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By C. Rathgar. Saint Xavier University.

We will try to be as up-to-date as possible in the information that we provide at the time that this chapter is being written buy discount avanafil 200mg. It should be noted that generic 50mg avanafil fast delivery, in this chapter order 100 mg avanafil with visa, most comparisons done between differ- ent drugs are restricted to our own personal viewpoint; because of legal reasons and personal pride, the drug developers would claim originality to their own discoveries. Hence, we would like the readers to read with an open mind and come up with their own interpretations of the information that we provide. During the process of changing a peptide drug to a peptide-like drug and eventually to a nonpeptide drug, the naming of each residue becomes confusing because two or more residues may be merged into one functional structure. We will be using the Schechter and Berger [1] nomen- clature that assumes that the substrate binds to the active site of an enzyme in an extended backbone conformation. Within the active site, subsites, also referred to as pockets, ′ are denoted as Sn and Sn, where n represents the number of subsite away from the catalytic S1 subsite, with the prime symbol denoting the opposite direction. Often, N-terminal residues are referred as Pn, whereas C-terminal ′ residues are referred as Pn. The naming of peptide drugs follows the same rules as ′ ′ that of peptide substrates. For example, P2–P1–P1–P2 is a tetrapeptide drug with a ′ scissile bond between the P1 and P residues. For peptide inhibitors, the inhibitory 1 unit, which is the unit that prevents enzyme cleavage, is assigned to the P1 residue. One should keep in mind that because the numbering is based on the subsites of the active site rather than the sequential order of the residues of the peptide drug, and that the chemical structures of the enzyme and peptide drug are three-dimensional by nature, that in some cases, the numbering of the residues of the peptide drug may not follow a sequential order. In simpler words, there are cases where the peptide drug does not bind to the active site in an extended backbone conformation. An example of an irregular order numbering is argatroban, a direct thrombin inhibitor, which has aP3–P1–P2 sequence (Section 5. Hence, it is often easier to commercialize natural enzymes or activators of enzymes found in nature, and to develop inhibitors of enzymes, than to create more potent enzyme activators. A philosophical reasoning for this observation could be that nature has selected the best enzymes and their activators, whereas man can only copy or destroy nature’s refnements. Despite the previous statement, researchers have designed a few enzyme activators, such as α-methyldopa and droxidopa (Section 5. Here, we are loosely equating the term enzyme activator to substrate, because as far as we are aware, there is no allosteric activator in the pharmaceutical market. Most activators of enzymes, or the enzymes themselves, are developed via either extraction of pharmacologically active natural substances from a crude inexpensive natural source or by replicating the natural substances by synthetic means. On the contrary, most potent inhibitors of enzymes are derived from natural lead compounds, or from natural substrates that have been corrupted to become enzyme inhibitors. From our own experience, the frst step in substrate-based drug design of modula- tors is to establish an assaying system for enzyme activity. A modulator is either an activator or inhibitor, which in our case, applies to a substrate or its peptide inhibitor. As the initial step, a reproducible enzyme activity assay system must be developed from a substrate and enzyme that both must be stable and pure. It is noteworthy that the enzyme often can process several different substrates and the choice of substrate, especially in substrate-based design of enzyme inhibitors, will determine the structural outcome of the derived modulators. In order to improve the processing effciency of the substrate by the enzyme, the substrate and enzyme may be structurally altered by synthetic means to improve purity and stability, so as to reduce variations between experiment results. Often, the fnal substrate used in the assay is a shortened yet active version of a natural substrate, and the enzyme is modifed from its natural form to prevent self-digestion. Any drastic change from the natural substrate or enzyme could be viewed by the scientifc community as a huge leap from the substrate and the natural form of the enzyme, and thereby negatively refecting on the research as a false image of nature. A common method of substrate-based design of inhibitors entails the introduc- ′ tion of an inhibitory unit near the scissile bond, between the P1 and P1 residues of the substrate. The inhibitory unit is a modifed version of