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Therefore purchase 0.625mg premarin with mastercard menopause frequent periods, the treatment choices renal insufﬁciency) are parenteral glucose or glucagon purchase premarin no prescription women's health clinic newcastle west. It acts rapidly to raise blood glucose levels and arouse the than SC client best purchase premarin womens health nurse practitioner programs. If the client is at home or elsewhere purchase premarin 0.625mg with visa womens health yakima, glucagon may be given • Drug interactions that decrease blood glucose levels if available and there is someone to inject it. A family member or • Increased physical exertion roommate may be taught to give glucagon SC or IM. Glucagon is a pan- Hormones That Raise Blood Sugar creatic hormone that increases blood sugar by converting liver Normally, when hypoglycemia occurs, several hormones (glucagon, glycogen to glucose. It is effective only when liver glycogen is pres- epinephrine, growth hormone, and cortisol) work to restore and ent. Some clients cannot respond to glucagon because glycogen maintain blood glucose levels. Glucagon and epinephrine, the stores are depleted by such conditions as starvation, adrenal insufﬁ- dominant counter-regulatory hormones, act rapidly because they ciency, or chronic hypoglycemia. The hyperglycemic effect of are activated as soon as blood glucose levels start declining. People with diabetes who develop hypoglycemia may have Caution is needed in the treatment of hypoglycemia. Although impaired secretion of these hormones, especially those with type the main goal of treatment is to relieve hypoglycemia and restore the 1 diabetes. The client having a hypoglycemic re- cretion of epinephrine also occurs in people who have been action should not use it as an excuse to eat high-caloric foods or treated with insulin for several years. Health care personnel caring for the client creases tachycardia, a common sign of hypoglycemia, and may should avoid giving excessive amounts of glucose. Posthypoglycemia Care the Conscious Client Once hypoglycemia is relieved, the person should have a snack or Treatment of hypoglycemic reactions consists of immediate ad- a meal. Slowly absorbed carbohydrate and protein foods, such as ministration of a rapidly absorbed carbohydrate. For the conscious milk, cheese, and bread, are needed to replace glycogen stores in client who is able to swallow, the carbohydrate is given orally. In addition, the episode needs to include: be evaluated for precipitating factors so that these can be mini- • Two sugar cubes or 1 to 2 teaspoons of sugar, syrup, honey, mized to prevent future episodes. Repeated episodes mean that the or jelly therapeutic regimen and client compliance must be re-evaluated • Two or three small pieces of candy or eight Lifesaver candies and adjusted if indicated. Glitazones tion increases or restores the effectiveness of circulating insulin and results in increased uptake of glucose by pe- • These drugs, pioglitazone and rosiglitazone, are also ripheral tissues and decreased production of glucose by called thiazolidinediones or TZDs and insulin sensitizers. The drugs stimulate exercise or in combination with insulin, metformin, or receptors on muscle, fat, and liver cells. The drugs lower blood sugar by decreasing absorption or production of glucose, by increasing secretion of insulin, or by increasing the effectiveness of available insulin (decreasing insulin resistance). They are also con- should be skipped; if a meal is added, a drug dose traindicated in clients who are hypersensitive to them. Glitazones increase plasma volume and may cause HERBAL AND DIETARY fluid retention and heart failure. In people who did not With most herbs and dietary supplements, even the commonly take a glitazone, 2. Thus, anyone with diabetes who Meglitinides wishes to take an herbal or dietary supplement should consult • Nateglinide and repaglinide are nonsulfonylureas that a health care provider, read product labels carefully, seek the lower blood sugar by stimulating pancreatic secretion of most authoritative information available, and monitor blood insulin. Described • They can be used as monotherapy with diet and exercise below are some products that reportedly affect blood sugar and or in combination with metformin. They are metabolized in the liver; Blood Glucose Levels metabolites are excreted in urine and feces. After a dose of 2 mg is reached, increase dose in increments of 2 mg or less at 1- to 2-week inter- vals, based on blood glucose levels. In combination with insulin, PO 8 mg once daily with the ﬁrst main meal. Alpha-Glucosidase Inhibitors Acarbose (Precose) Delays