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Twice-daily radiotherapy improved median sur- vival as compared with once-daily radiotherapy Second-Line Therapy (23 months vs effective 52.5 mg nicotinell quit smoking 6th day. However cheap nicotinell express quit smoking research study, No curative regimens for patients with recur- grade 3 or 4 oesophagitis was significantly more rent disease have been identified buy discount nicotinell 52.5mg quit smoking 5 as. In general these designs are based on the ily based on Bayesian statistical modelling of the paradigm that with the increased myelosuppres- dose–toxicity relationship with a targeted toxicity sion nicotinell 52.5mg line quit smoking 36 hours, tumour cells are more likely to be killed, probability for the MTD. With radiotherapy con- leading to shrinkage of tumours, and that there cerned with late-onset toxicities as the primary is a monotonically increasing dose–response and endpoint, the standard dose-escalation design for dose–toxicity relationship. It is also assumed that phase I clinical trials is inadequate because of the tumour shrinkage will eventually lead to clinical long-term follow-up required for late-onset toxic- benefit such as prolonged survival or improved ities associated with radiotherapy. In essence, tumour shrinkage has toxicities, the continual reassessment method has served as a surrogate for clinical benefit. In typical phase I clinical trials with acute dose- PHASE II CLINICAL TRIALS limiting toxicities as the primary endpoint, a standard dose-escalation scheme with a cohort In phase II clinical trials with cytotoxic chemo- of fixed number of patients treated at each dose therapy, multi-stage designs with objective tumour level is used to estimate the so-called maximum response defined as shrinkage of tumour by more tolerated dose (MTD) or safe dose46,47 to be than 50% as the primary endpoint are widely used in subsequent phase II studies. Worse yet, the standard patients for establishment of clinical efficacy is dose-escalation design does not provide a well- predicated by the observed clinical efficacy or defined basis for estimation of the MTD and safety with the patients from the previous stages. Given these design parame- for phase I clinical trials has served a useful ters available from historical data, there are many function in this setting. In order to select a design, In order to avoid slow dose-escalation and one may use either the minimax or the opti- underestimation, a number of variations on the mality criterion. Oftentimes they are As was noted earlier, small-cell lung cancer is very disparate, causing confusions to those not known to be biologically distinct from other his- so statistically sophisticated. A graphical search tologic subtypes of lung cancer in both laboratory method may be used to search for what appears and clinical studies. It is the most chemosensitive to be a compromise between the minimax and type of lung cancer and as a consequence it poses the optimal designs with more desirable practi- some difficulties in development of investiga- cal features such as having much smaller max- tional cytotoxic drugs. For example, there is eth- imum sample size than the optimal design and ical concern for testing investigational cytotoxic much smaller expected sample size than the min- 57 drugs in previously untreated small-cell lung can- imax design. As a result of these observations, it has PHASE III CLINICAL TRIALS been suggested that different phase II designs be used depending on whether patients had Overall survival typically being the ultimate been previously treated with cytotoxic drugs or criterion for evaluation of the efficacy of cancer have relapsed following treatment with cytotoxic treatment in phase III clinical trials, a traditional drugs. Different However, depending on the disease setting, other considerations should be given to elderly patients endpoints such as time to disease progression, or patients with poor prognosis as well. These new agents are not expected sequential Bayesian phase II/III design has been to shrink tumours. Instead they are expected to proposed for a non-small-cell lung cancer involv- inhibit tumour growth or prevent metastasis as ing an adjuvant adenovirus for p53. With the emergence of these different stage II or III NSCLC and overall survival are classes of agents with entirely different mode of 168 TEXTBOOK OF CLINICAL TRIALS action and expected therapeutic effects, the tradi- REFERENCES tional designs for phase I, II and III clinical trials appear no longer adequate. Jemal A, Murray T, Samuels A, Ghafoor A, With these cytostatic agents, it is unclear Ward E, Thun MJ. CA whether there is a clear dose–toxicity and Cancer J Clin (2003) 53: 5–26. Revisions in the international sys- dose–response relationship to help guide us tem for staging of lung cancer. Frost JK, Ball WC, Levin M, Tockman MS, Baker paradigm for dose-escalation designs for cyto- RR, Carter D, Eggelston JC, Erozan YS, Gupta PK, Khouri NF, Marsh BR, Stitik FP. Early lung toxic agents for phase I clinical trials appears no cancer detection: results of the initial (prevalence) longer relevant as acute toxicities may not be radiologic and cytologic screening in the Johns meaningful with such agents. Am Rev Respir Dis (1984) 130: This obviously calls for new methods for esti- 549–54. Flehinger BJ, Melamed MR, Zaman MB, Hee- mating a safe, but effective dose in phase I clini- lan RT, Perchick WB, Martini N. In such a setting with cytostatic drugs, cer detection: results of the initial (prevalence) it was suggested that a biological endpoint other radiologic and cytologic screening in the Memo- than toxicity be used in phase I trials to define the rial Sloan–Kettering study.