the P1 residue of the substrate such that the enzyme can recognize and bind to the inhibitory unit at the catalytic site, but the enzyme cannot readily cleave the inhibitor. A common mech- anistic feature of protease inhibitors is the presence of a transition state isostere, as a part of the inhibitory unit, to simulate the transition state of amide bond hydrol- ysis, as depicted in Figure 5. B from enzyme from enzyme Transition state mimetic inhibitor Pro N H O O O H H O O − O N N H O H O Figure 5. Our recent studies combined neutron diffraction crystallography to conclusively pro- vide direct experimental evidence of the catalytic mechanism of the protease and its inhibition by the inhibitory unit [5]. In the initial design of protease inhibitors, other than the central inhibitory unit, the remaining residues of the inhibitor are kept similar to that of the substrate. In simpler words, the inhibitor is a mimic of the substrate and cannot be processed by the enzyme. If the enzyme can cleave the inhibitor, albeit at a slower rate, or if the inhibitor can be washed out over time, the inhibition is considered reversible. If the inhibitor forms strong interactions with the enzyme to the extent that the inhibitor cannot be removed until the enzyme is degraded, then the inhibition is irreversible. If an unforeseen adverse drug effect is observed with an inhibitor, the adverse effect is expected to be more prolonged in an irreversible inhibitor than a reversible inhibitor. Hence, due to safety concerns associated with mammalian enzymes, the design of reversible inhibitors is often preferred over that of irreversible inhibitors. However, when it comes to nonmammalian enzymes, such as those of viruses and parasites, irreversible inhibitors may be favored over reversible inhibitors, in order to eliminate completely and quickly the viral or parasitic threat, once it has been ascertained that there is absolutely no chance of recognition by other mammalian host enzymes. Following the introduction of the inhibitory unit in the design, several attempts are performed to minimize the peptide nature of the molecule to avoid most peptide-associated problems that we have discussed in the introduction (Section 5. Of course, for the case of substrate-based design of activators, an inhibitory unit is obviously not introduced. During the ensuing rational drug optimization process, quantitative structure–activity relationship studies are performed to statistically confrm and suggest any potency trend observed in modulatory activity. The peptide drug is truncated to reduce size-related pharmacodynamic and pharmacokinetic problems. In consideration that the enzyme can most likely be able to process several different substrates, natural amino acid substitution studies are done on each amino acid residue of the peptide drug to improve inhibitory activity against the enzyme. Nonnatural amino acids are also substituted to avoid recognition and premature degradation by other enzymes. Generally speaking, amino acids serve as simple units that can somewhat be readily assembled, to probe the active site of the enzyme and obtain valuable information on the nature of the subsites [7]. Further structural changes to the drug are performed to improve several aspects, which may include balancing hydrophilicity and hydropho- bicity so as to improve blood–brain barrier permeation, oral bioavailability, and duration of action, or reducing adverse drug reactions and cost of synthesis. During the process of drug optimization, these modifcations progressively decrease the peptide nature of the molecule. After the peptide bonds of the peptide drug are altered, the fnal drug is then reclassifed by its inventors as being a nonpeptide. Three-dimensional structural information pro- vides a computer image of a complex of an enzyme and its inhibitor. It is noteworthy that the shape of the enzyme in complex with an inhibitor is completely different from that of an unbound enzyme. Hence, examining a three-dimensional depiction of an unbound enzyme is an exercise in futility. Moreover, it is obviously practi- cally diffcult to obtain a substrate-enzyme complex because peptide hydrolysis of the substrate would occur before any data could be gathered. Inspecting the coordi- nates of an inhibitor bound to an enzyme provides information about the nature of the subsites including pocket shapes and sizes, presences of sub-pockets, hydrophilic and hydrophobic surfaces, and potential sites for hydrogen bond, van der Waals, or hydrophobic interactions. Moreover, because we believe that inhibitor-enzyme bind- ing follows an induced-ft model, when several complexes of different inhibitors in the same enzyme are available, the fexibility of the subsites to accommodate for differ- ent residues can be deduced. From studies aimed at improving the cleavage effciency of a substrate, researchers can also obtain valuable information