Solubility of Pharmaceutical Ingredients in Natural Edible Oils.

Natural edible oils (NEOs) are common excipients for lipid-based formulations. Many of them are complex mixtures comprising hundreds of different triglycerides (TGs). One major challenge in developing lipid-based formulations is the variety in NEO compositions affecting the solubility of active pharmaceutical ingredients. In this work, solubilities of indomethacin (IND), ibuprofen (IBU), and fenofibrate (FFB) in soybean oil and in coconut oil were measured via differential scanning calorimetry, high-performance liquid chromatography, and Raman spectroscopy. Furthermore, this work proposes an approach that mimics NEOs using one key TG and models the API solubilities in these NEOs based on perturbed-chain statistical associating fluid theory (PC-SAFT). Key TGs were determined using the 1,2,3-random hypothesis, and PC-SAFT parameters were estimated via a group-contribution method. Using the proposed approach, the solubility of IBU and FFB was modeled in soybean oil and coconut oil. Furthermore, the solubilities of five more APIs (IND, cinnarizine, naproxen, griseofulvin, and felodipine) were modeled in soybean oil. All modeling results were found in very good agreement with the experimental data. The influence of different NEO kinds on API solubility was examined by comparing FFB and IBU solubilities in soybean oil and refined coconut oil. PC-SAFT was thus found to allow assessing the batch-to-batch consistency of NEO batches in silico.

The effect of cinnarizine and cocculus indicus on simulator sickness.

Pensacola Simulator Sickness Questionnaire (SSQ) is a valuable method to analyse symptoms evoked by exposure to a flight simulator environment that can also be adopted to evaluate the effectiveness of preventive tools, aiming at reducing simulator sickness (SS). In this study we analysed SSQ data in subjects undergoing a standard ground based spatial disorientation training inside a flight simulator, in order to evaluate the SS prevention obtained with two different pharmacological tools. Twelve males volunteers participated to an experimental design based on a double-blind, balanced administration of either 30 mg cinnarizine (CIN), or Cocculus Indicus 6CH (COC), or placebo (PLC) before one trial of about one hour spent inside a spatial disorientation trainer. All subjects underwent the three different conditions (CIN, COC, PLC) during 3 non-consecutive days separated by at least 2 weeks. During each experimental day, all subjects filled in SSQ. In addition, both postural instability (with the use of a static stabilometric platform), and sleepiness symptoms were evaluated. All the tests were performed before and after the simulated flight, at different times, in one-and-half-hour intervals. Results indicated a strong increase of sickness after flight simulation that linearly decreased, showing pre-simulator scores after 1.30 hours. In contrast to both PLC and COC, CIN showed significant side effects immediately following flight simulation, with no benefit at the simultaneous SSQ scores. Globally, no highly significant differences between COC and PLC were observed, although a minor degree of postural instability could be detected after COC administration. As far as the present exposure to a simulator environment is concerned, none of the pharmacological tools administered in this study resulted effective in reducing SS symptoms as detected by the SSQ. Moreover, CIN significantly increased sleepiness and postural instability in most subjects.

Memory effects of the Ca2+ and 5-HT antagonists dotarizine and flunarizine.

In experiments on Wistar and Long Evans rats, using behavioral methods for passive (step-down and step-through) and active (shuttle-box two-way avoidance with punishment reinforcement) the newly synthesized diphenyl-methyl-piperazine derivative with Ca2+ and 5-HT antagonistic action dotarizine (DOT) administered repeatedly at oral doses of 50 and 10 mg/kg in some cases improve memory process. Under the same experimental conditions the chemically related to dotarizine Ca2+ antagonist flunarizine significantly facilitated retention. In old (Long Evans and Wistar) rats DOT in large dose decreases values of learning criterion. Probably this is a manifestation of the inherent to drugs with nootropic action "therapeutic window". Earlier investigations of the same and other authors suggest the participation of serotonergic neurotransmission in the mechanism of the memory effects of the drug DOT.

Effects of cinnarizine on different experimentally induced oedemas.

Experiments with male mice (28-32 g) of the CFLP strain showed that cinnarizine in doses of 2.5, 5.0 or 10.0 mg kg-1 significantly inhibited the extent of ear oedema induced by croton oil, capsaicin or dithranol, in a dose-dependent manner. In rats of the Wistar strain, oedema was induced in the hind paw by subplantar injection of carrageenin, and simultaneously by the application of croton oil to the inner surface of the ear. Preliminary cinnarizine treatment (5, 10 or 20 mg kg-1) inhibited the development of both types of oedema, to a statistically significant extent, in a dose-dependent manner.

