This article was downloaded by:[EBSCOHost EJS Content Distribution] On: 18 February 2008 Access Details: [subscription number 768320842] Publisher: Psychology Press Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Aphasiology Publication details, including instructions for authors and subscription information: http://www.informaworld.com/smpp/title~content=t713393920 Pharmacological approaches to the treatment and prevention of aphasia Rebecca J. Shisler; Gordon C. Baylis; Elaine M. Frank Online Publication Date: 01 December 2000 To cite this Article: Shisler, Rebecca J., Baylis, Gordon C. and Frank, Elaine M. (2000) 'Pharmacological approaches to the treatment and prevention of aphasia', Aphasiology, 14:12, 1163 - 1186 To link to this article: DOI: 10.1080/02687030050205705 URL: http://dx.doi.org/10.1080/02687030050205705 PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: http://www.informaworld.com/terms-and-conditions-of-access.pdf This article maybe used for research, teaching and private study purposes. Any substantial or systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material. Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 APHASIOLOGY, 2000, 14 (12), 1163–1186 REVIEW Pharmacological approaches to the treatment and prevention of aphasia Rebecca J. Shisler University of Georgia, USA Gordon C. Baylis and Elaine M. Frank University of South Carolina, USA Strokes cause a variety of cognitive impairments that may include aphasia. Speech-language pathologists and aphasiologists encounter an increasing number of patients treated with pharmacological agents. This review describes research regarding four main approaches to neuropharmacological intervention: pharmacotherapy or drugs used to facilitate language improvements following stroke, neuroreplacement to restore compromised levels of neurotransmitters, neuroprotective agents that minimise the extent of cell loss in the brain, and thrombolytic agents to restore blood flow to regions of the brain that have become ischaemic following stroke. Studies in each major approach are reviewed. INTRODUCTION Recent trends in pharmacological treatment of aphasia and stroke have led to new therapy developments in rehabilitation. These trends have built on past successes and failures to produce realistic possibilities for treatment and prevention of aphasia. This paper is a review for speech-language pathologists of pharmacological approaches to the treatment of stroke and secondary aphasia. As more patients are treated with pharmacological interventions, awareness of these interventions is becoming ever more important. In order to understand why certain drugs have succeeded while others have failed, it is first important to briefly review what occurs during a stroke and the subsequent deficits. The process of stroke There are two types of strokes: haemorrhagic and ischaemic. Ischaemic strokes represent the majority of all strokes, accounting for approximately 80% of clinical cases, and will be the primary focus of this review. Nonetheless, it should be noted that many of the principles for psychopharmacological intervention may also transfer to haemorrhagic strokes. When an ischaemic stroke occurs, three zones of damage form concentric circles, similar to a bullseye target. The primary area of damage is the central ischaemic zone (the ‘‘centre’’ of the Address correspondenc e to: Rebecca J. Shisler, Department of Communication Sciences and Disorders, 528 Aderhold Hall, The University of Georgia, Athens, GA 30602, USA. Email: [email protected] The authors would like to thank Drs R.R. Robey and Richard C. Gilman for their time and helpful comments on this article. Ó 2000 Psychology Press Ltd http://www.tandf.co.uk/journals/pp/02687038.html Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 1164 SHISLER, BAYLIS, FRANK bullseye), where loss of oxygen contributes to an inflammatory reaction (Matsuo, Yamasaki, & Kogure, 1996), leading to tissue destruction in this zone. Surroundin g this central zone is the ischaemic penumbra in which blood flow is reduced but cell function is only temporarily depressed (Benson & Ardila, 1996). Damage to this penumbra is potentially reversible, if intervention is timely, and so this is the main target for pharmacological and other medical intervention. The final, outermost ring, termed the collateral zone, contains little or no tissue damage, thus requiring minimal treatment (Matsuo et al., 1996). After an ischaemic event, a chain of events referred to as ‘‘the calcium cascade’’ occurs (Brailowsky, 1988). This cascade begins with failure of the sodium-potassium pump and other energy-dependent mechanisms for regulating intracellular ion concentrations. Failure of the sodium-potassium pump allows sodium to flow into the cell, causing cytotoxic oedema and changes in the cell’s ionic balance. The resulting failure of mechanisms also leads to a significant increase in the amount of intracellular calcium, initiating the main events of the calcium cascade proper (Scheinberg, 1991; Siesjo, 1992; Turkstra, 1997). Increased intracellular calcium levels lead to release of a number of excitatory neurotransmitters (such as glutamate) that can bring about excitotoxic neuronal death. The cumulative effects of these transmitters leads to an increased influx of calcium into neighbouring cells, thus initiating a spiralling intensification of the effects of ischaemia (Rothman, 1983; Scheinberg, 1991). An increase in intracellular calcium also activates many autolytic enzymes that further break down the cell’s protein, DNA, and lipids that form an essential part of the cell’s membrane (Turkstra, 1997). Moreover, the breakdown of lipids leads to the production of arachidonic acid and subsequent formation of free radicals (Reilly & Bulkley, 1990). Free radicals are highly unstable molecules that cause rapid oxidation of biological molecules (Reilly & Bulkley, 1990). Although free radicals are formed during normal cell functioning, antioxidants and free radical scavengers neutralise them as part of the normal neuroprotective defence mechanisms (Turkstra, 1997). However, when there is low energy availability during an ischaemic event, free radicals are not efficiently scavenged. Therefore, the free radicals may react with molecules in cells, causing further deterioration (Fishman, 1986; Reilly & Bulkely, 1990). This cascade of dysfunction highlights three crucial areas for treatment and neuroprotection: the re-establishment of regulation of intracellular calcium, the regulation of excitatory neurotransmitters, and the containment of free radicals. Research in animal models of stroke suggests that these events take place over hours or days (Dyker & Lees, 1998). Thus, the window for intervention may in fact extend beyond the first few hours after the ischaemic event. With increasing knowledge of the mechanisms and time course of damage, a number of new drugs have been developed to address the cellular injury caused by stroke. Deficits associated with stroke Secondary impairments after a stroke include hemiparesis and deficits in vision, audition, cognition, and language including aphasia. Aphasia impairs an individual’s expressive and/or receptive language, and many people never recover the ability to communicate or process information (Hegde, 1994). More specifically, Darley (1982, p. 42) defined aphasia as: Impairment, as a result of brain damage, of the capacity for interpretation and formulation of language symbols; multimodality loss or reduction in efficiency of the ability to decode and encode conventional meaningful linguistic elements (morphemes and larger syntactic units). Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 PHARMACOLOGICAL APPROACHES TO APHASIA 1165 In the past, research has focused on rehabilitating individuals with aphasia primarily by using language therapy. Recent research has suggested that a more aggressive treatment regimen may be appropriate. One potentially productive research area is to attempt to protect brain tissue from permanent damage during the course of a stroke (i.e., neuroprotection). Because, as noted above, a large part of the damage site of a stroke (the penumbra) does not initially suffer irreversible damage, timely and appropriate pharmacotherapeutic intervention may prevent much of the brain damage, thus mitigating many of the deficits associated with stroke. With the advent of more and more pharmacological agents following stroke, it is increasingly important for speech-language pathologists to be aware of past and current approaches to drug treatment in stroke and secondary aphasia. Main approaches to treatment Four essential models of treatment that will be discussed in this review are: pharmacotherapy, neuroreplacement, neuroprotective agents, and thrombolytics (see Table 1). Pharmacotherapy refers to the use of drugs to facilitate language improvements following stroke. This area has a long history of research and has been essential in stimulating additional research into pharmacological approaches to the treatment of aphasia. A similar approach to optimising maximum rehabilitation is neuroreplacement, which focuses specifically on the neurotransmitter systems of the brain. Although this approach can be considered a subset of pharmacotherapeutic approaches, it operates on a different premise then conventional pharmacotherapy. Specifically neuroreplacement seeks to replace the neurotransmitters that were lost following stroke. This replacement in turn is believed to improve language function in individuals with aphasia. Thus a neuroreplacement section will be discussed separately. In contrast to these two approaches, two other approaches are directed at minimising the initial damage that occurs following a stroke. Neuroprotective agents attempt to TABLE 1 Drug categories and research type and status Drug Category Type of research Status of use in humans Bromocriptine Amphetamine Piracetam MK-801 GYKI52466 Nimodipine Monosialogangliosida Tirilazad Lubeluzole Citicoline Cerestat Eliprodil Selfotel Clomethiazole Streptokinase Tissue Plasminogen Activator Pharmacotherapy Pharmacotherapy Pharmacotherapy Neuroprotective agent Neuroprotective agent Neuroprotective agent Neuroprotective agent Neuroprotective agent Neuroprotective agent Neuroprotective agent Neuroprotective agent Neuroprotective agent Neuroprotective agent Neuroprotective agent Thrombolytic Thrombolytic Human Animal/Human Human Animal Animal Human Human Animal/Human Human Animal/Human Human Animal Human Human Human Human Accepted* Accepted Pending * Found ineffective in treating aphasia ** Discontinued in Europe Accepted Pending Pending** Pending Pending Discontinued (12/97) Discontinued (1995) Pending Pending Accepted Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 1166 SHISLER, BAYLIS, FRANK interrupt the chemical processes that lead to cell death in the ischaemic penumbra, thus minimising the extent of damage. This approach thus decreases the extent of deficits, reducing the need for rehabilitation of lost language functioning. Finally, thrombolytic agents are used to re-establish blood supply to the affected area of the brain as soon as possible, reducing the duration of the ischaemic episode. Although fundamentally different from the chemical neuroprotective approach, the effect is the same—to minimise the extent of destroyed tissue, reducing the deficits and the need for rehabilitation. PHARMACOTHERAPY The notion of pharmacotherapy to assist in the recovery of function in aphasic individuals is not new, although recent improvements in understanding the biochemical nature of stroke damage are leading to increased scholarship in this area. Research in the area of pharmacology primarily focused on two areas: frustration reduction and increased blood flow. Frustration reduction Early pharmacotherapy attempts in aphasia were based on the observed frustration among patients suffering from stroke. For example, Linn (1947) hypothesised that by lessening the frustration and inhibition of communication found in aphasia, language functioning could increase. Using the sedative sodium amytal, Linn reported that one woman with mixed aphasia demonstrated significant improvement in object naming and function naming tasks and on the Goldstein-Scheerer block test (Goldstein & Scheerer, 1945). In this study, a second woman was also administered the same amount of solution, resulting in similar improvements. However, this woman relapsed immediately after the effects of the drug dissipated. Linn (1947) surmised that sodium amytal may not necessarily change the underlying neuronal mechanisms that cause aphasia, but may temporarily increase verbal expression by lowering the frustration level of the individuals. Billow (1949) also reported temporary relief of aphasia in two patients when using sodium amytal. Nevertheless, subsequent studies using sodium amytal have reported conflicting findings. For example, in an investigation of 27 patients, Bergman and Green (1951) found a significant decrease in the language skills of patients with aphasia after administering sodium amytal. Despite these equivocal findings with sodium amytal, numerous investigators continued to pursue the hypothesis that reducing a patient’s frustration after aphasia would increase their language abilities. West and Stockel (1965) investigated the effects of meprobamate (a tranquilliser) on the language performance of 29 subjects. The results indicated that the use of meprobamate, in combination with language therapy, did not significantly increase language performance among those in the experimental group in comparison to those who received language therapy and placebo. Along a similar hypothesis, Darley, Keith, and Sasanuma (1977) investigated the effects of Ritalin (a psychostimulant) and Librium (a tranquilliser) on reducing anxiety and increasing alertness with the goal of improving linguistic cognitive performance. In this study, 14 patients diagnosed with aphasia were administered Ritalin, Librium, or a placebo across a three-day period. The specific drug or placebo was given 45 minutes prior to administration of the Porch Index of Communicative Ability (PICA; Porch, 1983) and a word fluency test. This design allowed for comparisons to be made within each subject. Subsequent results revealed no difference between the drugs or the placebo on patients’ PHARMACOLOGICAL APPROACHES TO APHASIA 1167 Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 performance on either assessment. In general, little support has been found regarding the hypothesis that reducing an aphasic patient’s frustration level would enhance their ability to communicate. Increasing oxygenation In contrast, a competing hypothesis within the area of pharmacotherapy speculates that increasing blood flow to the cerebral area may improve oxygenation, hence restoring functioning of partially damaged neuronal tissue. This oxygenation would in turn increase the language performance among individuals with aphasia. In this vein, Hemphill (1951) reported findings of short-term improvements (three hours) with an increase in speech fluency and sentence copying after administration of Priscol. Given the short-term effects of Priscol, Hemphill hypothesised that the cerebral structures that were not functioning in aphasia were functionally depressed rather than destroyed. This hypothesis can be viewed as an early characterisation of the ischaemic penumbra, with only temporarily depressed cell function that may be salvaged. In addition, Smith and Turton (1951) reported a dramatic improvement in verbal fluency and verbosity in a man with mixed aphasia after receiving 40 mg of Priscol (an antiadrenergic, peripheral vasodilator drug). In spontaneous speech, Smith and Turton reported that this improvement lasted for three hours, and suggested that the patient demonstrated ‘‘a good performance on learning tests and no evidence of memory failure’’ (Smith & Turton, 1951, p.891), although the outcome measures and experimental procedure of this study were not reported. Smith and Turton postulated that the effects were due to Priscol’s action as a dilator of brain arterioles, leading to an improved oxygen supply to the brain. However, some limitations in the design and the nature of the study should be noted. For example, assessment of this study is difficult due to the informal nature of testing and the lack of experimental details. In fact, in subsequent trials, the patient slowly returned to baseline after showing initial improvement, in spite of dosage increases (Smith & Turton, 1951). Hyperbaric oxygen has also been utilised in attempts to improve language functioning in individuals with aphasia (Sarno, 1969). For example, Sarno, Sarno, and Diller (1972b) exposed 16 participants to hyperbaric oxygen for 112 hours. Baseline measures were taken 24 hours before the first exposure and participants were then retested immediately following use of the hyperbaric chamber. Sarno et al. (1972b) found no significant improvements on the Token Test (De Renzi & Vignolo, 1962) and the Functional Communication Profile (FCP; Taylor, 1965). In a follow-up study (Sarno, Rusk, Diller, & Sarno, 1972a), 32 stroke patients with aphasia were administered portions of the Wechsler Adult Intelligence Scale (WAIS), the Token Test, and the FCP for communication assessment before, during, and