about the shape, size, hydrophobicity, and accommodating nature of the subsites, although with less details than three-dimensional structural data. It is noteworthy that because the fnal desired drug is a small molecule, complexes of small inhibitors in the enzyme are preferred over larger ones. Complexes of small inhibitors focus on the specifc subsites that are in close proximity to the catalytic subsite, whereas complexes of large inhibitors may induce distortions in the enzyme and lead to misinterpretations on the nature of the active site. Taken together what we have discussed, several three-dimensional structural coordinates of the derived small and potent inhibitors in complex with the enzyme are used to clarify the bound form of the active site of the enzyme. Knowing the fexibility, shape, and electronic properties of the active site means that novel mod- ulators, that is, inhibitors or substrates, can be designed without peptide drawbacks. At this stage of research, three-dimensional information of inhibitors bound to the enzyme along with information pertaining to the fexibility of the active site have provided suffcient data to search for potential nonpeptide lead compounds. From a generic chemical library, compounds that can ft and favorably electronically interact with the active site are searched through computer-assisted docking simulations, namely, vir- tual high throughput screening. These potential lead compounds are then synthesized and processed by high throughput assay screening to verify for activating or inhibitory activity toward or against the enzyme. Essentially, high throughput assay screening is an automated assaying method of a large library of potential lead compounds in microtiter plates. Once lead compounds are identifed, the compounds are structurally refned under rational drug optimization to derive potent compounds with desired pharmacodynamic and pharmacokinetic properties. Cellular and animal experiments are performed to confrm the expected pharmacodynamics and pharmacokinetics, as well as to examine for any unexpected adverse drug effects. Clinical trials are divided into four phases in which the drug is administered to volunteer trial participants. Because the tests are ethically conducted on living humans, there are extensive rules and standards governing the trials and their evalua- tions. Throughout the clinical phases, safety, effectiveness, adverse risks, and adverse reactions associated with the investigational drug in human are continuously moni- tored.

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In general order 50mg avanafil with amex, the introduction of a new product-contact material order avanafil 50mg fast delivery, however discount 50 mg avanafil mastercard, the proposed change is acceptable if the overall risk profile has increases risk and should be examined more thoroughly. If the overall risk profile, however, has increased for should be pursued, individual risks associated with the pro- the majority of critical parameters that were assessed, the pro- posed state (change) are not thoroughly explored through posed change should not be accepted until additional analyses this tool. These individual risks are best assessed through are conducted or risk mitigation measures are pursued. Ahunji Aoki, Hyogo University of Health Sciences, Japan Me and my Rotavapor Experience evaporation from the market leader The Rotavapor® System is a unique combination of cunning system configu- ration and trend-setting design. The benefits of working with the Rotavapor® System are: simple installation process, easy to use, time saving, sustainable, central process control and many more. Determine qualitative scales for insufficient Minor capacity (50L) likelihood and severity rankings. Identify critical parameters for the system under re- difficult to assign a likelihood score if there is no available view. Rank each potential failure for likelihood and severity tive approach and assign a likelihood score of “certain” to using the criteria established in Step 1. Two qualitative scales will be developed, each con- Because in this example the overall risk is driven primarily taining three potential scores. The likelihood scale addresses by a lack of data, mitigation efforts would focus on biocom- how likely is it that the failure will occur, given the cur- patibility testing to better understand the implications of rent controls in place. Once this action is taken, from remote (unlikely) through average (likely) to certain it is expected that overall risk would then be reduced to an (very likely or unknown). The severity scale ranges from minor (in- Conclusion significant impact) through moderate (moderate impact) to To ensure that the quality system and associated processes critical (significant impact). The application of quality risk management whether mitigation measures are required. Low-risk items principles