The effect of ethanol and calcium channel antagonists on rabbit EEG.

The influence of nifedipine, verapamil, and cinnarizine on the effect of ethanol on EEG of rabbits (frontal cortex, hippocampus, MRF) was tested. Nifedipine (1.75 mg/kg, IP) and cinnarizine (7.5 mg/kg, IP) were given 30 min before ethanol administration. Verapamil (0.2 mg/kg, IV) was given 15 min before ethanol injection in a dose of 0.8 g/kg IV. Ethanol caused the increase of the frequencies 0.5-4 cps in the recording, as well as a marked decrease of the fastest frequencies. Verapamil prevented ethanol's effect on EEG recording. Cinnarizine antagonized this action to a smaller extent and the influence of nifedipine is transitory and less pronounced.

Relaxation by calcium antagonists of potassium-contracted trachea from normal and sensitized guinea-pigs: influence of epithelium and the surface of drug entry.

A technique by which drug access was restricted to either the mucosal or the adventitial surface of tracheal rings, isolated from normal (unsensitized) or sensitized guinea-pigs, was used to study the role of the epithelium in the relaxation produced by calcium antagonists (verapamil, nifedipine, cinnarizine and flunarizine) of K(+)-induced contraction. In trachea from normal guinea-pigs, the relaxation to verapamil for unrestricted or mucosal drug entry was reduced in the absence of epithelium, whereas the relaxation produced by nifedipine, cinnarizine or flunarizine was unchanged. In sensitized trachea, the relaxation elicited by the calcium antagonists tested was similar in intact and epithelium-denuded tracheal rings irrespective of the surface of drug entry. These results confirm that the epithelium influences the relaxation to verapamil. This modulatory effect is absent in sensitized trachea and is not shared by other calcium antagonists.

[Effects of flunarizine on cerebral venous outflow and cerebral oxygen consumption].

1) Flunarizine (0.3 and 1 mg/kg, i.v.) and papaverine (1 mg/kg, i.v.) caused significant increases in cerebral blood flow and decreases in cerebral vascular resistance with concomitant increases in cerebrospinal fluid pressure, in spite of decreases in systemic blood pressure. The duration of these effects by flunarizine were longer than those by papaverine. 2) Heart rate increased markedly with papaverine, while it decreased with flunarizine only at a dose of mg/kg, i.v. Central venous pressure increased slightly and temporarily with flunarizine, but it was not changed with papaverine. 3) Cerebral arteriovenous oxygen difference decreased with either of the drugs at a a dose of 1 mg/kg, i.v. Meanwhile, cerebral oxygen consumption was not affected by flunarizine or papaverine. 4) Either of the drugs increased the PO2 of the cerebral venous blood temporarily and slightly, but significantly, as well as the end tidal CO2 concentration. These results suggested that flunarizine has a longer acting cerebral vasodilatating effect that papaverine does without any effect on the cerebral oxygen consumption.

Selective abolition of Ca-dependent responses of smooth and cardiac muscles by flunarizine.

The inhibitory effect of flunarizine on the Ca-dependent responses was compared with that of verapamil in isolated smooth and cardiac muscles. Flunarizine at a small dose shifted to the right the dose-response curve for Ca2+ of the phasic contraction due to electric stimuli in rabbit basilar strips, while in a large dose, flunarizine reduced the maximum tension and slope of the dose-response curve. The high K+-induced vasoconstriction of the rabbit basilar artery was inhibited by flunarizine. However, the action of flunarizine was about 30 times slower than findings with verapamil. The spontaneous activity of the rat portal vein was less susceptible to flunarizine, whereas that of rat uterus was completely inhibited by flunarizine. Flunarizine possessed moderate negative chronotropic and inotropic actions on the right atria and papillary muscles of the rabbit. Our experiments indicate that flunarizine is selective in antagonizing Ca-dependent contraction of the rabbit basilar artery, probably by blockade of the transmembrane Ca. It is also possible that the slow onset of action and nonsurmountable antagonism produced by flunarizine is due to other pharmacological interventions such as delayed effect of metabolites, stabilizing action or tight binding on the cell membrane of vascular smooth muscles.

Hypolipemic activity of clofibrate-related compounds. 2nd Communication.

Clofibrate-related compounds were synthesized from substituted phenoxyacetic acids by esterification with salicylic acid derivatives, by amidation of thiazolidines or by reaction with cinnarizine. Lipid lowering effect was investigated in normolipemic and hyperlipemic rats. The long-term hyperlipemic model used permits differentiation of hypolipemic efficacy, i.e., from clofibrate or compounds of similar activity.