To see why generic nicotinell 17.5 mg without prescription quit smoking laser treatment, consider a placebo lem – what if we do not have any efficacy mea- arm in a diary card study in asthma in which surements on treatment to use nicotinell 35 mg discount quit smoking health timeline. To avoid that the patients with worsening of symptoms drop problem in diary card studies purchase 17.5mg nicotinell with amex quit smoking meter, it is often better out progressively (the worse the symptoms order generic nicotinell from india quit smoking keep coughing, the to define the full treatment period as the period earlier they drop out). At low response values drop out, the group mean least that provides an effect measurement for each will increase, so the temporal behaviour of the individual who has started to fill in the diary mean values will indicate that the placebo group cards. However, this effect one patient can be the mean of 90 data points, is solely due to withdrawals! The next step is in general to analyse ral behaviour of variables some kind of impu- these period means with an ANOVA, and then tation of data is needed, in order to keep the the information of the precision of the computed denominator the same when computing mean val- mean is lost. The omission of such patients ciple, the mean values plotted can be interpreted 378 TEXTBOOK OF CLINICAL TRIALS as follows: the mean at time t is the mean of SAMPLE SIZE DETERMINATIONS the last recorded measurements up to and includ- ing time t. When using this principle for diary In order to certify that a proposed study is of card variables like PEF it is often better not an appropriate size, a sample size justification is to take only the last measurement, but rather needed in the protocol. More sophisti- ically to succumb a number of patients to a study cated approaches based on some kind of multiple protocol if there is no hope whatsoever to demon- imputation technique for missing data can also strate what you want to demonstrate. Similarly, if be considered, but the add-on value of doing that the study is heavily overdimensionalised we have is probably very small for the average study in put an unnecessary number of patients at what- respiratory diseases. However, sample size deter- mination is there to ethically justify the study MULTIPLE COMPARISONS in advance – it has no consequences when the results are obtained. A respiratory trial usually contains a number In the respiratory area many test hypotheses of effect variables, and often also a number are stated in terms of mean values, and for of different treatments. Thus there are multiple such variables the sample size is (essentially) comparisons to be done. This poses a major proportional to the ratio (σ/ )2,whereσ is the problem, because of the risk of over-emphasising residual standard deviation and is the mean fluke significances because of many comparisons. When using a To handle the many effect variables we there- multiplicative model for a variable, these entities fore have to predefine which one is to be con- refer to the logarithm of the variable in question. It is from the result on Note that σ means different things in a crossover this variable that the overall statistical conclusion trial and in a parallel group trial – in the former from the study can be drawn. In general one study case it refers to a within-patient variability (more √ can have a few different objectives that are not exactly 2× the residual standard deviation of closely related (like efficacy and safety), and then the ANOVA) and in the latter to a between- a primary variable for each objective should be patient variability. However, it is probably a too sta- residual standard deviation from the proposed tistical approach to focus only on the primary analysis of variance, which might contain a variable when trying to understand the results of baseline adjustment. No variable fetches all aspects of the following table shows some typical values a respiratory disease, and the approach should be of the sample size parameters that can be used for to select the most sensitive variable as primary asthma trials. Each example will be discussed in variable, to decide on the overall conclusion, but more detail below. When it comes to the problem of multiple PEF morning PG 40–45 10–20 4–20 treatment comparisons, the study logic should be (L/min) Symptom score PG 0. With precisely formulated questions the 20 multiplicity problem here should at least diminish substantially. This approach will be illustrated in Here the range is not a range – the lower number what follows. Similarly, for inevitably presents itself, as in so many areas of the range is more of a typical range for which medical statistics. It is however no more sensible to dimensionalise, not a range on what can be to do such analysis on data on lung function obtained. For the crossover measurements of the table, In airways diseases, asthma in particular, the we just note that the AUC refers to AUC-based disease severity varies among patients. Thus average over the full period and that for that the magnitude of the response attainable will variable the pre-dose FEV1 value is used as vary between patients. For PEF morning a baseline numerical effects than patients with large lung is obtained as the mean value over a number volumes, like tall men.