digestion of carbohydrate foods PO, initially 25 mg, three times daily with ﬁrst bite when acarbose and food are present of main meals; increase at 4- to 8-week intervals in gastrointestinal (GI) tract at the to a maximum dose of 50 mg three times daily same time (for patients weighing under 60 kg) if necessary, depending on 1-h postprandial blood glucose lev- els and tolerance. Clients weighing more than 60 kg may need doses up to 100 mg three times daily (the maximum dose). Miglitol (Glyset) Delays digestion of carbohydrates in the PO, initially 25 mg three times daily with the ﬁrst GI tract bite of each main meal, gradually increased if necessary. Maximum dose, 100 mg three times daily Biguanide Metformin (Glucophage) Older adults are at higher risk for devel- PO, initially 500 mg twice daily, with morning and opment of lactic acidosis, a rare but evening meals; increase dose in increments of potentially fatal reaction. Thus, smaller 500 mg/d every 2–3 weeks if necessary, up to a doses and monitoring of renal function maximum of 3000 mg daily, based on patient are recommended. Glitazones Pioglitazone (Actos) Increases effects of insulin; may be used PO 15–30 mg once daily alone or with insulin, metformin, or a sulfonylurea Rosiglitazone (Avandia) Increases effects of insulin; may be used PO 4–8 mg once daily , in one dose or two divided alone or with metformin doses Meglitinides Nateglinide (Starlix) Onset of action, within 20 min; peak, 1 PO 120 mg three times daily, 1–30 min before h; duration, 3–4h meals. Repaglinide (Prandin) Onset of action, within 30 min; peak, PO 1–2 mg 15–30 min. Combination Drug* Glyburide/metformin (Glucovance) Available in preparations with 1. Patients previously treated with glyburide or mg glyburide and 500 mg metformin; other sulfonylurea plus metformin: Initially, PO 2. States, may play a role in the development of diabetes Jean Watson, a 52-year-old type 2 diabetic, has been managed for and atherosclerosis. If so, beneﬁcial effects of a supple- the last 3 years on 500 mg of metformin (Glucophage) bid. Watson is sched- study of pregnant women and older adults with marginal uled for an intravenous pyelogram (IVP) to evaluate a series of re- levels of chromium, administration of a supplement im- cent urinary tract infections. Watson comes in for her test, she mentions that her blood glucose was elevated that morn- proved glucose tolerance. At present, there is insufﬁcient ing, so she took her metformin as usual with a sip of water but did evidence to recommend routine chromium supplementa- not eat breakfast as instructed. Some clinical trials have been done, but peo- ple with diabetes were excluded. Some sources report no known effects on blood Glucosamine, as indicated by animal studies, may cause glucose; others report a decrease in animals and hu- impaired beta cell function and insulin secretion similar mans. Some researchers also reported increased serum to that observed in humans with type 2 diabetes. Long- insulin and improvement in liver glycogen storage after term effects in humans are unknown, but the product is garlic administration. There is a potential for additive considered potentially harmful to people with diabetes hypoglycemic effects with antidiabetic drugs, although or impaired glucose tolerance (prediabetes). Several studies (generally small and not well- tidiabetic medications have not been reported. How- designed) indicate that ginseng lowers blood glucose ever, blood sugar should be monitored carefully. It may chondroitin, which is often taken with glucosamine for be useful in preventing diabetes or complications of dia- osteoarthritis, there is no information about effects on betes. However, larger and longer studies are needed be- blood sugar, use by diabetic clients, or interactions with fore general use can be recommended for diabetics or antidiabetic drugs.
Chapter 3 tations during childhood education in the 3Rs provides examples from functional imaging can be thought of as a build up of functional studies of cortical representational plasticity wiring driven by cerebral maturation and learn- that parallels changes in impairment and ing discount premarin breast cancer under armour. Just as an enriched environment may in a sleeve to force the animal to use its af- lead to synaptogenesis in rodent cortex premarin 0.625mg generic womens health care center, an en- fected hand (see Chapters 5 and 9 about riched environment and task-specific behav- forced use strategies for hemiparetic pa- ioral learning after a cortical injury may lead to tients) premarin 0.625 mg cheap breast cancer donation, the representation for the digits and growth of dendrites and dendritic spines and