after exposure to hyperbaric oxygen. Similar to the earlier Sarno et al. (1972b) study, hyperbaric oxygen did not improve the cognitive or communication functioning of these aphasic individuals (Sarno et al. 1972a, b). In sum, attempts at pharmacological interventions have yielded equivocal success. The frustration reduction hypothesis has generally produced ambiguous and conflicting results, with apparent improvements largely due to biases inherent in the methodology rather than the treatment per se. Subsequent investigations of this hypothesis using more stringent methodology have generally yielded non-significant findings. In addition, the increasing oxygenation hypothesis showed limited and short-term effects on a patient’s language, if improvements were seen at all. Therefore, it appears both the frustration 1168 SHISLER, BAYLIS, FRANK Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 reduction and increasing oxygenation hypotheses may only help to improve language on a limited and temporary basis, if at all. NEUROREPLACEMENT A more recent approach to pharmacological rehabilitation following stroke concerns the replacement of lost neurotransmitters, or neuroreplacement. According to this view, the replacement or augmentation of neurotransmitter systems in the brain is thought to play a role in the recovery from stroke and its subsequent deficits including aphasia. One of the early precursors to this approach might have been through the use of certain foods (see Bachman & Albert, 1990). For example, previous stroke research hypothesised that individuals given roots and cashew nuts would demonstrate increased language performance. Such foods are rich in amino acids that serve as precursors to neurotransmitters, and it is possible they replaced lost neurotransmitters and therefore aided in recovery (Mettler, 1947; Mlcoch & Gupta, 1995). More contemporary theories focus on both the catecholaminergic and GABA-minergic neurotransmitter systems as sources of neuroreplacement, as both have been suggested to play a role in the recovery of language following stroke. Many researchers have argued that a combination approach of speech-language therapy with these pharmacological interventions increasing neurotransmitters will lead to an increase in functional language recovery (Enderby et al., 1994; Walker-Batson et al., 1992). The following sections will discuss drug administration alone as well as combining therapy with drug interventions in regards to the two major systems targeted in neuroreplacement. The two major systems include: the catecholamine system and the GABA-minergic system. Catecholamine systems Theories of the effect of catecholaminergic systems on language recovery were initially based on improvements after amphetamine administration (see Mlcoch & Gupta, 1995; Small, 1994; Walker-Batson et al., 1992). Amphetamine is known to have effects on two distinct catecholaminergic systems: the norepinephrine and dopamine systems. Some researchers have argued that changes in norepinephrine functioning after stroke show a relationship with rate of recovery after brain injury (e.g., Feeney, Gonzales, & Law, 1982). Thus, in order to determine the effects of amphetamine in the recovery of speech and language functioning, Walker-Batson et al. (1990) studied a man diagnosed with moderate-to-severe Broca’s aphasia. Amphetamine was administered approximately 45 minutes prior to a 75-minute speech and language therapy session every 4 days across a 6-week period. Instead of using an explicit control in this study, the improvement in this patient was compared to known normative recovery, using Porch’s prediction method (Porch, 1981). The prediction method calculated that the patient would be expected to improve by 3.8 points, and the patient actually achieved a 16-point ‘‘Target Difference Score’’ at 6 months post-onset. Similar improvements were also noted at 12 months postonset, again exceeding the improvement that would be predicted without intervention. It must be noted that due to the single-subject study design (and therefore only descriptive results), it is difficult to isolate the true therapeutic effect of amphetamine, as opposed to the effects of the speech-language therapy or spontaneous recovery. Because of this limitation, Walker-Batson et al. (1992) replicated the study with six participants diagnosed with aphasia according to the Porch Index of Communicative Ability (PICA). The authors again compared the improvements seen with intervention to the baseline improvements predicted by the Porch (1981) method. Results indicated that at just 3 Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 PHARMACOLOGICAL APPROACHES TO APHASIA 1169 months post-onset, five of the six patients achieved 100% of the predicted 6 month PICA scores—a dramatic improvement over predicted recovery. Taken together, these findings suggest the possibility that the use of amphetamines in conjunction with speech and language therapy may aid in the recovery of aphasia. Nevertheless, given the lack of control groups, these results should be interpreted with caution until more stringent studies are designed. Further support for the efficacy1 of amphetamines in treating deficits following stroke comes from studies where the use of the drug was combined with intense physical therapy for disorders other than aphasia. Crisostomo, Duncan, and Dawson (1988) gave eight patients with right hemisphere stroke a combination of amphetamines and physical therapy. After comparing recovery with individuals who received physical therapy alone, significant improvements were found in the group that received amphetamines in addition to physical therapy. Similarly in a randomised double-blind placebo-controlled study, Walker-Batson et al. (1995) reported full recovery of motor control in five patients receiving this combination therapy, even when tested 12 months after completion of the study. In view of the effect on motor function, Hassid (1995) suggested that the apparent success of amphetamine in treating aphasia is mediated by its effects on motor function— an essential component in the formation of speech. Other researchers have argued that dysfunction of the dopaminergic system may lead to impaired fluency in patients diagnosed with nonfluent aphasia. This suggests that the effects of amphetamine may be mediated via its dopaminergic system (e.g., Bachman & Albert, 1990; Freedman, Alexander, & Naeser, 1984). Indeed, Freedman et al. (1984) found that lesions in the dopamine tracts of the left dorsal and medial frontal areas (especially the left supplementary motor area) corresponded to significant decreases in speech initiation. Based on this finding, subsequent research has sought to increase dopamine activity using bromocriptine, a dopamine agonist that, unlike amphetamine, has no effect on the norepinephrine system. In one early study using bromocriptine, Albert, Bachman, Morgan, and HelmEstabrooks, (1988) attempted to improve the language performance of an individual diagnosed with transcortical motor aphasia. Using the Boston Diagnostic Aphasia Exam (BDAE; Goodglass & Kaplan, 1983) as the outcome measure, the researchers noted improved language performance after 10 days of treatment. The investigators also reported continued improvement in language performance after 1 month of treatment, although improvement became markedly slower as the duration of the treatment progressed. When bromocriptine use was discontinued for one month, the patient exhibited a complete return to baseline performance. Albert et al. (1988, p. 878) noted that ‘‘formal language testing . . . failed to capture his dramatic gains in conversational fluency’’, indicating that bromocriptine might have alleviated some of the language deficits of the individual. However, this study was a single-subject design and did not use a placebo control, thereby limiting the strength of the conclusions that can be drawn. Noting this limitation, MacLellan, Nicholas, Morley, and Brookshire, (1991) investigated the effects of bromocriptine in doses ranging between 2.5 and 20 mg, on a man diagnosed with transcortical motor aphasia. This study employed single-blind procedures, using either bromocriptine or a placebo over a 4-week period. Results indicated no significant improvement in language performance of the participant. 1 For the purpose of this article, we have adopted the definition of efficacy such that it refers to the extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal circumstances (Last, 1995). Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 1170 SHISLER, BAYLIS, FRANK Unfortunately, MacLellan et al. (1991) used only parts of the BDAE to determine improvement, once again limiting the ability to compare this investigation with others. Nonetheless, it is tempting to conclude that the ‘‘unequivocal improvement’’ that Albert et al. (1988, p. 878) noted may be due to the lack of a placebo condition. Without a measurement of spontaneous recovery it is difficult to determine the effect of the intervention itself. In addition, both studies were single-subject designs, thus limiting their generalisability. In a more recent study, Gupta and Mlcoch (1992) studied two patients with nonfluent aphasia more than 18 months post-stroke. The patients were given both 10 mg and 30 mg of bromocriptine, beginning with 10 mg per day during the first week and increasing to daily doses of 30 mg over 8 weeks. The researchers obtained a 10- to 15-minute speech sample and administered the BDAE and The Boston Naming Test (BNT; Kaplan, Goodglass, & Weintraub, 1993). Both patients demonstrated an increase in the number and type of words used as measured by these assessments. However, because of methodological limitations of the study (e.g., no placebo control group), the results must be interpreted with caution due to the fact that spontaneous recovery may have contributed to the increasing speech fluency. Sabe, Leiguarda, and Starkstein (1992) administered various doses of bromocriptine (15, 30, 45, and 60 mg) to seven participants diagnosed with various severities and types of aphasia. The Western Aphasia Battery (WAB; Kertesz, 1979, 1982) was used for assessment of language performance every two weeks. Sabe et al. (1992) hypothesised that ‘‘bromocriptine may significantly improve language disturbances in patients with moderate, but not severe, nonfluent aphasia’’ (p.42). In this particular study, improvement was only seen when moderately large doses of the drug were administered. These doses were higher than those used in the study of MacLellan et al. (1991), in which no beneficial effect of bromocriptine was observed. Thus, improvement in language performance may be a function of dosage level. Nevertheless, while Sabe et al.’s (1992) finding showed promise for individuals with moderate forms of nonfluent aphasia, some potential limitations were noted. First, a caveat has to be placed on the use of these doses of bromocriptine, as all patients administered the highest doses experienced painful side effects, including dystonias (bizarre movements of the arms, legs, neck, and face) (Ciccone, 1996). The second caveat comes from the fact that the study did not employ a double-blind, placebo-controlled design. Indeed, in a follow-up study that did use appropriate controls, Sabe et al. (1995), failed to replicate this improvement in seven patients diagnosed with various levels of severity and types of aphasia. In summary, bromocriptine studies have produced conflicting results. Typically, wellcontrolled studies have shown that the use of bromocriptine does not produce any improvement in the degree of recovery compared to that seen in the controls. The suggestion that bromocriptine may have beneficial effects has come from studies that include experimental confounds, such as placebo effects, experimenter bias, the influence of behavioural therapy, and spontaneous recovery. GABA-minergic system A second target of neuroprotective therapy is the GABA-minergic system. Gammaamniobutyric acid (GABA) plays a role in the events associated with a stroke and is thought to interact closely with glutamate (Schallert & Hernandez, 1998). In addition, GABA also interacts with other neurons (e.g., noradrenergic and cholinergic), which are associated with recovery of function (Francis & Pulsinelli, 1982; McIntosh, 1994; Metz, Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 PHARMACOLOGICAL APPROACHES TO APHASIA 1171 1971; Schallert & Hernandez, 1998). Therefore, the GABA-minergic system is important in relation to recovery after ischaemia. One drug that is thought to act as a GABA agonist is Piracetam, although its exact mode of action is unknown (Bachman & Albert, 1990). Piracetam is in a class of drugs called nootropics, or drugs that enhance cognitive function, and has been used in a number of studies investigating cognitive recovery following stroke (Cohen & Muller, 1993; Hickenbottom & Grotta, 1998; Stoll, Schubert, & Muller, 1991). How this, and other drugs lead to the functional effect of improved cognition is much debated, but nootropic agents may act by increasing the density and restoring the function of muscarinic (Stoll et al., 1991) and NMDA receptors (Cohen & Muller, 1993). In an early study, Stolyarova et al., (1978) administered Piracetam to 35 patients with aphasia and reported a significant improvement in speech and language recovery for 20 of them (57%). Similar findings have been reported in more recent studies (e.g., Von Herrschaft, 1987; Willmes, Huber, Poeck, & Poersch, 1988). In one such study, patients with mild to moderate language losses were found to improve if treatment began shortly after the onset of the stroke (Willmes et al., 1988). Von Herrschaft (1987) also found improvements in individuals with aphasia when using nootropic agents. In a double-blind parallel-group study, Huber et al. (1997) studied the effects of Piracetam on 50 individuals with aphasia. Over a 6-week period the investigators gave a combination of the drug treatment and intensive speech-language therapy. The experimental group received 4.8 g of Piracetam every day and the control group received a placebo on the same schedule. At the end of 6 weeks, the group receiving Piracetam scored significantly higher than the placebo group on the Written Language and Token Test subtests of the Aachen Aphasia Test (AAT; Willmes, Poeck, Weniger, & Huber, 1980). Unfortunately, no follow-up was carried out to assess the long-term significance of this improvement. Enderby et al. (1994) conducted a double-blind parallel-group study, in which participants were randomly assigned to receive 4.8 g of Piracetam or placebo each day for 12 weeks. All participants received speech and language therapy during the study. Drug efficacy was assessed with the AAT, a rating of activities of daily living (ADL) using the Barthel Index (Mahoney & Barthel, 1965), and the Kuriansky Performance Test (Kuriansky & Gurland, 1976), and tests of perception (Rivermead Perception Assessment Battery; Whiting, Lincoln, Bhavani, & Cockburn, 1985). Tests were administered at the beginning of the study, at 5 weeks and 12 weeks, and 12 weeks after termination of therapy. Similar to the results from Huber et al.’s (1997) study, patients receiving Piracetam demonstrated significant improvement of language functioning, but no improvement on the ADL or in perception measures. Enderby et al. (1994) suggested that Piracetam is specifically improving language functioning for individuals with aphasia. However, one might raise questions as to the functional significance of these improvements if an index of daily living abilities does not also improve. In a large phase II study, De Deyn (1995) demonstrated benefit when Piracetam was administered within 12 hours post-onset. However, in a later randomised placebocontrolled study, 927 patients were given intravenous Piracetam within 12 hours of stroke onset. De Deyn et al. (1997) reported no difference in mortality or neurologic outcome at 12 weeks post-stroke. Post-hoc analysis revealed that individuals treated within 7 hours of onset indeed showed a trend towards a better outcome (Hickenbottom & Grotta, 1998). Taken overall, De Deyn and colleagues’ findings are consistent with the literature regarding the limited time window in which neuroreplacement agents are effective in treating stroke. Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 1172 SHISLER, BAYLIS, FRANK Despite a lack of comparability of the assessment measures in different studies, and the small sample sizes used, a consensus emerges that both amphetamine and Piracetam are promising neuroreplacement agents to study. In the past, these agents have always been tested in combination with intensive language therapy. It should be noted that there is every reason to believe that these drugs alone would be unlikely to be effective. Although both amphetamine and Piracetam have been shown to improve learning in a variety of populations, this learning occurs due to the pairing of therapy with pharmaceutics. Presumably these drugs demonstrate efficacy in aphasics due to their ability to enhance the relearning that is induced by the combination of speech-language therapy with drugs. Further research of the pairing of therapy and neuroreplacement could expand to include the investigation of the length of time benefits are available after termination of combination therapy. NEUROPROTECTIVE AGENTS IN STROKE Neuroprotective agents have a complex method of action, typically directed at preventing or salvaging the ischaemic penumbra after a stroke (Hickenbottom & Grotta, 1998). While the previously mentioned studies in pharmacotherapy and neuroreplacement focused on recovery of function, neuroprotective therapy involves protecting neurons and minimising the extent of the lesion and the initial deficits. As noted earlier, researchers have targeted the ischaemic penumbra, which contains potentially viable tissue in patients with acute ischaemic stroke (Heiss & Graf, 1994). Protection of the penumbra has been demonstrated in animal models of stroke using neuroprotective agents (Dorman & Sandercock, 1996; Trembly, 1995). Human research with neuroprotective agents has typically focused on reducing mortality and morbidity, and on broad measures of outcome. As a result, discrete aspects of behaviour, such as language functioning, have been left relatively unstudied. Due to the difference in outcome measurement, usefulness of neuroprotection versus pharmacotherapy or neuroreplacement in aphasia should be compared with caution. Although neuroprotection is not a direct ‘‘treatment’’ of aphasia, the underlying principle is that by minimising destroyed tissue, deficits are reduced and subsequent aphasia, and therefore the need for rehabilitation, is decreased. The theory behind the following neuroprotective treatments has focused on three main areas: prevention of glutamate-induced excitotoxicity, scavenging free radicals to mitigate their cytotoxic effects, and repair of neuronal membranes. Each approach will be discussed in turn. Prevention of glutamate excitotoxicity Researchers have hypothesised that interventions to reduce glutamate excitotoxicity following an ischaemic event may minimise cell loss. Indeed, glutamate blockade may explain one of the earliest successes in neuroprotection, when Wright and Ames (1964) used sodium pentobarbital to reduce ischaemic brain damage in cats. The drug intervention doubled the time frame in which global ischaemia could be reversibly sustained in cats. Although unknown at that time, it has subsequently been shown that the effects of this drug may have been due to blockade of glutamate receptors (Olney et al., 1991). Since this original study, a number of pharmacologically distinct approaches have been attempted to protect the brain from the glutamate-induced excitotoxicity following a stroke. These approaches include drugs to prevent glutamate release (e.g., lubeluzole) and drugs that block glutamate receptors such as N-methyl-D-aspartate (NMDA) antagonists (e.g., Cerestat). It is also possible to prevent the subsequent effects of glutamate, for PHARMACOLOGICAL APPROACHES TO APHASIA 1173 Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 example, with protein kinase inhibitors (e.g., GM-1) and calcium channel blockers (e.g., Nimodipine). Prevention of excessive glutamate release. Lubeluzole is a compound that restricts the release of glutamate, and might therefore be expected to prevent further damage in the ischaemic penumbra (Heiss & Graf, 1994; Scheller et al., 1995). The use of lubeluzole normalises neuronal excitability in the ischaemic penumbra (Buchkremer-Ratzmann & Witte, 1995) and inhibits neurotoxicity induced by excessive glutamate activity (Lesage, Peeters, & Leysen, 1994). For example, using a rat model, De Ryck et al. (1996), found that lubeluzole administered 5 minutes after an ischaemic infarct was induced led to reduced infarct volume 4 hours later. Similar success has been found in a study investigating lubeluzole in acute ischaemic stroke in humans (Diener et al., 1996). This study utilised double-blind, placebocontrolled procedures with stroke patients administered lubeluzole or a placebo control within 6 hours of stroke onset, and again over a period of 5 days. Neurological function was assessed on days 3, 5, 7, 14, and 28. The investigators found that lubeluzole administration decreased mortality rate by 6% and led to a decreased number of patients with severe disability (Diener et al., 1996). In addition, two combined trials on lubeluzole for patients with mild to moderate strokes demonstrated a statistically significant mortality reduction as well as increased patient outcome (Hantson & Wessel, 1998). However, a phase III trial using lubeluzole between 0 and 8 hours post-onset had reportedly negative results (Hickenbottom & Grotta, 1998). This suggests that findings with lubeluzole may not be as clear as previously thought and further studies should be completed. Receptor antagonists of glutamate. Two glutamate antagonists, MK-801 and GYKI52466 , have been studied in both rats and cats (Sutton, Hovda, & Feeney, 1989) with little research completed in humans. Both agents were found to aid in neuronal protection when administered up to 2 hours after the ischaemic event. In a number of studies, these antagonists have also been shown to block the excitotoxic cascade of ischaemia (Lyden & Lonzo, 1994). Furthermore, the authors found that combining MK801 and a GABA agonist (muscimol) was more effective in rats than either agent used alone. Specifically, the use of these two agents protected visual-spatial learning as measured by the Morris water maze, in rats with induced cerebral infarcts. Muscimol may block the voltage-gated intracellular calcium inflow associated with glutamate, and in combination with receptor antagonist for glutamate, appeared to provide the best neuroprotection (Lyden & Lonzo, 1994; see Traystman, 1994 for a further explanation). NMDA antagonists. N-methyl-d-aspartate (NMDA) is a widespread amino acid neurotransmitter that may be involved in neuronal plasticity and learning (Cooper, Bloom, & Roth, 1996). Glutamate acts on several different postsynaptic receptors, one of which is the NMDA receptor. NMDA has been implicated in decreasing the likelihood of widespread extent of damage in animal models of focal cerebral ischaemia because of this interaction with glutamate (Lees, 1997). Evidence for contribution of the NMDA receptor to ischaemic injury has been shown in recent research with animals (McCulloch, 1992). For example, NMDA antagonists have shown considerable promise in animal models of stroke, particularly when administered prior to the onset of trauma (Bullock & Fugisawa, 1992). For example, a non-competitive receptor antagonist of NMDA, eliprodil, has been found to reduce the size of cortical infarction following middle Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 1174 SHISLER, BAYLIS, FRANK cerebral artery occlusion in mice and rats (Gotti, Benavides, MacKenzie, & Scatton, 1990). Similar results have been shown following traumatic brain damage in rats with the volume of cortical damage decreased by 60% after 6 days of eliprodil administration (Toulmond, Serrano, Benavides, & Scatton, 1993). Of most interest is the surprising result that a similar sparing of cortical damage could be seen even when the first administration of neuroprotectant was delayed until 12 hours post-trauma (Toulmond et al., 1993). This suggests that neuroprotection by NMDA antagonists may have a longer window of opportunity than other techniques. Another neuroprotectant that has been studied in animal models is Cerestat. It has been shown that Cerestat (a non-competitive NMDA antagonist) reduced cellular damage in rats if the drug was given 15 minutes after occlusion of the middle cerebral artery (Minematsu et al., 1993). In addition, Cerestat has been investigated in human trials with equivocal results. Unfortunately, initial phase III human trials of Cerestat were discontinued in December 1997 due to safety and efficacy concerns (Cambridge Neuroscience Inc., 1997; Turrini, 1996). However, a recent human trial suggests that Cerestat is ‘‘reasonably tolerated’’ (Dyker et al., p. 2041), although increases in blood pressure and central nervous system effects were observed. Another NMDA antagonist examined in human trials is Selfotel, which was evaluated in a randomised, double-blind, placebo-controlled dose escalation phase IIa human study. In this study, Selfotel’s safety and tolerability was demonstrated; however, adverse neuropsychiatric side-effects were reported (Grotta et al., 1995; cf. Hickenbottom & Grotta, 1998). In addition, two phase III trials with Selfotel administered at 1.5 mg/kg within 6 hours post-onset were terminated early due to an increase in mortality rates in the Selfotel group versus the placebo group (Davis et al., 1995). Inhibition of protein kinase C. Many of the excitotoxic effects of glutamate are thought to be