By C. Dolok. Villanova University.
However strattera 25mg online treatment zinc overdose, these processes have not been fully characterized in terms of location discount strattera 40 mg overnight delivery symptoms ulcerative colitis, transport capacity or specificity cheap strattera 18mg with amex treatment writing. However order 18 mg strattera medications not to take with blood pressure meds, as the oral cavity becomes increasingly important as a potential site of systemic absorption, particularly for high molecular weight 175 drugs which are generally thought to cross epithelial cells endocytically, future studies will tend to focus on attempting to better understand these processes. The degree of ionization of a drug species in the oral cavity will depend on the pK of the drug and the pH ata the mucosal surface; salivary pH is in the region 6. The degree of ionization can be quantified using the Henderson-Hasselbalch Equation (see Section 1. Physiological differences between these two regions means that they are suitable for different applications and thus different types of dosage forms. As discussed above the sublingual route is: • relatively permeable; • capable of giving rapid and appreciable absorption of low-molecular weight lipophilic drugs; • unsuitable for retentive systems, due to high salivary flow, excessive movement and patient discomfort. As a result of salivary flow, drug concentrations in this region are sustained only for a relatively short period of time, probably in the order of minutes. For these reasons, the sublingual route is ideally suited to the delivery of low molecular weight lipophilic drugs where rapid onset of action is required (e. Dosage forms that have been developed that are suitable for these types of applications include: • sublingual sprays; • sublingual fast-dissolving tablets. In contrast, as discussed above, the buccal route is: • relatively less permeable than the sublingual route; • does not generally give the rapid onset of absorption seen with sublingual delivery; • highly suited to retentive systems. Specific physicochemical properties of the various dosage forms are discussed below. A brief overview of both the advantages and disadvantages of oral transmucosal drug delivery is given below. This accessibility obviates the need for complex delivery devices to enable the drug to reach its absorption site. Thus devices for oral delivery are simpler in design than those intended to deliver drugs to, for instance, the alveolar region of the lung. Ease of use Oral transmucosal devices, such as sprays, tablets or patches, are also simple for the patient to use and might be expected to be more acceptable to the patient than the use of pessaries or suppositories for the intravaginal and rectal delivery routes respectively. Rich blood supply The highly vascular surface of the oral mucosa ensures rapid absorption and onset of action, as well as the maintenance of sink conditions. The buccal cavity offers the combined advantages of a relatively rapid onset of action, with the potential for sustained delivery over several hours. Furthermore, this route avoids first-pass effects of degradation in the intestinal wall or the liver, prior to the drug reaching the systemic circulation. Low variability This route has less variability than, for example, the oral route, where factors such as intestinal motility, presence of food and extremes of pH combine to make oral drug delivery highly variable. However, factors such as salivary flow and certain disease states can contribute to a degree of variabiliy associated with this route. Robust The oral mucosa is routinely exposed to a multitude of different foreign compounds and is relatively robust and less prone to irritation than, for example, the nasal mucosa. Prolonged retention Prolonged retention of the drug is possible in the buccal cavity, if the appropriate delivery system is used. Intestinal alternative The buccal cavity is a useful alternative to the intestinal route for drug absorption in situations where the gastrointestinal route is unfeasible. Examples include: • patients with nausea and vomiting; • patients with swallowing difficulties; • drugs that cause gastric irritation; • drugs that are unstable in the gastrointestinal fluids; • drugs that undergo extensive first-pass effects in the gut wall or liver. Zero-order controlled release Buccal drug delivery offers the potential to achieve zero-order controlled release. However, as described above, the oral epithelium is relatively robust and this factor is not as limiting as in other highly sensitive mucosal sites, such as the nasal cavity. Mucus and salivary clearance Mucus and salivary clearance reduces the retention time of drugs within the oral cavity and thus the opportunity for absorption. Mucus barrier Drug diffusion may be limited by the physical barrier of the mucus layer and also the specific or non- specific binding of drugs to the mucus layer. Patient acceptance A buccal patch comprises a relatively novel dosage form, which is placed in an unconventional drug delivery site. As such, there may be difficulties encountered in trying to get patients to accept this route. It can be imagined that patients may be more reluctant to use a buccal patch in comparison to, for example, a transdermal patch, which has become a well-known and well-established dosage form. Commercial Novel approaches, such as the use of buccal adhesive patches for the systemic delivery of large molecular weight drugs, require a huge input of time, effort and money, and are also associated with a large amount of risk. These issues can contribute to significant delay in the development and marketing of a new delivery system and can also make these systems relatively expensive.