wrist still decreased in size compared to when improved behavior best buy premarin menstrual anemia. Nudo and colleagues have developed a corti- the degree of functional improvement in cal injury model in the squirrel monkey that al- successful pellet grasping in the monkeys in lows the study of aspects of plasticity and the these experiments often did not differ sub- effects of rehabilitation training. The model is stantially from the level of success in hand- less a duplication of changes associated with grasping skill achieved by animals that did not stroke than a method to drive cortical repre- train and did not show reorganization in M1. The investigators resented in yet another portion of the sensori- perform tedious cortical microstimulation with motor cortices, probably the ventral premotor glass electrode penetrations into layer 5 of M1 area or cingulate motor cortex or both. They delineate the move- liminary work by Nudo and colleagues, the ment representations for the digits, wrist, and ventral premotor region for digital and wrist proximal arm of the monkeys. Such studies movements also expands in relation to the per- show that motor skills training with the digits centage of loss of the digital area in M1. In- as the monkeys grasp pellets in a small well deed, an increase in synaptogenesis is also leads to an expansion of the representation for found despite the loss of M1 inputs to the ven- the wrist and digits and a reduction in the rep- tral premotor area, perhaps arising from added resentation for the arm in M1 (see Chapter 1). Other investigators have found a rein- M1, within the representation for the digits. Animals that do not re- motor region is injected to block neurotrans- ceive any specific retraining to use the hand mission. Thus, evidence is accumulating to sug- to pick up food pellets evolved a 30% smaller gest that neuronal assemblies in spared regions representational map for the hand. From 10 to 12 hours of ing in poststroke patients adds to this evidence training and greater success in pellet retrieval (see Color Figure 3–5 in separate color insert). When prac- cortex, and retested the representational move- tice for grasping food pellets was delayed for ment map after the animals were given either 2 months after the digit region infarct, the skilled, unskilled, or no retraining for the hand map in the monkeys was larger than af- task. The untreated group Biologic Adaptations and Neural Repair 101 lost the motor map for both proximal and dis- stroke and continued for up to 9 weeks. Thus, in animal models, be- layer 5 pyramidal cells of the forelimb motor havioral and neural compensation are influ- cortex on the nonlesioned side had greater enced by the type of rehabilitation experience. In addi- This representational plasticity with skills re- tion, perilesional sprouting and synaptogenesis learning is accompanied by parallel changes, occur when a cortical infarct in a rodent is fol- such as an increase in the number of synapses lowed by general training, and after injection per neuron. The patchwork of substances that attract, than on corticospinal pathways. How neural repel, and modulate axonal regeneration has network differences between a macaque and a grown so complex that the clinician may have human may differ in reaching to pinch a raisin difficulty seeing the whole fabric. More important, the Nudo and tial to manipulate some of these substances for Kleim models may have limited application to neural repair, however, puts some clinical im- the human pathologic condition, in which portance on knowledge of the following exper- many, but not all patients suffer lesions large imental studies in animal models. An enriched environment improved retinal ganglia cells survived an induced injury. The Schwann cells of the pe- reaching with the affected forelimb to obtain ripheral nerve protected and sustained the reti- food pellets was added to the social group and nal growth cones. This study pointed to the in- toys of an enriched environment, the function hibitory aspects of the CNS milieu compared of the forelimb on reaching for pellets and foot to the PNS. Oligodendrocytes, for example, placing tasks did improve compared to the an- produce Nogo, the inhibitor of axon regenera- imals living in standard conditions. Peripheral the gains did not generalize to weight-bearing nerve bridges and Schwann cells embedded in movements on the affected forelimb. The artificial matrices are still, 20 years after the training in this study began 15 days after the first experiments by Aguayo and colleagues, a 102 Neuroscientific Foundations for Rehabilitation Table 2–7. Criteria for Confidence in the Experimental Regeneration