and tools facilitate this understanding, allowing may not require any mitigation activities or resource ex- for more comprehensive strategy development and informed penditure, whereas high-risk items will require additional decision-making. It is not always, however, necessary to per- risk control measures to reduce risk to an acceptable level. Returning to the hypothetical saline solution scale-up, For simple systems and processes as well as for changes that the risk team would first brainstorm potential failures as- are well understood, less-formal tools such as the compari- sociated with each critical parameter for the saline solution son matrix and risk estimation matrix provide a comprehen- process. For example, the batch could fail the bioburden sive picture of the associated risk in an easily applied format. This article is the fifth a proposal for the analytical assessment and control of both drug paper in the series and focuses on specifications. These recommendations take into consideration the differences in clinical trials in early development versus those in later development and provide a starting point to stimulate discussion on specifications in early development. Due to the high attrition rate in early develop- Frank Swanek works in Analytical Development, both at ment, consistent specifications that ensure patient safety are desir- Boehringer Ingelheim Pharmaceuticals Inc. Trone works in and corresponding synthetic and formulation process undergo Analytical Development–Small Molecule at Millennium Pharmaceuticals, Inc. Hovione’s comprehensive approach provides multiple particle engineering technologies to address your specific development needs. Our experienced team of scientists and engineers applies state-of-the-art principles and tools to improve bioavailability. With a proven track record of commercialization, Hovione will drive your molecule from early clinical to market. To learn more about how Hovione can overcome the solubility issues that stand in the way of your success, visit hovione. These tests can be performed to collect information for Inno vative Solutions product and process understanding, or to allow for tighter control (i. If the tox batch is also intended to be used in a clinical study, Coupons there is an advantage in that the qualification of impurities for the clinical studies is inherently assured. As development progresses towards commercialization, specifications may be introduced. Internal testing may have target acceptance criteria tighter than the release testing criteria. Description, or appearance, is a test describing the analytical methods is assessed. The recommended early phase acceptance criteria is often a recommended range is 97. This testing ensures that the drug being dosed is potency factor that takes into account related substances, residual traceable to the same chemical entity that was qualified in the solvents, moisture, counterion, and inorganic impurities present. In early phase development, there is limited exposure to the ous impurity scenarios to illustrate the utilization of the proposed clinical candidate and low numbers of individuals participate in early clinical identification and qualification thresholds and their these early clinical studies. It is recognized that individual companies criterion often correlates with what is known about the individual within industry may choose to apply different impurity qualifi- impurities. However, a higher upper of safety in the context of the individual development program. Chiral impurities are usually held to the same have not been qualified by toxicology studies. However, the target limit for the minor enan- would be assessed from a toxicological perspective, appropriately tiomer can vary based on understanding of its pharmacological qualified as necessary, and the relevant specifications updated ac- activity, toxicological qualification, metabolism pathway, and cordingly. Later in development (Phase 2b and beyond), when a purging capabilities of the synthetic process. The early development specifications for residual- later steps of the synthetic process (e. Attribute Proposed acceptance criteria Release testing Internal testing Stability testing Describe color, shape and dosage form (e. For water content, there is normally limited infor- These tests are often linked to process consistency, and in early mation available about a compound’s sensitivity to moisture in phase development there is sometimes a temptation to set wide early development. Although it is important that data be collected, limits based on limited manufacturing experience. Instead, it is initially the acceptance criteria should be “report results” unless the recommended to gather data through internal/characterization product quality is known to be sensitive to water. Limits for mutagenic or potentially phic form can impact on solubility, stability, and bioavailability, mutagenic