mediated, in part, by the translocation of protein kinase C to the cell membrane, where it becomes activated. Thus, inhibition of glutamate induced protein kinase C would be expected to mitigate against excitotoxicity. The ganglioside class of drugs, of which monosialogangliosida (GM-1) is a member, has been associated with nerve growth and repair (Carolei, Fieschi, Bruno, & Toffano, 1991). The protective effects of GM-1 are thought to be achieved by blocking the effects of glutamate on protein kinase C (Vaccarino, Guidotti, & Costa, 1987). In a randomised, placebocontrolled, double-blind, multicentre study conducted by Lenzi et al., (1994), patients that received GM-1 as compared to placebo, experienced an average of 10% improvement in terms of clinical severity. Clinical severity was determined by level of consciousness, orientation, speech, and motor deficit assessed using the Canadian Neurological Scale (Cote et al., 1986). The authors also noted that the greatest improvement was found if GM-1 was presented less than 4 hours after the initial onset of stroke, similar to that found in studies using other drugs. Other studies with GM-1 have not been as promising. In a phase III human trial with GM-1, the Syngen Acute Stroke Study (SASS; Alter, 1994), investigated mortality rates. Their results indicated similar mortality rates between groups receiving GM-1 and groups receiving placebo. Nevertheless, future studies with GM-1 have not been planned (Hickenbottom & Grotta, 1998). Calcium channel blockade. The sudden increase in intracellular calcium associated with a stroke can lead to activation of autolytic enzymes that ultimately cause cell death. Blockade of the calcium channels using a drug such as Nimodipine (Gotoh et al., 1986) Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 PHARMACOLOGICAL APPROACHES TO APHASIA 1175 has been shown to protect neurons from an influx of calcium in the rat. However, findings suggest that Nimodipine administered in humans may reduce infarct severity only if the drug is administered within 18 hours of stroke onset (American Nimodipine Study Group, 1991). One example of the neuroprotective effects can be demonstrated in a study conducted by Popovic, Danks, and Siu (1993). They assessed the efficacy of Nimodipine in preventing delayed ischaemic deficits resulting from aneurysmal subarachnoid haemorrhage (SAH). In this study, Nimodipine treatment began as soon as a diagnosis had been reached and continued for 12 days. Popovic et al. (1993) found that treatment with Nimodipine after aneurysmal SAH reduced mortality and neurological deficits, and benefits remained at follow-up 12 months after treatment. Roine, Kaste, Kinnune, and Nikki (1987) also found benefits from Nimodipine for patients with global ischaemia. In this study, patients resuscitated after ventricular fibrillation were given Nimodipine or a placebo control. For those with prolonged cerebral ischaemia (greater than 10 minutes), Nimodipine was shown to markedly increase 1-year survival from 8% (2/26) to 47% (8/ 17), suggesting that this drug had a neuroprotective function. In contrast, Kaste et al. (1994) found no benefit on functional outcome following treatment with Nimodipine, but this null finding could have been due to the amount of time elapsed between the onset of stroke and the administration of the drug. In the Kaste et al. (1994) study, only 19% of patients received Nimodipine within the first 6 hours, so the vast majority probably received the drug well outside the window for effective treatment. Indeed, most researchers agree that the maximum time window for Nimodipine, and possibly other therapeutic drugs, is 3 hours after the initial onset of stroke symptoms (Fisher & Bogousslavsky, 1993). Currently, this drug is being evaluated further in the Very Early Nimodipine Use in Stroke (VENUS) study, where the time window should not exceed 12 hours (de Keyser, 1997). However, this time window may indeed prove to be too large as well, and without benefits from this study, the use of Nimodipine may be discontinued (Hickenbottom & Grotta, 1998). In summary, results from pharmaceutics that prevent glutamate excitation are equivocal at best. While there appears to be some success in various areas of research within this field, other research indicates that this success is limited. Difficulties include increased side-effects and mortality rates in addition to time of administration restrictions. As indicated in previous sections, further human research is necessary to determine the potential of this class of neuroprotective agents. Free radical scavenging A second area of neuroprotective research deals with the scavenging of free radicals. Although free radicals are formed in the brain under normal conditions, healthy cells are able to neutralise them with free radical scavengers. However, free radicals are not neutralised in ischaemic regions of the brain, and may increase during stroke and intensify the severity of damage. Damage occurs as a reduction in the amount of available oxygen decreases production of free radical scavengers. Xue, Slivka, and Buchan, (1992) found that tirilazad, a free radical scavenger, reduced the amount of cerebral damage in rats with induced cortical infarction. The Safety Study of Tirilazad Mesylate in patients with Acute Ischaemic Stroke Investigators (STIPAS; 1994) examined 111 ischaemic stroke patients and determined that patients given tirilazad within 12 hours of stroke were able to tolerate this drug. It is unfortunate that no language or cognitive recovery data were collected in this study, as the large sample sizes were such that even modest benefits Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 1176 SHISLER, BAYLIS, FRANK would have been detectable. The results of efficacy studies of tirilazad as an intervention in adults suffering from stroke are less clear. On the one hand, tirilazad has been found to reduce mortality in individuals with subarachnoid haemorrhage (Kassell et al., 1996) and ischaemic stroke (STIPAS, 1994). However, other safety and efficacy studies have shown no significant differences using tirilazad in patients with acute cerebral ischaemia (Peters et al., 1996; RANTTAS investigators, 1996). Even more problematic, a European study for severe head injury had to terminate a study of tirilazad prematurely due to excess mortality in the experimental group (Marshall & Marshall, 1995). Thus, while its use as a free radical scavenger in principle suggests value in neuroprotection, further studies are needed to determine its safety and worth in stroke rehabilitation. Membrane repair Citicoline is an intermediate in the biosynthetic pathway of the structural phospholipids of cell membranes (Secades & Frontera, 1995), and so may perform a neuroprotective function by assisting in the repair of injured cell membranes. Following an ischaemic event, citicoline may limit the number of cells that die and may aid the brain in repairing damaged circuits or creating new ones (National Stroke Association, 1997). Initial research in this area was conducted with animals. For example, Yamamoto, Shimizu, and Okamiya (1990), administered citicoline to rats 20, 80, and 140 minutes post-ischaemia and anoxia induced by treatment with nitrogen, and assessed the effects 48 hours after the anoxia. It was found that citicoline led to a significant decrease in the incidence of neurological deficits in rats, especially when administered at the shorter intervals (20 and 80 minutes) post-anoxia (Yamamoto et al., 1990; cf. Kakihana, Fukuda, Suno, & Nagaoko, 1988). In human studies, it was found that patients in the advanced clinical trials using citicoline demonstrated 20–30% better scores on tests of cognition than those who did not receive the drug (National Stroke Association, 1997). Further human research by Clark et al. (1999) found conflicting results. Clark et al. (1999) reported that citicoline was safe but showed no clear effectiveness when all patients were considered. However, post hoc analyses suggested that those individuals with moderate to severe stroke, as opposed to mild, might show improved outcome with citicoline (Clark et al., 1999). Therefore citicoline may be beneficial only for individuals with moderate to severe stroke. A newer neuroprotective agent called clomethiazole reached phase III trials in North America in 1997 (Green, 1998). Clomethiazole has been reported to enhance GABA receptor activity, which could help diminish glutamate release (Hales & Lambert, 1992). A phase III study with 560 patients demonstrated benefits in patients with large cortical infarcts (Wahlgren & the CLASS Group, 1997). Further studies by Wahlgren et