend upon their pre-experimental drug histories. The drug-experienced animals developed complete tolerance within five weeks while the previously drug-naive animals did not so do even after five months exposure to the drug. However, no residual or long-term effects were observed following termination of the chronic drug regimen.The authors thank Dr. Monique C. Braude for her advice and support and Dr. Wolfgang Mueller for gas chromatography analysis. Research funded by National Institute of Mental Health Contract HSM 42-71-15. Synthetic ⁹-THC obtained by approval of the FDA-NIMH Psychotomimetic Agents Advisory Committee. The animals involved in this study were maintained in accordance with Guide for Laboratory Animal Facilities and Care as published by the National Academy of Sciences-National Research Council.     

Some anticholinergic-like behavioural effects of trans (—)-Δ8 tetrahydrocannabinol

Mice were intraperitoneally dosed with trans(–)- ⁸ tetrahydrocannabinol, various anticholinergic agents, hallucinogenics, or other behaviourally active drugs immediately prior to a habituating experience. The anticholinergic agents and trans(–)- ⁸ tetrahydrocannabinol inhibited the subsequent influence of the habituating experience relative to the other drugs and to solvent treated subjects. The habituation modifying effects of these drugs were antagonized by tacrine, but not by d-amphetamine. The results suggest that the behavioural effects of tetrahydrocannabinols might involve an anticholinergic mechanism.The research described herein was done while the author was a Summer Research Fellow at the University of Manitoba.The author is indebted to Dr. A.B. Morrison,Deputy Director-General, Canadian Food and Drug Directorate, Ottawa, for supplying the trans(–)- ⁸tetrahydrocannabinol.