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Mix- important for detecting adverse drug reactions purchase 52.5 mg nicotinell free shipping quit smoking recovery chart, evaluat- ing with orange or apple juice improves taste; grapefruit ing disease status buy discount nicotinell 17.5mg on-line quit smoking 36 hours, evaluating drug responses and indi- juice should not be used because it affects metabolism cations for dosage change buy cheap nicotinell 35mg on line quit smoking 6 months pregnant, and having blood tests or of cyclosporine buy 35 mg nicotinell overnight delivery quit smoking injection. Rinsing en- out notifying the physician who is managing immuno- sures the entire dose is taken. Immunosuppressant drugs may ✔ Take mycophenolate on an empty stomach; food de- influence reactions to other drugs, and other drugs may creases the amount of active drug by 40%. Thus, mycophenolate tablets and do not open or crush the taking other drugs may decrease therapeutic effects or in- capsules. In addition, vaccinations may be ✔ Take sirolimus consistently with or without food; do not less effective, and some should be avoided while taking mix or take the drug with grapefruit juice. If ✔ People of reproductive capability who are sexually active also taking cyclosporine, take the sirolimus 4 hours after should practice effective contraceptive techniques during a dose of cyclosporine. With methotrexate, If taking the oral solution, use the syringe that comes use contraception during and for at least 3 months (men) with the medication to measure and withdraw the dose or one ovulatory cycle (women) after stopping the drug. Empty the dose into a glass or plastic With mycophenolate, effective contraception should be container with at least 2 oz (1⁄ cup or 60 mL) of water or 4 continued for 6 weeks after the drug is stopped. Do not use any other liquid to dilute the sirolimus, effective contraception must be used before, drug. The drug was Refill the container with at least 4 oz (1⁄2 cup or 120 mL) toxic to embryos and fetuses in animal studies. For example, with etanercept, rotate injec- tion sites, give a new injection at least 1 inch from a Self-Administration previous injection site, and do not inject the medication ✔ Follow instructions about taking the drugs. This is vital to into areas where the skin is tender, bruised, red, or hard. If unable to take a medication, report to the pre- form at least the first injection under supervision of a scribing physician or other health care provider; do not qualified health care professional. In Risk–Benefit Factors addition, all health care providers need to review research studies and other current literature regularly for ways to max- Immunosuppression is a serious, life-threatening condition imize safety and effectiveness and minimize adverse effects that may result from disease processes or drug therapy. The rejection reaction involves T and B a decision is then made that immunosuppressant drug ther- lymphocytes, multiple cytokines, and inflammatory media- apy is indicated and benefits outweigh risks, the therapeu- tors. For example, most organ vidual immunosuppressant drugs, general risks of immuno- transplantation centers use a combination regimen (eg, aza- suppression include infection and cancer. Infection is a major thioprine, a corticosteroid, and either cyclosporine, sirolimus, cause of morbidity and mortality, especially in clients who or tacrolimus) for prevention and treatment of rejection reac- are neutropenic (neutrophil count <1000/mm3) from cyto- tions. Once the transplanted tissue is functioning and rejec- toxic immunosuppressant drugs or who have had bone mar- tion has been successfully prevented or treated, it often is row or solid organ transplantation. For the latter group, who possible to maintain the graft with fewer drugs or lower drug must continue lifelong immunosuppression to avoid graft dosages. Some recommendations to increase safety or effec- rejection, serious infection is a constant hazard. Extensive tiveness of drug combinations include the following: efforts are made to prevent infections; if these efforts are un- • Lymphocyte immune globulin, antithymocyte globulin is successful and infections occur, they may be fatal unless rec- usually given with azathioprine and a corticosteroid. Common infections • Azathioprine is usually given with cyclosporine and are bacterial (gram-positive, such as Staphylococcus aureus prednisone. Cancer, most commonly lymphoma or skin cancer, may A corticosteroid should always accompany cyclosporine result from immunosuppression. In pro- is thought to recognize and destroy malignant cells as they phylaxis of organ transplant rejection, the combination develop, as long as they can be differentiated from normal seems more effective than azathioprine alone or azathio- cells. With immunosuppression, the malignant cells are no prine and a corticosteroid.