impurities have been the subject of much discussion any change in form is typically monitored during stability studies. In early develop- impurities continues to evolve, the recommendation is to follow ment, many of the formulations are relatively simple (e. If so, these should be suitably This guidance provides classifications and permitted daily ex- determined using pharmacopeial procedures. For many tests, it is important that charac- 92 Pharmaceutical Technology OctOber 2012 PharmTech. Dissolution may quently established for capsules and tablets that are used in early be performed as an internal specification (i. In these cases, acceptance criteria should be included in formulation process control while accounting for typical assay the specification. The proposed limit for product and process changes that occur early in development. In closing, it is recognized that each company hydrolysis, and oxidation is still being acquired. Later in develop- needs to evaluate these early development recommendations ment, process control, formulation design, and product protection based on the objectives of their individual drug development strategies to minimize product degradation can be implemented programs and may choose not to adopt this industry proposal after the compound sensitivities are better understood and thus on phase appropriate specifications. Uniformity of dosage units:The uniformity of active material in dos- References age units is important to the integrity of the clinical trial and to 1. Cosmetic coatings are used to achieve an appealing appearance, to help differentiate between different dosage forms, and to Chelp with blinding the samples in clinical trials. Functional coatings are required for the protection of the drug from moisture, to mask the bitterness or smell of drugs, and to modify the release of actives by, for example, providing gastric resistance, targeting certain regions in the gastrointestinal system, or prolonging the release. A coating with a functional polymer is often applied directly after the drug-layering step. Coating liquids, substrates, and the type of coating Common polymers used in coating have a range of proper- application all play a role in the difficulty of the ties and functions, and some examples are shown in Table I. The authors describe the coating amount of polymer in the coating is given as a range because the process and propose a matrix to calculate the actual amount depends on several factors, including: relative difficulty of a particular coating system, • Surface area of the particles, with smaller particles re- quiring higher amounts of polymer to achieve the which can be used as a tool for choosing the desired functionality. The actual polymer amount should be calculated based on the measured, specific surface area. Coating liquids Polymers for liquid coating are available as solutions or dispersions with a broad range of viscosities, and the liquids may contain sus- pended particles. Liquid properties should always be considered when choosing the right equipment for processing. With revolutionary, proprietary technology, Captisol is rationally engineered to significantly improve solubility, stability, bioavailability and dosing of active pharmaceutical ingredients. Polymer amount Polymer (Eudragit, Evonik) Property Function % (w/w) mg/cm² Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl Cationic, Moisture protection 10–30 1–6 methacrylate) 1:2:1 (Eudragit E types) soluble < pH 5 Taste masking 5–10 1–2 Anionic, Enteric protection, Poly(methacrylic acid-co-ethyl acrylate) 1:1 (Eudragit L 30 D-55 and L 100-55) 10–30 4–6 soluble > 5. Particles in close contact Film formation and curing Particles deformation The mechanism of film formation is different for dispersions Packing of deformed particles and solutions. Mechanically Free volume With solutions, the polymer and the liquid phase are in a ho- coherent dry films mogeneous system, as shown in Figure 2. Established in 1976, the world’s leading pharmaceutical com- panies have come to depend on Coating Place as their most trusted and reliable source of Wurster processing for: >> Feasibility studies >> Process validation >> Formulation development >> Scale-up >> Analytical laboratory support >> Technology transfer >> Commercial manufacturing >> And more We offer unsurpassed knowledge and expertise in the microencapsulation of powders, granules, and crystals for: >> Oral delivery for controlled, delayed, sustained, or enteric release >> Taste or odor masking >> Moisture or oxygen barrier applications >> Time release ion resin suspension technology email: info@coatingplace. The film is formed by evaporation of the solvent, and the process temperature de- fines the evaporation speed. If the solvent is evaporated too fast, free volume in the polymer film will be generated, and aging Concentrated Dense polymer effects can occur as described above.

