Adults with autism spectrum disorder (ASD) and intellectual disability (ID) are the majority of population in residential settings. Many clients in residential settings engage in problem behavior that interferes with their daily routine and work requirements. Restricted and repetitive behavior are one of the features of ASD diagnosis, typically in the form of invariable responding and predictable responses. Differential reinforcement has been used to produce and maintain response variability. I evaluated the utility of a fixed ratio 1 (FR1) schedule on variability to increase the diversity of activity selections in the treatment of problem behavior occasioned by the interruption of routines. Chase engaged in problem behaviors in his bathroom routine, no matter by himself or with his housemate. Results demonstrated a reinforcement-based treatment increased both variable and novel selections while decreasing the rate of self injurious behavior.

Cette thèse se propose d’étudier la discrimination des comportements par les quantités de réponses itérées. Ce champ de recherche s’inscrit dans celui, plus large, de la discrimination des comportements par les quantités. Nous avons tout d’abord cherché à explorer la façon dont les comportements peuvent être discriminés par des quantités différentes d’itérations de réponses et de quelle façon l’installation ou non de cette discrimination peut être mise en correspondance avec une évolution de l’entropie du débit des réponses itérées. Ensuite, nous avons exploré la dynamique des réponses itérées en fonction de la quantité des itérations requises. Après cela, nous avons cherché à savoir s’il était possible de mettre en correspondance l’existence de dynamiques de réponses propres à des quantités avec l’installation ou non d’une discrimination des comportements par des couples différents composés de ces mêmes quantités. Enfin, en vue d’explorer en quoi l’installation d’’une dynamique des réponses permettait l’installation d’une discrimination des comportements, nous avons perturbé, en modifiant la topographie des réponses requises, l’installation de cette dynamique de réponses, et en avons mesuré les effets sur l’installation de la discrimination de comportements par ces quantités de réponses itérées. Les résultats montrent que l’évolution de l’entropie des débits de réponses itérées est orientée en fonction de l’installation ou non d’une discrimination des comportements par des quantités différentes d’itérations de réponses requises : l’entropie diminue lorsque la discrimination par des quantités de réponses itérées est installée, et augmente dans le cas contraire. Ce résultat n’est vrai que pour les participants ayant atteint au moins une fois le critère de décision que nous nous étions fixé pour juger de l’installation de la discrimination. L’analyse de la dynamique des réponses itérées en fonction de chaque quantité d’itérations requise montre qu’il existe presque systématiquement une dynamique propre à chaque quantité d’itérations de réponses requise, pour tous les participants, cette dynamique de réponses étant également propre à la topographie de la réponse requise. La perturbation de l’installation de la dynamique des réponses a, en outre, un effet sur l’installation de la discrimination des comportements par les quantités d’itérations de réponses. Au regard de ces résultats, nous pouvons conclure qu’il existe une correspondance entre l’installation ou non de la discrimination par des quantités de réponses itérées et l’évolution de l’entropie des débits de ces réponses itérées. Néanmoins, tandis que nous pouvons conclure à la pertinence d’analyser la dynamique des réponses itérées pour en étudier la complexité, la mise en correspondance entre celle-ci et la façon dont chaque quantité d’itérations de réponses prend ou non le contrôle de comportements spécifiques n’est pas possible à ce stade, bien que des pistes vers de futures études aient été proposées, pour explorer plus avant cette relation / This dissertation focuses on discrimination of behaviors by iterated responses, which falls in the scope of field of discrimination by quantities. First, we investigate how discrimination by several couples of iterated responses quantities could be related with the evolution of instantaneous rates of iterated responses entropy. Then, iterated responses dynamic was analyzed for several iterated responses quantities, and response topographies. The third experiment investigates the correspondence between specific dynamics of responses exhibited in fixed-ratio schedules and discrimination by couples of quantities of iterated responses. At last, effects of the disruption of the installation of the dynamic of responses on discrimination by these quantities of iterated responses have been measured. Results show that discrimination by quantities of iterated responses is possible, and that specific dynamics of responses match specific quantities of iterated responses. Although correspondence between such dynamics and discrimination have not been demonstrated, effects of disruption of dynamic of responses installation have been observed suggesting that a link between dynamic of responses and discrimination exists.