al. (1999) tested the efficacy and safety of clomethiazole in a double-blind placebo-controlled trial in 1360 patients. They reported that clomethiazole is safe for patients; however, no longterm benefits for patients were observed (Wahlgren et al., 1999). In summary, neuroprotective agents have demonstrated efficacy in salvaging tissues and increasing recovery after an ischaemic stroke. Many drugs are quite promising, although no single neuroprotective agent has been shown to prevent major functional loss after stroke. Current directions in therapy include combining neuroprotective agents with behavioural therapy and neuroreplacement approaches. One important limitation associated with neuroprotection is the need to administer drugs very early post-stroke. It is a clinical and experimental challenge to diagnose and treat the patient with neuroprotective agents given the narrow time window of approximately 3 hours. PHARMACOLOGICAL APPROACHES TO APHASIA 1177 Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 THROMBOLYTIC AGENTS In ischaemic strokes due to embolism, attempts have been made to reduce the duration of the ischaemic episode by using drugs to dissolve the embolus, and thus restore blood flow to the affected brain region, thereby reducing subsequent deficits such as aphasia. This is a separate approach to preventing damage in that it seeks to prevent or limit damage by restoring blood flow. Thrombolytics are often termed ‘‘clot-busters’’, as their function is to break down an embolus, and thus, unlike neuroprotective agents, they do not work at the level of the neuron. This approach is clearly inapplicable in the case of haemorrhagic strokes, where their administration can increase the degree of brain damage, even fatally. Therefore it is crucial to determine whether a stroke is ischaemic or haemorrhagic prior to the initiation of this treatment. The two main thrombolytic agents used are streptokinase and tissue plasminogen activator (tPA), although other thrombolytic drugs have occasionally been studied. Streptokinase This facilitates the breakdown and dissolution of formed clots by converting inactive plasminogen to its active form, plasmin (Sherry & Gustafson, 1985). In turn, plasmin has been shown to break down fibrin clots, which then reopens the occluded blood vessels found in ischaemic stroke (Ciccone, 1996). However, it has been found in some studies that the use of streptokinase even for an embolic stroke can lead to intracranial haemorrhage (O’Connor et al., 1990). For example, the Multicentre Acute Stroke Trial– Italy (1995) conducted a study comparing and combining streptokinase and aspirin, which has anticoagulant effects. Disturbingly, this study found that streptokinase significantly increased the risk of early death in acute stroke patients if the drug was given in combination with aspirin. It is important to note that in this study streptokinase was administered up to 6 hours after the onset of symptoms. This means that some proportion of the participants received treatment more than 3 hours after stroke onset, a time limit that has been suggested by a number of studies (Fischer, 1997). Using streptokinase later than the 3-hour time window may result in what has been termed an ischaemic–haemorrhagic cycle. In this, the initial ischaemic event is followed by a later haemorrhagic event that causes additional damage to the brain. Additional studies could be done to test the validity of streptokinase if given within a more restricted time frame of perhaps 3 hours. The importance of early administration is underscored by the Australian Streptokinase (ASK) Trial Study Group (Donnan et al., 1996). The results of their study showed that administration of streptokinase up to 4 hours post symptom onset led to an increase in morbidity and mortality. In contrast, treatment with streptokinase within 3 hours was found to be safer, but did not show significant benefits over placebo (Donnan et al., 1996). Tissue plasminogen activator (tPA) This acts on clots in a similar way to streptokinase, but is much more strongly activated in the presence of fibrin, making it likely that tPA may be more efficacious in the dissolution of clots (Loscalzo & Braunwald, 1988). Treatments involving tPA have been generally positive, demonstrating increased percentages of stroke victims who walk away with little or no disabilities (Barinaga, 1996). For example, Haley et al. (1993) found that six patients treated with tPA within 90 minutes of stroke onset had significantly improved scores on the Stroke Scale after 24 hours. A full-scale trial of tPA by the NINDS rt-PA Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 1178 SHISLER, BAYLIS, FRANK Study Group (1995) noted that 31% of patients treated within 3 hours of the initial onset of stroke showed complete or nearly full recovery within the first 3 months after the stroke, as compared to 20% of the untreated patients, a difference that was statistically significant. Further analysis of the NINDS data revealed that there was a benefit for patients in every category of severity of stroke (Lyden, 1999; NINDS TPA Stroke Study Group, 1997). Similar findings were also reported by Hacke et al. (1995) after tPA was administered to patients up to 6 hours post-onset. Although many studies suggest that the use of tPA is promising, the drug is not without risks. In a manner similar to streptokinase, tPA has been found to cause cerebral haemorrhage in some stroke patients (Sloan & Gore, 1992). Further, Hacke et al. (1995) found that tPA was effective only in a subgroup of stroke patients with moderate to severe neurologic deficits and without extended infarct signs on an initial computerised tomography (CT) scan. Findings with tPA consistently reveal significant side-effects if treatment is begun later than 6 hours post-onset (The NINDS rt-PA Study Group, 1995). For this reason, Fischer (1997), among others, argues that tPA should be used only in the first 3 hours after stroke onset. Thrombolytic drugs are useful in removing the clots that cause ischaemic damage, but the risk of haemorrhage requires extreme caution in administration of the drug. Similar to neuroprotective agents, thrombolytic drugs should be administered very early post-stroke. Again, the clinical and experimental challenge is to diagnose and treat the patient with such a narrow time window of 3 hours or less. DIFFERENCES BETWEEN HUMAN AND ANIMAL STUDIES It is important to appreciate both the strengths and weaknesses of using animal models to understand human rehabilitation. Although animal models obviously cannot directly study aphasia, they may be very informative in constraining the necessary human trials that could ultimately lead to improved recovery from aphasia. Amphetamine has been studied with animals and subsequently led to clinical trials with humans (Clark & Mankikar, 1979). Other drugs, such as tPA or Nimodipine have recently moved from laboratory to clinical trials (American Nimodipine Study Group, 1992; Feeney, 1997; Fischer, 1997). Animal studies have an important advantage over human studies in that there is much greater ability to control the experimental conditions. Therefore, these highly controlled situations are an excellent arena for screening possible pharmacological agents that may aid in the recovery or protection of function following a stroke. If a drug does not prove highly effective in such tightly controlled conditions, that drug will probably not be of clinical use (Hachiniski, 1996). One specific form of control that has proved very important is that of timing of administration. Using animal models has allowed researchers to obtain a time course of the cascade that occurs during stroke, and the time window that could be considered in drug therapy (Grotta, 1996). The time window of 3 hours post-onset for reperfusion was initially suggested from animal models (Yang & Betz, 1994). Although animal studies can act as an important screen for a new drug or treatment regimen, often the transfer to human trials has proved disappointing, with human studies showing little or no benefit. The first and most obvious reason for this lack of transfer is the fact that human trials have much less control over many experimental factors such as lesion location and size. This may dramatically reduce the statistical power of the studies with an increased variance in lesion localisation, size, and severity. Moreover, control Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 PHARMACOLOGICAL APPROACHES TO APHASIA 1179 over experimental manipulations that are straightforward in animal studies may prove challenging in human trials—the timing of drug administration is a