of a Central Circuit Survival of axotomized neurons Synapses made with proper targets Axonal regeneration over a long distance Electrophysiologic demonstration of functional connectivity Penetration of gray matter Behavioral effects of circuit Form synapses with arbors and boutons Loss of behavioral effects with experimental disruption of regenerated path potentially powerful means to direct long dis- were placed near a spinal cord injury site in ro- tance CNS axonal growth. This group also dents, resulting in greater axon growth com- showed that neurons from the adult rodent pared to not inhibiting Nogo. Immunization inhibit axonal sprouting, although these cells against specific myelin-associated inhibitors do protect nearby neurons and protect the may also produce a favorable milieu for the blood-brain barrier. Myelin-associated production of inhibitory molecules by the five glycoprotein94 and Nogo-A95 inhibit axonal re- cell types that secrete them. MAG is found in eral proteoglycans and semaphorins would be uncompacted myelin and in the innermost less available to inhibit axonal sprouting and membrane of myelin, where it contacts its growth after meningeal irradiation or by in- axon. Nogo-A is a protein associated with the stilling a drug that limits fibroblast migration. Both proteins inhibit the growth droitin sulfate proteoglycans can be dissolved cone, perhaps especially when released from with local infusions of protein enzymes. Indeed, Davies, Silver, and colleagues during CNS development, include members of showed that in the absence of scar, normal and the netrin, ephrin, semaphorin, and slit fami- degenerating white matter in adult rats per- lies of axon guidance proteins. Specific pro- mitted rapid growth of axons from implanted teases cleave molecules such as the sema- embryonic neurons and from adult spinal dor- phorins. Another approach to the injury site sal root ganglia sensory neurons over long dis- would alter the gene expression for a sema- tances. Another approach is to block the To permit axon regeneration, antibodies intracellular messenger that inhibits, for exam- have been directed against several of the ple, the formation of structural proteins such growth cone inhibitors. The C-3 toxin from come into greater use as the components of in- Clostridia botulinum is an antagonist to Rho, hibitory molecules are characterized. The drug inacti- ample, cells that make an antibody to Nogo vated Rho, promoted axonal growth, and had Biologic Adaptations and Neural Repair 103 a neuroprotective effect in a crush model of cific inteventions are discussed in the section the optic nerve in rats and in the spinal cord on repair of SCI. Studies suggest that by increasing -integrin Many of the neurotrophins have both trophic levels in cells, especially dorsal root ganglion and tropic effects. Their trophism supports the neurons, regeneration regains much of the vi- survival and proliferation of cells and axons. An- Reports point to the survival of neurons in- other clever approach would place plasmids jured by ischemia or axotomy after treatment with DNA that encode for neurotrophins in the with NGF, NT-3, NT-4/5, and BDNF. For ex- proximal and distal stumps of an injured nerve ample, NGF was infused into the lateral ven- or tract. Gene-activated the medial septum to the dorsal hippocampus, matrices may contain other promotors of cell an important pathway for memory. Apoptosis of neurons and glia contribute to the most likely first-line approach for pa- the pathology of stroke, TBI, SCI, and degen- tients will include pharmacologic manipulation erative neurologic diseases. By increas- cell death involve a shift in the balance be- ing endogeneous levels of cAMP by, for exam- tween pro-apoptotic and anti-apoptotic pro- ple, priming the milieu of injured axons with teins. Thus, courages the axon growth cone to extend its fi- apoptosis may have proregenerative actions. Fibroblast growth factor regulation of arginase I and polyamine synthe- prevented this degeneration after infusion in an sis. Several spe- viding antiapoptotic proteins such as bcl-2 to a 104 Neuroscientific Foundations for Rehabilitation region at risk or by providing certain caspase most human clinical trials, the outcome mea- inhibitors. Ciliary neurotrophic factor, which is sures may not have been sensitive to change or produced by Schwann and glial cells, and appropriate to the most likely biologic effects of GDNF are among the other developmentally the drug.