Polyploidy induced by teniposide was demonstrated by flow cytometry techniques in Chinese hamster ovary cells (Zucker et al trusted strattera 18mg treatment yellow fever. In general 40mg strattera sale medicine cabinets with lights, the effects of teniposide in mammalian cells in vitro occurred in the absence of exogenous metabolic activation cheap strattera 10 mg amex symptoms you may be pregnant. Various metabolic species of teniposide have been identified cheap strattera 40 mg symptoms in dogs, but their mutagenic properties have not been studied. Most of the mutational events reported in mammalian cells, including point mutations, chromosomal deletions and exchanges and aneuploidy, can be explained by this activity. Teniposide does not inhibit bacterial topoisomerases and may not mutate bacterial cells by the same mechanism as mammalian cells. It possesses readily oxidizable functions: Teniposide formed phenoxy radical intermediates in the presence of horseradish peroxidase or prostaglandin synthase (Haim et al. The first is that teniposide itself causes the translocations, perhaps through a cytotoxic action. The second possibility for the role of teniposide in causing translocations is that it selects for cells that already have translocations. Chemotherapy has profound effects on the kinetics of the marrow: it causes cell death, forcing many marrow stem cells to divide, which might select for the rare stem cells with a translocation (Knudson, 1992). In the case–control study, the use of other potentially leukaemogenic agents was adjusted for in the analysis; however, the possibility cannot be excluded that interaction occurred between teniposide and those agents. It is unlikely that the large excess risk for acute myeloid leukaemia can be explained fully by misclassification or phenotypic change of the initial haematological malignancy. Other cohort studies have also reported strongly increased risks for acute myeloid leukaemia after treatment of various primary malignancies with teniposide-containing regimens that also included alkylating agents or teniposide-containing regimens in combination with etoposide. In these studies, the possibility cannot be excluded that the excess risk for leukaemia was partly or wholly due to the other agents. About 45% of a radiolabelled dose of teniposide was excreted in the urine, 4–14% occurring as the parent drug. In mice, the pharmacokinetics of teniposide differs from that of etoposide, a closely related drug, with lower clearance, a larger volume of distribution and a longer terminal elimination half-time. The accumulation of teniposide in leukaemic cells in vitro was some 15 times higher than that of etoposide applied at the same concentration. The major dose-limiting toxic effect of teniposide in clinical trials is myelo- suppression, manifest mainly as leukopenia. Less severe effects, including nausea and vomiting, diarrhoea and alopecia, are common; less common effects include transient increases in liver enzyme activity, hypertension and hypersensitivity reactions. Embryo- toxicity and teratogenicity, especially in the heart and central nervous system, have been observed in mice. Teniposide is orders of magnitude more toxic in mammalian than in microbial cells and is mutagenic in mammalian cells. There is inadequate evidence in experimental animals for the carcinogenicity of teniposide. In reaching this conclusion, the Working Group noted that teniposide causes distinctive cytogenetic lesions in leukaemic cells that can be readily distinguished from those induced by alkylating agents. The short latency of these leukaemias contrasts with that of leukaemia induced by alkylating agents. High-performance liquid chromatography is the most useful analytical tool for analysing mitoxantrone and its metabolites in biological matrices. Ion-pair chromato- graphy and radioimmunoassay have also been used (Beijnen et al. This product is aromatized with chloranil as the oxidant, and it is converted into mito- xantrone hydrochloride by treatment with hydrogen chloride in ethanol (Beijnen et al. Mitoxantrone, a dihydroxyanthracenedione derivative, was the most active of a series of compounds synthesized (Zee-Cheng & Cheng, 1978; Dunn & Goa, 1996). It was found to have anti-tumour activity in advanced breast cancer (often in patients in whom other treatments have failed), non-Hodgkin lymphoma and certain leukaemias. It is still most commonly used in these tumours, typically in combination with other cytotoxic drugs, and has also been used in the treatment of other cancers such as ovarian, prostate and lung cancer (Faulds et al. The typical dose is the equivalent of 12–14 mg/m2 mitoxantrone once every three weeks in patients with lymphomas and tumours of solid tissues, and 12 mg/m2 per day for five days in patients with leukaemia. When mitoxantrone is used in combination with other cytotoxic drugs, these doses are often lower (Dunn & Goa, 1996; Royal Pharmaceutical Society of Great Britain, 1999). In recent years, mitoxantrone has been used to a limited extent in the treatment of multiple sclerosis, typically at doses lower than those used in malignant disease and on a monthly schedule (Gonsettte, 1996; Millefiorini et al. Studies of Cancer in Humans The Working Group considered only studies in which mitoxantrone was given to patients who did not receive treatments with alkylating agents, with the exception of low doses of cyclophosphamide.