Cancer is responsible for upward of 13% of human deaths. Contemporary chemotherapy of disseminated cancer is often thwarted by dose limiting systemic toxicity and by multi-drug resistance (MDR). Riminophenazines are a novel class of potential anticancer agents that possess a potent multi-mechanistic antineoplastic action. Apart from their broad action against intrinsic, non-classical resistance, Riminophenazines inhibit the action of Pgp and hypothetically all ABC transporters demonstrating their great utility against classical MDR. Considering that combination chemotherapy is the norm, the vision directing R&D efforts was that Riminophenazines could be used with benefit within many standard chemotherapeutic regimes. The strategic intent of this project was to attain improved therapeutic benefit for patients through gains in both pharmaco dynamic and pharmacokinetic specificity for cancer cells over what is currently available. Tactically, this was driven through the use of synergistic Fixed-Ratio Drug Combinations (FRDC) encapsulated within tumour-targeting Nanoparticulate Drug Delivery Systems (NDDS). Long-term aims of this R&D project were to: 1) Screen FRDC of clofazimine (B663) and the lead derivative (B4125) with etoposide, paclitaxel and vinblastine for synergistic drug interactions in vitro. 2) Design, assemble and characterize a novel nanoparticulate, synergistic, anticancer co-formulation. 3) Evaluate the in vivo safety and efficacy of the developed product/s in accordance with international regulatory guidelines. Using the median effect and combination index equations, impressive in vitro synergistic drug interactions (CI<1) were shown for various FRDC of the three standard chemotherapeutics tested (etoposide, paclitaxel and vinblastine) in combination with either B663 or B4125 against MDR neoplastic cell cultures. Considering in vitro results and with the view to advance quickly to clinical studies, the already approved clofazimine (B663) was elected as the combination partner for paclitaxel (PTX). Considering the potency and wide action of PTX, a novel coformulation (designed to circumvent drug resistance) has the potential to greatly impact upon virtually all cancer types, particularly if selectively delivered through innovative delivery systems and loco-regional administration. A passively tumour targeting, micellular NDDS system called Riminocelles™ that encapsulates a synergistic FRDC of B663 and PTX has been designed, assembled using thin film hydration methods and characterized in terms of drug loading, particle size, zeta potential, CMC and drug retention under sink conditions. An acute toxicity and a GLP repeat dose toxicity study confirmed Riminocelles to be well tolerated and safe at clinically relevant dosages whilst Taxol® (QDx7) produced statistically significant (P<0.05) weight loss within 14 days. The same study demonstrated statistically significant (P<0.05) tumour growth delays superior to that of Taxol at an equivalent PTX dosage of 10 mg/kg. Importantly, all components (amphiphiles and drugs) used in assembly of Riminocelles are already individually approved for medicinal use - this promotes accelerated development towards advanced clinical trials and successful registration. Although these results are very promising (outperforming Taxol), this system was however found in a pharmacokinetic study to suffer from in vivo thermodynamic instability due to the high concentration (abundance) of albumin present in plasma. For this reason, in vivo longevity within circulation, permitting passive tumour accumulation was not fully realized. A second NDDS called the RiminoPLUS™ imaging system was additionally developed. This lipopolymeric nanoemulsion system has successfully entrapped Lipiodol® Ultra fluid (an oil based contrast agent) within the hydrophobic core of a monodisperse particle population with a size of roughly 100 nm and a stability of one week. This formulation is therefore thought capable of CT imaging of tumour tissue and drug targeting after either intravenous or loco-regional injection. In vivo proof of the imaging concept is warranted. The results of this study serve to highlight the great potential of in vitro optimized synergistic FRDC against drug resistant cancers. Lipopolymeric micelles are an effective way to formulate multiple hydrophobic drugs for intravenous administration and present a means by which cancer can be readily targeted; provided that the delivery system possess the prerequisite in vivo stability and surface attributes. Further experiments exploring synergistic drug and biological combinations as well as “intelligent” NDDS actively guided through specific molecular recognition are called for. / Thesis (PhD)--University of Pretoria, 2012. / Pharmacology / unrestricted