Explicit memory network centered in the change in efficacy order premarin cheap women's health clinic st louis, then purchase premarin 0.625mg amex menopause 6272, improves perform- hippocampus and a closely related emo- ance on associations that were not relearned buy generic premarin 0.625 mg online womens health associates columbia mo. Working memory and executive function bases for rehabilitation retraining 0.625 mg premarin menstruation flow. Spatial awareness network centered in the posterior parietal cortex and frontal Explicit and Implicit eye fields Memory Network 4. Face and object recognition network with can be recalled consciously and reported. This centers in the midtemporal and tem- form of memory includes episodic memories, poropolar cortices300,306 which are personal experiences, images and the neural mechanisms that select and co- everyday events with their rich contexts and re- ordinate distributed brain activity for the rapid creation over time, and semantic memories, adaptations needed for learning and thought which refer to the recall of factual knowledge probably include electrical synchronization of about the world and general information about neuronal assemblies in a network. Declarative memory stands in nous networks recorded by electrodes over contrast to implicit or procedural memory, wide regions of the brain emerge and disap- which cannot be overtly reported, such as how pear in waves that last 100–300 ms, which is one types on a keyboard after training. Knowledge about the qualities of rive from the finding that multiple associa- items that place them in the same category can tional, sensory, and motor areas of the brain also be acquired implicitly, so that even an am- contain features of what was learned in the nesic patient can learn the pattern that classi- past, although a particular modality may carry fies items. These networks, gies have been developed around the notion especially the parahippocampal regions and that impairments may be ameliorated by tap- hippocampus, receive new sensory information ping into one or more of the distributed grids regarding facts and events and sketch a mem- that remain connected. On the other hand, since ory trace until it is bound onto the remote cor- cognitive domains appear to be mapped at mul- tical modules that consolidate the memory. For mechanism that depends on a distributed sys- example, episodic memory mediates a synthe- tem. Relearning a few forgotten words of a for- sis of all the auto trips a person takes around a eign language or of a poem often triggers the city. Even without looking at a paper map, one recall of many other words or phrases. This can make navigational inferences while driving spontaneous recovery is a generic characteris- that are built upon past spatial (streets that run tic of the CNS, in which associations are dis- east to west) and visual memories (relation- tributed over many processing units, such as ships to a previously passed supermarket and Plasticity in Sensorimotor and Cognitive Networks 55 theater) and other personal experiences (a con- infarcts that damage the hippocampus. The versation with a friend about the intended tar- medial temporal lobe is not needed for suc- get) to arrive at a new location. MECHANISMS OF the hippocampal region is not required for EXPLICIT MEMORY immediate recall. The prefrontal cortex man- ages working memory and neighboring areas the hippocampal region of the medial tempo- are involved in the maintenance and manipu- ral lobe, a jelly roll of interleaved neuronal lation of ongoing working memory. The amyg- fields, projects from the subiculum through the dala is a center that mediates emotional mem- fornix to the cortex. The parahippocampal re- ory and modulates the strength and persistence gion includes the parahippocampal and perirhi- of memories in other memory systems. Prospec- nal cortices, which provide the major inputs to tive memory has a declarative component (what the hippocampus. Damage to the hippocampal needs to be recalled) and a temporal or con- formation causes profound amnesia for re- textual component (when or where the inten- cently acquired declarative memories, but gen- tion or action is to be carried out). Cerebral trauma often impairs this func- communication to and from the hippocampus. Other specialized areas of the brain allow Color Figure 3–3 (in separate color insert) re- for rich and stable new associations. Memories veals some of this interacting circuitry by show- of faces and complex visual patterns, for ex- ing the distribution of hypometabolism after ample, are encoded in the inferotemporal cor- a stroke in the dorsal and anterior thalamus. For example, a whole word is recalled tum are differentially engaged by declarative after a subject is given only the first syllable of and procedural learning tasks, respectively. Priming is not sensitive to associa- These