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This finding suggested to the authors the relative independence of experiencing time from the act of judging time 200mg avanafil visa. Thus he avoids the frustration of having to remain in the situation at a time when he might otherwise expect release 100 mg avanafil visa. The importance of time orientation in influencing response to isolation and confinement is well documented buy 200mg avanafil fast delivery. Burney (13) describes the elaborate procedures he developed for telling time and of his precise knowledge of dates during eighteen months of solitary confinement. Anecdotal reports have cited very complex schemes worked out by subjects to maintain their orientation in time. Just as deprivation and isolation appear to disrupt general cognitive orientations, so too this situation appears to have similar disruptive effects on time perception. As such, resistance to the disintegrative effects of deprivation and isolation might well emphasize the importance of developing orienting anchors in the external environment for both time and space. Stimulus Hunger Although the implication of most studies thus far discussed has been that deprivation produces "stimulus-hunger," only one study has made a direct attempt at its measurement. The boredom and restlessness mentioned in the section on feeling states may refer to the phenomenon. If one can inhibit such maneuvers long enough, intense satisfaction is derived from later self-stimulations. These records contained the following types of material: eight repetitions of the 16-bar chorus of "Home on the Range"; two talks for children, taken from a religious primer; radio commercials for soap; and part of a stock market report. One group heard the records before isolation, whereas the second group was told nothing about it until several hours after entering isolation. Once in the experimental situation, subjects were told they could hear any of these materials, whenever and as often as they liked. They found that the four subjects exposed to the material before isolation universally disliked the records and only asked to hear them a total of nine times. The other group asked for the records fifty-three times, and reported that they helped to relieve the boredom. In addition, it was found that the rate of requests for the records was dramatically higher during the second half of the confinement period. Previous exposure to the material seemed to be the principal factor influencing the demand for stimulation. One major problem that subjects report in the deprivation situation is the lack of things to see, hear, do, or think about. This subjective complaint seems to have clear relevance to the notion of curiosityexploratory drive studied in experimental work with animals. The isolation conditions thus seem to increase receptivity to otherwise dull, uninteresting material. Quantification of these phenomena might provide a useful index for comparing the relative severity of deprivation conditions. Influence of Experimental Setting We have already referred to the findings of Ruff et al. Such factors as provision of tasks during isolation, specification of the length of deprivation, and previous exposure to isolation result in making the experimental conditions more tolerable to subjects. The comparison of two conditions of confinement in the tank respirator has also pointed to the increase -84- in stress and decreased length of stay that accompanies an increase in isolation and reduced contact with experimenters and environment (47). Additional papers discuss other variables operating to influence response to isolation and deprivation (18, 46). Kandel, Myers, and Murphy (45) compared the effects of two sets of instructions on the reporting of visual sensations in ten minutes of darkness. They found that one group, who were told the experiencing of such sensations was to be expected under these conditions, reported significantly more visual sensations than did another group, told that these sensations appeared in psychiatric patients. Prior verbalization of "fantasy material" through exposure to Rorschach cards did not increase the number of sensations reported when compared with a group not given this test. We have mentioned earlier that all of these studies have employed volunteer subjects, generally paid volunteers, with the exception of that of Ruff et al. When, in one study (80), these volunteers were questioned about their motivation for participating, they offered, in addition to the money, reasons such as aiding science and testing themselves. There is no such data available on possible differential reactions of volunteers and nonvolunteers. These studies highlight the importance of procedural variables and limit the direct comparison of studies utilizing different procedures. They emphasize again the need for specification of experimental purposes and for procedural choices consistent with those purposes. In this connection the importance of evaluating the total context and its implicit motivational and emotional consequences needs to be clearly recognized. One of the earliest interests in this area was reported by Spitz in a series of articles (73, 74, 75) which dealt with the deleterious developmental and behavioral effects of institutionalization and separation from the mother upon infants. A reading of these reports indicates that perceptual deprivation was a prominent feature of the experience