Recent well-publicized examples include the alleged use of mescaline against Cardinal Mindszenty (S buy 25mg strattera with amex medicine wheel images. Ryan purchase strattera 18 mg otc treatment 911, I came back from a Red death cell purchase strattera 40 mg online treatment tinea versicolor, Saturday Evening Post cheap strattera 40 mg fast delivery medications 247, January 17, 24, 31, and February 7, 1953); and the account by the Communist editor, Henri Alleg, of an alleged use of sodium pentothal in interrogations he received while held by French forces in Algeria (H. A series of nonpharmacologic factors within the total transaction of a person giving another person a drug has been found to be more or less capable of contributing to the responses occurring with administration of the drug. These factors may be listed and what is known about each will be taken up separately. Reactions to attitudes or motivations of the person administering the medication and interacting with the informant. The studies of Beecher and his group (7, 8) indicate that 30 to 50 per cent of individuals are placebo reactors, that is, respond with symptomatic relief to taking an inert substance. If one is interested in the pharmacology of a new drug and tries it out on a group of patients, a third to a half of this group will be relieved of their symptoms by a placebo; they react favorably to the syringe, pills or capsule, regardless of what it contains. Thus they dilute the significant data derived from the half or two-thirds of the group that react only to the active ingredient in the syringe or capsule. In studying a new drug-whether one is interested in applying its pharniacologic effect toward the alleviation of pain, amelioration of emotional distress, or the facilitation of communication of covert information-the scientist is not primarily interested in the subjective and behavioral effects of syringes and pills. Thus the scientist is obliged to take into account the placebo reactors, who must be screened out if one is to get an accurate idea of what the drug itself does. Of course, to relieve pain or facilitate communication in a patient or prisoner, the "placebo phenomenon" can be made use of itself and -99- the investigator can expect that in 30 to 50 per cent of trials pain may be relieved or interrogation may be facilitated. Some additional factors are known which increase the likelihood of a placebo effect: 1. A sympathetic woman investigator can obtain a higher percentage of pain relief from various niedicatimis than can a colder, more remote male (7). Clinical psychiatric findings in the same study regarding placebo reactors found greater responsiveness characteristic of individuals who are more anxious, more self-centered, more dependent on outside stimulation than on their own mental processes; persons who express their needs more freely socially, who are talkers, and who drain off anxiety by talking and relating to others. In contrast to the placebo reactors, the nonreactors are clinically more rigid and more emotionally controlled than average for their age and background. If one is interested in ascertaining whether a drug produces a given effect to a degree greater than a placebo, it becomes obvious that the effect produced by the drug must exceed the chance variations of the placebo effect to a reliable extent. In experimental investigations exploring the usefulness of drugs for various purposes, the placebo and other nonspecific reactions to medicaments must be separated from the effects specific to the active drug. Devising an experimental study using infrahuman animals to assess the pharmacologic effect of a drug only postpones the assessment of the complicated responses likely to occur when the drug is given to a human being. For the researcher interested in discriminating specific from nonspecific effects of drugs, Beecher (7) has outlined a series of principles and practices on the basis of seventeen drug studies in which he has participated, as follows: • 1. Subjective responses are the resultant of the action of the original stimulus and the psychic modification of that stimulus. Man is the essential experimental subject for a definitive answer to questions in this field, and men are easier to work with than women, for with men the controls are simpler. The agents tested and the time they are tested are unknown not only to the subjects but to the observers as well. When a new agent is to be compared with the agents of past experience, and this is nearly always the case, a standard of reference is required (morphine in standardized dosage is used as the standard for analgesics, etc. Significant comparisons of side actions of agents can be made only on the basis of equal strength in terms of their primary therapeutic effect. Mathematical validation of supposed difference in effectiveness of the two agents is necessary. The subjective (and behavioral) effects of drugs can be quantified accurately and rapidly only when placebo reactors are screened out. Silent Administration The obverse of placebo administration, the deliberate administration of an inert material, is silent administration, the unknown administratiou of a pharmacologically potent substance. The act of administering a medication usually potentiates its effect since it invokes the status of a professional person and the prestige of social institutions and organizations that are a part of the setting. A general recognition of this fact has made the control of the placebo effect a routine feature of all carefully designed drug studies. A minimal requirement is the successful masking of the drug by substances otherwise introduced into the body, such as foods, liquids, smoke, or air. From this point of view the ideal drug would be tasteless, odorless, and completely soluble. Theoretically, the net effect of a silently administered drug should be equal to its effect following routine procedures minus its placebo effect. In practice this effect would be modified by the state of the organism, the general setting in which the subject finds himself, and his typical and persistent modes of reacting, i.