systems may compete, however, de- tions with other knowledge. Poldrack and colleagues found subsystems, such as those that process word that subjects may rely on the medial temporal forms and visual objects. Each hemisphere, in lobe early in training, but dependence changes fact, may store different representations. Activations by example, changing the font of letters did not fMRI between the hippocampus and caudate affect word-stem priming when fragments of a correlate negatively as learning proceeds. A lesion in the amygdala subjects following a traumatic brain injury, her- may leave declarative memory intact, but could pes encephalitis, and posterior cerebral artery abolish the autonomic responses that had been 56 Neuroscientific Foundations for Rehabilitation associated with the recall of events and biog- and imagery. The activation may also repre- raphical information, as well as reduce the abil- sent the actual storage of an image and later ity to recognize emotion in faces. It helps separate what is mundane from what is Memory Storage important by modulating the salience of events. After a lesion of the left amygdala, for exam- the hippocampus is not the final storage site ple, a subject loses the usual enhanced per- of declarative memories. The parahippocampal re- as a potential LTP-reducing stressor during gions receive convergent information from cor- rehabilitation. In prefrontal events that make up an episodic memory, re- and temporal regions that are modulated by trieve that memory by reexperiencing some novelty during an encoding task of words or facet of prior events, and link the continuing pictures, the magnitude of activation predicts experience to other stored representations of whether the events will be remembered. For exam- Multiple prefrontal-temporal circuits that each ple, rats have been electrophysiologically stud- depend on the content of the task support the ied as they reach the junction of a T-maze, encoding of events to create a flexible, long- where they must learn whether to turn left or term memory trace. Other cells fire voluntary recall, from a medial temporal-to- as the rat moves along the stem of the T re- neocortical backward signal for automatic re- gardless of whether the rat has to turn left or call, or from both in relation to the need. The hip- Phase-locked synchronization of electrical pocampus, then, has encoded both left-turn waves lasting a few hundred ms within the and right-turn experiences and has cells that hippocampal-cortical loops may correlate with link both experiences. When a subjects viewed a particular category of items stimulus associated with a consolidated mem- or imagined the items. Indeed, the neurons ory reactivates that memory, some of the cel- that processed what was viewed, say an object lular events that occurred during the intiial but not faces, animals, or visual patterns, were consolidation are reenacted. The firing of the same neurons may plicit or explicit knowledge, may return a con- correlate with some percept common to vision solidated memory to a labile state, which can Plasticity in Sensorimotor and Cognitive Networks 57 reinforce or degrade knowledge of the old ex- tivity in rodents. A high degree of attention at the time fects of BDNF in the brain by infusing an an- of retrieval may increase reconsolidation, in tisense protein impaired the learning of a spa- part by noradrenergic neuromodulation. This tial task and recall from spatial memory, which potential for degradation may have a highly are medial temporal lobe functions. In such patients, the retrieval of pocampal computations made over the life of past knowledge could be contaminated by new an animal. Of in- DECLARATIVE MEMORY terest, NMDA receptor-dependent neurons in the hippocampus reactivate spontaneously in Positron emission tomography and fMRI can the immediate period after learning. This reen- assess network and within-region activations try reinforcement may be one of the drives that for a variety of memory processes. Encoding and retrieval en- pocampus share some of the same mecha- gage prefrontal cortex, the medial temporal nisms. Encoding and storage may respond in a lobe, and parieto-occipital regions, but consid- similar way to neuropharmacologic interven- erable within-region differences arise across tions with memory molecules that will be tasks. Semantic retrieval of knowledge about available in the near future, such as drugs or categories, such as animals versus tools or the genetic modulations that increase nuclear cal- color of objects based on knowledge of the cium levels to activate CREB-mediated tran- world, usually engages the left prefrontal cor- scription and learning. Memory traces may also studies of subjects during declarative memory involve neurogenesis. Neurogenesis in the hip- tasks have revealed two separately localizable pocampus has been found in all adult mam- memory processes in the medial temporal lobe. By ex- the subiculum is more active during retrieval, perimentally reducing the number of new whereas the parahippocampal cortex is espe- neurons entering the dentate gyrus of the hip- cially activated by encoding new inputs.