of these children. A more direct application of isolation and deprivation to clinical procedures has been attempted recently (1, 2, 3, 4). In these procedures, patients with a variety of clinical diagnoses were kept in a darkened hospital room, wore translucent goggles, and had their arms in cardboard cylinders. Although few of the cognitive changes described earlier were observed, these investigators concluded that deprivation led to a state of disorganization, and in some cases precipitated psychotic reactions. On the other hand, some groups, particularly depressives, seemed to show improvement in the form of increased motivation, socialization, and assertiveness. Phenomena akin to those reported in isolation and deprivation have also been reported in aviators, especially in high speed, high altitude flying. Citing clinical material on these flyers, Bennett (6) compared their reactions to those seen in isolation studies. Operating in a severely restricted environment with extremely monotonous stimulation, aviators have reported feelings of isolation, unreality, and dreamlike states. Evidence suggests that these feelings, called by some the "breakoff phenomenon," occur at times in approximately one-third of jet pilots. Earlier reference was made to the response of prisoners who in solitary confinement apparently experience similar reactions. These included, on the one hand, occasional tense pacing, restlessness, tension, and assaultiveness. On the other hand, some prisoners exhibit a regressed, dissociated, withdrawn, hypnoid, and reverielike state. Already mentioned is the work of Mendelson and Foley (54) which showed the importance of isolation and deprivation in polio patients. Two recent papers have appeared that stress the importance of these findings in understanding a number of phenomena seen in medical -86- practice (48, 81). These reports stress the relevance of this work to the hallucinations of cataract patients, and to the disturbances seen in patients with orthopedic disorders who are suspended in traction. Perceptual deprivation also has relevance to prolonged and repetitive tasks in man- machine systems, such as long distance driving, flying, assembly line production, continuous monitoring duty at isolated stations, etc. The factor of the external environment and its influence upon behavior is increasingly being recognized for its role in a wide variety of practical situations. The findings discussed in this chapter may account for such things as accidents, loss of efficiency, and emotional alienation often observed in these situations. Interpretations and Implications Focused research on the responses of human subjects exposed to reduced environmental stimulation has only recently begun. The phenomenal growth of interest in this problem and some reasons for this have been discussed. Many of the investigations referred to in this paper are pilot studies; others leave much to be desired in rigor, elegance, and methodological sophistication. At the same time, these investigations now provide a rich source of new observations and hypotheses, which touch on a wide variety of issues. The results of this work, of the research on curiosity or exploratory drive, and of studies on early sensory deprivation converge to provide a revised conception of human motivation. This conception recognizes and emphasizes the "immediate drive value of cognitive experience" as a necessary factor in a theory of motivation (37). From the viewpoint of theory this work has important implications for several scientific disciplines. Methodologically it makes available a technique for the relatively controlled study of imagery and hallucinations, a problem thus far inaccessible to experimental observation without the use of drugs. Practically, it suggests a whole range of applications from management of medical patients to highway design. Theoretical accountings of how reduced environmental input produces the various responses described in previous sections have varied widely. Our purpose here will be simply to indicate the range of explanations used and some of the terms of their analyses. Rapaport (62) discusses these data from the viewpoint of psychoanalytic theory, in the context of the relationship between id and ego functioning. In a detailed discussion of these issues, he states that -87- in the absence of external stimulation, the ego becomes unable to maintain its autonomy from the id and the "effectiveness of these (ego) structures in controlling id impulses may be impaired" (page 19). The reduced control of these impulses may be manifested in the difficulty of thinking, in the unpleasant affect, emotionality, and content of imagery previously discussed. Orientation in time and space structure the situation and may thus help the individual retain ego autonomy by keeping some ego functions in operation. Since isolation destructures the id-ego relationship, initial variations in the differentiation of ego boundaries may account for the individual differences seen. The increased awareness of primary process material states in psychoanalytic terminology what others have described as the heightened awareness of internal bodily states. A recent paper by Bruner (12) places the work on deprivation in a functional context. Perception is seen as instrumental behavior that permits the organism to manage its necessary transactions with the environment.

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