perfect example. Although it may be extremely easy to ensure that animals are treated within 30 or 60 minutes of injury, this would prove extremely difficult given the real-world situations in which strokes occur (Grotta, 1995) and, of course, pre-treatment is not an option in human studies. Second, the experimental designs that are possible in animal studies may not be feasible in human trials. For example, many animal studies do not compare the current drug they are studying to other drugs or therapy. Instead they compare a new therapy to a control condition in which no therapy is given. This strategy clearly increases the statistical power of the experiment, and the likelihood of finding a significant effect. However, in human studies it is simply not an option to withhold any treatment from one group (Grotta, 1995). Moreover, human trials also differ in the types of outcome measures that can be used. Thus, whereas animal models typically use outcome measures, obtained within a few days of the ischaemic event, the appropriate measure for human trials is functional outcome many months later (Grotta, 1996). As a result, drugs that lead to a transient improvement may show promise in animal studies that is not seen in longerterm human studies. A third and final source of differences may relate not to the actual results of experiments, but to the dissemination of results by the process of publication. It has been noted (e.g., Grotta, 1995) that negative results in animal studies are rarely published. Despite the bias against publication of negative results, such results in human studies may appear in the literature due to the valuable information they provide. A challenge is to create a bridge between these highly controlled animal studies, and the inevitable variability seen in human trials. Animal studies may determine which factors need to be closely controlled for treatments to be effective. Human studies would then emphasise tight experimental control over those factors shown to be predictive of positive outcome in the animal studies. The use of carefully piloted human studies should ensure correct dosage and determine side-effects and time window information (Grotta, 1996). There is a definite need for good clinical research to further investigate the area of drug therapy of stroke and aphasia, particularly in conjunction with speech-language therapy. Future studies should include blind or double-blind procedures where appropriate, and always employ placebo control groups to partial out the effects of recovery that are not due to the drug or procedure being studied. FUTURE DIRECTIONS: COMBINATION THERAPY One consensus emerging from research on therapy for aphasia is that neuroprotective agents show promise, but they must be administered within a very short time window— perhaps only 3 hours after stroke onset. The evidence found with amphetamine and Piracetam strongly suggests that pairing intensive language therapy with pharmaceutics could lead to much improvement in recovery from aphasia (Feeney et al., 1982; Poeck, Huber, & Horlacher, 1993). Therefore, drug therapy will not replace traditional speech and language therapy but can be used to augment its effectiveness. Another emerging consensus in the literature is that there is great difficulty in treating or preventing aphasia with a single drug. There are increased positive effects when a combination of drugs is used (Aronowski , Strong, & Grotta, 1996b; Onal et al., 1997). Therefore research points to a need for combination drug therapy in the protection and treatment of stroke and aphasia. Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 1180 SHISLER, BAYLIS, FRANK Currently there are a number of studies examining combinations of drugs in treating stroke during the acute stage to maximise neuroprotection by using complementary approaches. It has been argued that such combinations might result in more complete protection of the ischaemic area than would a single compound (Aronowski et al., 1996b). One such combination treatment currently being studied in animals is tPA and Citicoline (Andersen et al., 1999). This combination would be used to prevent significant damage to the neurons after the onset of a stroke. TPA would be used to dissolve the clot, restoring blood supply to the brain’s tissues, and Citicoline would aid in brain cell repair. Another example of combination therapy involves a study using Citicoline and MK-801 in rats conducted by Onal et al. (1997). Citicoline is important in the generation of phospholipids (Aronowski , Strong, & Grotta, 1996a), while MK-801 is a potent, noncompetitive NMDA receptor antagonist that blocks the excitotoxic sequelae of ischaemia, reduces infarct size, and improves neurological outcome (Minematsu & Fisher, 1993; Onal et al., 1997). The combination study (Onal et al., 1997) demonstrated a reduced infarct volume in rats after experiencing a temporary focal cerebral ischaemia. Onal et al. (1997) noted that neither drug was effective when administered by itself. A third example of combination neuroprotective therapy involved the use of lubeluzole and diaspirin cross-linked hemoglobin (DCLHb), which is a ‘‘blood substitute’’ and not a drug (Aronowski et al., 1996b, p.1571). DCLHb is believed to operate by increasing the ‘‘offloading’’ of oxygen to tissues (Bowes, Burhop, & Zivin, 1994). As mentioned previously, lubeluzole prevents the increase in extracellular glutamate concentrations after ischaemia (Scheller et al., 1995), and DCLHb has been shown to ameliorate ischaemic damage in rat and rabbit stroke models (Bowes et al., 1994; Cole et al., 1992; Cole et al., 1993). It was found that the combination of the neuroprotectant and the blood substitute were complementary. Lubeluzole worked to reduce the size of the infarcted region while DCLHb delayed the onset of ischaemic damage (Aronowski et al., 1996b). Finally, other combination research was initiated regarding a combination of lubeluzole and tPA; however, it was interrupted due to reported negative findings with a phase III study using lubeluzole independently (Hickenbottom & Grotta, 1998). The goal of the combined approaches under study thus far has been simply to minimise the initial lesion by different neuroprotectant approaches. Another level of combination in terms of therapy is to be expected as these approaches transfer to humans. In most human cases, such strategies might lead to a reduced size of infarct and reduction in deficits, but nonetheless it might be expected that some deficits would remain. Future treatment regimens might include subsequent treatment with pharmaceutics such as amphetamine or Piracetam in order to assist in the restoration of lost function during intensive language therapy. Although such a multi-stage strategy would seem well designed in principle, almost no clinical research has so far investigated the effects of combining acute use of neuroprotective agents with the use of pharmacotherapy during recovery. CONCLUSIONS The pharmacology of reduction and treatment of aphasia following stroke has progressed rapidly in recent years. An increasing number of drugs demonstrating clinical significance have been approved and studied in clinical trials across the world. Research in these areas of pharmacotherapy and neuroprotection presents realistic and exciting new therapy trends in rehabilitation. Although single mechanisms rarely solve the complex Downloaded By: [EBSCOHost EJS Content Distribution] At: 13:00 18 February 2008 PHARMACOLOGICAL APPROACHES TO APHASIA 1181 dysfunctions of the brain, combination therapy holds much promise for the future treatment of stroke and aphasia. We might expect to see an initial acute management regimen that employs a combination of neuroprotectant approaches with later pharmacotherapy combined with intensive language therapy. This area of research is extremely important in helping to increase the efficiency and possibly the efficacy of treatment for stroke patients. It holds the hope of both an increase in the quality of rehabilitation and recovery, and also a decrease in the resources used in rehabilitation. REFERENCES Albert, M.L., Bachman, D.L., Morgan, A., & Helm-Estabrooks, N. (1988). Pharmacotherap y for aphasia. Neurology, 38, 877–879. Alter, M. (1994). Ganglioside GM1 in acute ischemic stroke. The SASS trial. Stroke, 25(6), 1141–1148. American Nimodipine Study Group (1992). Clinical trial of Nimodipine in acute ischemic stroke. Stroke, 23(1), 3–8. Andersen, M., Overgaard, K., Meden, P., Boysen, G., & Choi, S.C. (1999). Effects of citicoline combined with thrombolytic therapy in rate embolic stroke model. 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