Following a trial that stopped early: what A Bayesian reassessment of two Phase II trials of next for adjuvant intra-arterial iodine-131-labelled gemcitabine in metastatic nasopharyngeal cancer discount premarin 0.625 mg online women's health clinic in toronto. Analysis of serial measurements in medical als: experience of order premarin 0.625 mg on-line menstrual neck pain, and proposals under consid- research purchase premarin 0.625mg without a prescription menstruation lunar cycle. STATA Statistical Software: Release the British Medical Research Council buy premarin 0.625mg lowest price women's health clinic yuma arizona. Stat Med melanoma patients: an application of multilevel (1994) 13: 1385–9. Br J Cancer Short Form Health Survey (SF-36) I: conceptual (1993) 68: 1047–50. Quality of Life: Assess- Introducing New Treatments for Cancer: Practical, ment, Analysis and Interpretation. Oxford: Oxford University Press (1998) Souhami RL, Altman DG, van der Scheuren E. Scand J Public Health (1979) 6: Statistical guidelines for contributors to medical 65–70. Practical guide- Gardner MJ, eds, Statistics with Conﬁdence, 2nd lines for multiplicity adjustment in clinical trials. London: British Medical Journal Books Contr Clin Trials, (2000) 21: 527–39. Begg C, Cho M, Eastwood S, Horton R, Moher D, line comparisons in clinical trials. Lancet (1990) Olkin I, Pitkin R, Rennie D, Schultz KF, Simel D, 335: 149–53. Commonly misused approaches in domized controlled trials: the CONSORT state- the analysis of cancer clinical trials. Gardner MJ, Machin D, Campbell MJ, Altman New York: Marcel Dekker (2000) Chapter 24. Analysis of Machin D, Bryant TN, Gardner MJ, eds, Statistics survival by tumor response. A class of k-sample tests for comparing approach in reproductive health. Statistical princi- ples for clinical trials: ICH harmonised Tripartite 81. Statistics notes: trials ran- approaches to analysis of failure times with domised in clusters. Practical Statistics for Medical Re- Improving the quality of data in randomized clin- search. Management of Data in Clinical cular and microvascular complications in type Trials. Trials to Hays RD, Fayers PM, eds, Quality of Life assess equivalence: the importance of rigorous Assessment in Clinical Trials: Methods and methods. Guidelines for the Ethical Conduct of Studies to Evaluate, published in 1995, reported that: Children are subject to many of the same diseases as adults, and are often treated with the same • In 1973, 78% of medications included a dis- drugs and biological products. Even today, no treatment is available treat children with potentially beneﬁcial medica- for many of the thousands of rare and serious tions, or treat them with medications based either diseases that largely affect neonates, infants and on adult studies or anecdotal empirical experi- children. Such non-validated administra- diseases in both children and adults have not been tion of medications may place more children at investigated in children at all. Over 50% of all risk than if the drugs were administered as part drugs prescribed in paediatric practice are either of well-designed, controlled clinical trials. The motto of the campaign has been what human studies could be funded by NIH Textbook of Clinical Trials. Green 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5 46 TEXTBOOK OF CLINICAL TRIALS to the exclusion of paediatric subjects. The REGULATORY ISSUES OF CLINICAL TRIALS exclusionary circumstances were: IN CHILDREN? But these • the relative rarity of the condition in children; efforts have, thus far, not substantially increased • the number of children is limited; the number of products entering the marketplace • Insufﬁcient data are available in adults to judge with adequate paediatric labelling. Considerable differences between marketed drugs and biological products must now the pharmacokinetics and pharmacodynamics evaluate the safety and effectiveness of the prod- of drugs in children and in adults frequently ucts in paediatric patients if the product is likely make it impossible to bridge conclusions from to be used in a substantial number of children, or data obtained in adults. Children cannot even provide a more meaningful therapeutic