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Legal responsibilities in other aspects of drug therapy are • Verify the identity of all clients before administering less tangible and clear-cut nicotinell 52.5 mg with amex quit smoking 5th day. One reason is their great diversity 52.5mg nicotinell sale quit smoking commercials, in age from birth to MEDICATION ERRORS 18 years and weight from 2–3 kilograms (kg) to 100 kg or more nicotinell 52.5mg on-line quit smoking timeline day by day. Another is that most drugs have not been tested Increasing attention is being paid to the number and conse- in children buy nicotinell 35mg overnight delivery quit smoking 3 months ago and still tired all the time. A third reason is that many drugs are mar- quences of medication errors. In one study of 1116 hospi- keted in dosage forms and concentrations suitable for tals, medication errors (a total of 430,586) were reported in adults. This often requires dilution, calculation, prepara- approximately 5% of admitted patients. Each dose of a drug must be recorded require additional treatment, or death). Specific drugs often associated with errors include in- ized, locked cabinets for which each nurse on a unit has a sulin, heparin, and warfarin. These automated systems maintain an inventory getting each dose of a medication to the intended client. Each step or person has a potential for contributing to a Controlled drugs, such as opioid analgesics, are usually medication error (Box 3–1). All health care providers in- kept as a stock supply in a locked drawer or automated cabi- volved in drug therapy must be extremely vigilant in all net and replaced as needed. Each nurse must comply with legal regulations and agency policies for dispensing and recording controlled drugs. The unit- MEDICATION ORDERS dose system, in which most drugs are dispensed in single- dose containers for individual clients, is widely used. The main pur- for information about prescription and nonprescription drugs pose of including potential sources of errors here is to increase the when needed. Drugs may have similar names that can lead to erroneous pre- Health Care Providers scribing, dispensing, or administration. As a result, the FDA-proposed labeling function, and disease process when selecting a drug or dosage; fail changes to make the differences more noticeable. The FDA is to consider other medications the client is taking, including pre- also looking at proposed trade names of new drugs prior to mar- scription and over-the-counter drugs; lack sufficient knowledge keting, to see if they are likely to be confused with older drugs, about the drug; fail to monitor for, or instruct others to monitor for, and increasing surveillance of medication errors attributed to effects of administered drugs; and fail to discontinue drugs appro- drug name confusion. This can dispense incorrect medications, mislabel containers, or fail to ask lead to errors if container labels are not read carefully, especially outpatients about other drugs being taken. Nurses may have in- if the products are shelved or stored next to each other. Clients/Consumers People may take drugs from several prescribers; fail to inform one Circumstances physician about drugs prescribed by another; get prescriptions Prescribers, pharmacists, and nurses may have a heavy workload, filled at more than one pharmacy; fail to get prescriptions filled or with resultant rushing of prescribing, dispensing, or administering refilled; underuse or overuse an appropriately prescribed drug; medications. They may also experience distractions by interrup- take drugs left over from a previous illness or prescribed for some- tions, noise, and other events in the work environment that make one else; fail to follow instructions for drug administration or stor- it difficult to pay needed attention to the medication-related task. Occasionally, verbal or telephone orders are accept- DRUG PREPARATIONS AND able. Some drugs are available in only one dosage pharmacy staff prepare a computer-generated MAR for each form; others are available in several forms. For clients in ambulatory care settings, the procedure is es- Dosage forms of systemic drugs include liquids, tablets, sentially the same for drugs to be given immediately. For drugs capsules, suppositories, and transdermal and pump delivery to be taken at home, written prescriptions are given.