He concludes that for isolation two to eight days seems to produce relatively little of the painful effects seen in the autobiographical reports of sailors and explorers cheap 18mg strattera mastercard medicine in balance. However cheap 40 mg strattera amex medicine you can take while pregnant, specific investigations of the social factors in the sensory deprivation studies will be necessary in order to make a more precise generalization buy cheap strattera 25 mg line symptoms for strep throat. We have earlier elaborated some aspects of the differences in motivation between the experimental situations and the real life conditions buy strattera 25 mg with mastercard treatment narcolepsy. Because of these differences, and of limited data, caution in generalizing the relevance of these experimental studies is necessary. Pending clarification of these issues, some tentative implications may be suggested as relevant. The boredom, restlessness, irritability, and other mood changes observed also may well apply. The stimulus-hunger and increased suggestibility which have been observed may make an individual more vulnerable to revealing information he might otherwise withhold, particularly when accompanied by the social uncertainty induced in the interrogation situation. Unprepared for these consequences of isolation and deprivation, like many experimental subjects, an individual may become apprehensive and indeed panicked by his reactions. The appearance of hallucinatory- like phenomena and their emotional accompaniments have often been quite anxiety provoking. On the other hand, previous exposure to these circumstances, familiarity with their consequences, and training individuals in techniques of dealing with them may well increase resistance. Knowledge of the importance of retaining spatial and time orientation, and self-stimulation in concrete tasks, are two examples of techniques for reducing stress by increasing psychological structure. Schachter (66) points out that isolates who are able to keep occupied with distracting activities appear to suffer less and be more prone to the state of apathy. Schonbach (68), in an experimental study, has demonstrated that a state of deprivation is far more bearable under conditions of irrelevant and distractive thought than under conditions where thought is concerned almost wholly with the source of deprivation. Since direct research on the problem of resistance to interrogation in a realistic setting is difficult, some reliance on the type of study reviewed here is necessary. Further investigation of these problems will undoubtedly continue to shed new light on resistance to the disorganizing consequences of deprivation. However, despite their often dramatic results, these studies have remained within the limi- -90- tations posed by ethical considerations and have not pushed subjects to their ultimate limits. Indeed, polio patients survive years in respirators without psychosis, whereas prisoners, sailors, and explorers often successfully endure long months of severe deprivation and monotony. Furthermore, the autobiographical evidence, even if selfselected, implies that the long term effects are reversible and in some instances leave the individual with a sense of having achieved a new and better personality synthesis. From this point of view, the findings reviewed must be considered as suggestive, rather than spelling out in final terms the complete and precise parameters of response. Lackland Air Force Base, Texas; Air Force Personnel and Training Research Center, December 1956. The effects of sensory isolation on suggestible and nonsuggestible psychology graduate students. Sensory deprivation: (1) Effects of social contact, (2) Effects of random visual stimulation. The relation of eye movements during sleep to dream activity: An objective method for the study of dreaming. Infant development under conditions of restricted practice and of minimum social stimulation. Experimental interference with reality coiltact (perceptual isolation): Method and group results. Influence of prior verbalization and instructions on visual sensations reported under conditions of reduced sensory input. Are there common factors in sensory deprivation, sensory distortion, and sensory overload? Factors used to increase the susceptibility of individuals to forceful indoctrinations Observations and experiments. An abnormality of mental function affecting patients with poliomyelitis in tank type respirators. The effects of sensory deprivation and sensory bombardment on apparent movement thresholds. Effects of interruption of the visual pathway on the response to geniculate stimulation. The Chinese indoctrination program for prisoners of war; A study of attempted brainwashing. This problem in communication is not an unfamiliar one to the psychiatrist, who often aims to recover unconscious conflicts or memories from the neurotic or psychotic patient in the hope of producing therapeutic benefit. Coercion may be used, however, if the patient is considered to be behaving in a manner that is destructive to himself (e. Furthermore, the code of ethics, particularly of the psychiatrist, ordinarily binds the physician to keep -96- confidential the secrets that his patients impart to him, whether or not the patient has been aware or unaware of their nature. In the practice of psychiatry, the code of respecting and keeping the confidences of a patient is considered to be a tool that facilitates the confession or expression of otherwise taboo material from the patient.