beneﬁt to be considered a homogeneous group, since paediatric patients than existing treatments. The absence regulation has been in force in the countries of of paediatric testing and labelling may also the European Community as well as in the US. Failure to develop to achieve effective improvement in paediatric a paediatric formulation of a drug or biological drug therapy. The Food and Drug Administration product, where younger paediatric populations (FDA) Modernization Act established economic cannot take the adult formulation, may also incentives for pharmaceutical manufacturers to deny paediatric patients access to important conduct paediatric studies on drugs for which new therapies. CLINICAL TRIALS IN PAEDIATRICS 47 However, there is likely to be a consensus development by Autumn 2002. This legislation during the coming years–at least in the ICH is considered by many to be pressing, creating GCP regions–over requirements for conducting the conditions needed to improve medicines for clinical trials on new drugs and other thera- children. But before this consensus can supported a legal and regulatory framework be reached, a number of points have to be for improving child health, especially regarding addressed and discussed, underlined by the fol- the labelling of medicines. The FDA needs to be created in Europe, since as a result addressed this issue in April 2001, calling on of reluctance to perform such studies up to institutional review boards to review study proto- now, there is a serious shortage of trained and cols that include children and ensure they adopt experienced people and centres of excellence. The study will address: developing a European dimension to improv- ing medicines for children. ICH GUIDELINE ON PAEDIATRIC STUDIES EXAMPLE 2–ONGOING DISCUSSIONS OF THE LEGISLATION OF PAEDIATRIC TRIALS the International Conference on Harmonisa- tion (ICH) Guideline E11–Clinical Investigation Based on feedback from a consultation document, of Medicinal Products in the Pediatric Popu- the European Commission was expecting to lation–became operational in January 2001 in prepare draft legislation on paediatric medicinal the United States, Europe and Japan. The E11 48 TEXTBOOK OF CLINICAL TRIALS guideline outlines critical issues in paediatric • For medicinal products for diseases predom- drug development. In summary, this new and inantly or exclusively affecting paediatric important ICH document states that paediatric patients, the entire development programme patients should be given medicines that have will be conducted in the paediatric population, been appropriately evaluated for their use. It says except for initial safety and tolerability data, safe and effective therapy in paediatric patients which will usually be obtained in adults. The goal of there are currently no (or limited) therapeutic this guideline is to encourage and facilitate timely options, there is need for relatively urgent and paediatric medicinal product development inter- early initiation of paediatric studies. This guideline addresses ﬁve issues, • For medicinal products intended to treat other namely considerations when initiating a paedi- diseases and conditions there is less urgency. Testing of these medicinal WHEN INITIATING A PAEDIATRIC products in the paediatric population would PROGRAMME? Some of the • Unique paediatric-speciﬁc endpoints; most important are: • Age ranges of paediatric patients likely to be treated; • When a medicinal product is to be used • Unique paediatric safety concerns; in the paediatric population for the same • Unique paediatric formulation development. In such cases, pharmacokinetic (PK) studies in all the age • Most important is the presence of a serious or ranges of paediatric patients likely to receive life-threatening disease for which the medici- the medicinal product, together with safety nal product represents a potentially important studies, may provide adequate information. This situation suggests rel- • When a medicinal product is to be used in atively urgent and early initiation of paedi- younger paediatric patients for the same indi- atric studies. In such cases, eral approaches can be used to minimise the pharmacokinetic studies in the relevant age amount of blood drawn and/or the number of groups of paediatric patients together with venipunctures: safety studies may be sufﬁcient. Thus, a PK/PD approach combined with safety and the principles in study design, statistical consid- other relevant studies could avoid the need for erations and choice of control groups are detailed clinical efﬁcacy studies. But there are also certain features the medicinal product in paediatric patients, unique to paediatric studies.