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Models of motor behavior have explored the Another theory of motor control suggests properties of neurons and their connections to that stored central motor programs allow sen- explain how a network of neurons generates sory stimuli or central commands to generate persistent activity in response to an input of movements purchase nicotinell 17.5mg quit smoking nhs. Having achieved This approach purchase nicotinell 52.5mg visa quit smoking quebec, however cheap nicotinell 35 mg quit smoking 24, needs some elabora- a behavioral goal 35mg nicotinell visa quit smoking results timeline, the reinforced sensory and tion to explain how contingencies raised by the movement experience is learned by the motor environment and the biomechanical character- network. Learning results from increased istics of the limbs interact with stored programs synaptic activity that assembles neurons into or with chains of reflexes. A more elegant the- functional groups with preferred lines of com- ory of motor control, perhaps first suggested munication. He hypothesized that lower levels of the CNS Several experimentally based models sug- control the synergistic movements of muscles. Higher levels of the brain activate these syn- Target-directed movements can be generated ergies in combinations for specific actions. This model says pend on the physical properties of muscle, such little about other aspects of actions, including as its elasticity. The computations used by neu- how the environment, the properties of objects rons to compose the motor command may be such as their shape and weight, and the de- broadly tuned to the velocity of movements. All but the simplest motor activi- these simple flexor and extensor actions may ties are managed by neuronal clusters distrib- be fashioned by supraspinal inputs into the vast uted in networks throughout the brain. The variety of movements needed for reaching and regions that contribute are not so much func- walking. The motor cortex, then, determines tionally localized as they are functionally spe- which spinal modules to activate, along with cialized. Higher cortical levels integrate sub- the necessary coefficient of activation, pre- components like spinal reflexes and oscillating sumably working off an internal, previously brain stem and spinal neural networks called learned model of the desired movement. The interaction of a dy- representations for the movement, described namic cortical architecture with more auto- later, are stored in sensorimotor and associa- matic oscillators allows the cortex to run sen- tion cortex. Thus, some simplifying rules gen- sorimotor functions without directly needing to erate good approximations to the goal of the designate the moment-to-moment details of reaching or stepping movement. Systems for parameters such as the timing, intensity, and error detection, especially within connections duration of the sequences of muscle activity to the cerebellum, simultaneously make fine among synergist, antagonist, and stabilizing adjustments to reach the object. A variety of related concepts about neural For certain motor acts, the motor cortex network modeling for the generation of a needs only to set a goal. This system accounts for cortical cells in the primary motor cortex (M1) how an equivalent motor act can be accom- encode. The activity of these neurons may en- plished by differing movements, depending on code the direction or velocity of the hand as it Plasticity in Sensorimotor and Cognitive Networks 7 moves toward a target14 or the forces at joints torques, the equilibrium points of muscle or the control of mechanical properties of mus- movements mentioned above, and the position cles and joints. Each distributed neighborhood of Indeed, multiple representations of aspects of neurons is responsible for a specific role in as- movement are found among the primary and pects of planning and directing movements. The neurons the matrix of cortical, subcortical, and spinal of each region have interconnections and cell nodes in this network model of motor control properties that promote some common re- are described later, along with some of the at- sponses, such as being tuned in a graded and tributes that they represent. Prominent cortical, subcortical, and spinal modules and their connections within the sensorimotor networks for locomotor control. Each anatomic region has its own di- ease, the map represents what was, but not all verse neuronal clusters with highly specified in- that is. These regions reflect the dis- patient may solve motor problems by practice tributed and parallel computations needed for and by relearning.

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