Delivery of anti-HIV nucleosides to the central nervous system

advanced

drug delivery ELSEVIER

Advanced Drug Delivery Reviews 14 (1994) 199 209

reviews

Delivery of anti-HIV nucleosides to the central nervous system James M. Gallo Department of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme A venue, Philadelphia, PA 19111, USA

(Received April 23, 1992; Accepted August 23, 1993)

Contents Abstract .............................................................................................................................................

199

1. A I D S and the central nervous system .................................................................................................

200

2. Membrane transport of anti-HIV nucleosides .......................................................................................

200

3. CNS uptake of anti-HIV nucleosides .................................................................................................. 3.1. Zidovudine ................................................................................................................................ 3.2.2',3'-Dideoxyinosine (ddI) ............................................................................................................ 3.3.2',3'-Dideoxycytidine (ddC) .......................................................................................................... 3.4. Other anti-HIV nucleosides .........................................................................................................

201 201 203 203 203

4. Experimental approaches to enhance anti-HIV nucleoside C N S delivery .................................................. 4.1. Direct C S F administration .......................................................................................................... • 4.2. Inhibition of C N S effiux ............................................................................................................. 4.3. First-pass brain extraction ........................................................................................................... 4.4. Prodrug ....................................................................................................................................

203 204 204 206 206

5. Conclusions ....................................................................................................................................

207

References ..........................................................................................................................................

207

Abstract The ability of the human immunodeficiency virus (HIV) to enter and harbor in the central nervous system (CNS) results in a devastating A I D S - d e m e n t i a complex. As a class, the anti-HlV nucleosides penetrate the blood brain barrier (BBB) poorly, and drug therapy is less than optimal. A variety of drug delivery techniques has been proposed to enhance the CNS delivery of the nucleosides. These include constant rate infusions, transport inhibitors, and prodrug approaches. Evaluation of these methods in various animal models has not always differentiated vascular, extravascular and cerebrospinal fluid drug concentrations, and has led to some controversies with regard to C N S uptake of the nucleosides. The application of brain microdialysis to quantitate brain disposition will facilitate assessment of BBB

SSDI 0 1 6 9 - 4 0 9 X ( 9 3 ) E 0 0 5 0 - O

200

J.M. Gallo/Advanced Drug Delivery Reviews 14 (1994) 19~209

transport. Due to the insidious nature of HIV, successful drug delivery systems will not only enhance brain parenchyma concentrations, but also maintain them for a controlled period of time. Combined developments in drug delivery technologies and means to quantitate CNS drug transport should lead to improved treatment modalities. Key words."AIDS; Pharmacokinetics; Drug delivery; Brain; Cerebrospinal fluid

1. AIDS and the central nervous system

Although a number of questions remain concerning the neuropathology of human immunodeficiency virus (HIV), particularly the role of direct versus indirect effects of HIV, it is certain the neurological abnormalities associated with acquired immunodeficiency syndrome (AIDS) are profound and widespread [1]. HIV infection is associated with numerous early and late stage central nervous system (CNS) abnormalities. CNS symptoms may begin with acute encephalitis, headache and progress to AIDS dementia complex, which can be categorized into five stages [2]. HIV can directly enter the cerebrospinal fluid (CSF) compartment, and the brain via the blood-CSF and blood-brain barriers, respectively [3]. HIV-infected macrophages are also able to cross the blood brain barrier (BBB). Once inside the CNS, HIV can replicate in brain monocytes/macrophages and microglial cells [4]. Transmission of HIV to other cell types, such as astrocytes, of the CNS is still controversial, and is based on morphological identification and the presence of antigenic markers [4]. Improvement in cognitive function of AIDS patients has been attributed to anti-HIV nucleoside (viz. nucleoside) therapy and, thus, the importance of adequate CNS delivery of these compounds is high. CNS uptake, expressed as a percentage of plasma concentration, of the nucleosides can vary significantly between nucleosides as can HIV-inhibitory concentrations; therefore, it is unknown if one agent is more centrally active than another. Based on the use of multiple oral dosage regimens, brain and CSF nucleoside concentrations will vary, and in the absence of nonlinear pharmacokinetics, parallel plasma concentrations. It is unknown if these concentration fluctuations compromise the therapeutic benefits. Because of the overall low extent of CNS uptake of

the nucleosides, and variations in CNS concentrations, a concerted effort has been made to increase the CNS delivery of the nucleosides by various experimental approaches. This paper will review what is known about the CNS disposition of the anti-HIV nucleosides and the means to modulate their CNS delivery.

2. Membrane transport of anti-HIV nucleosides

Membrane transport of purine and pyrimidine nucleosides in numerous cell types is characterized as a reversible, saturable, non-concentrative, carrier-mediated or facilitated-diffusion process [5,6]. These nucleoside transporters have broad specificity. Active or energy-requiring, concentrative nucleoside transport systems have been reported for various cell systems particularly epithelial cells, although methodological questions have tainted interpretation of some studies [7]. Nucleoside transport at the BBB is considered to be of the facilitated-diffusion type with a higher affinity system specific for adenosine [8,9]. An active transport system has been described for nucleosides at the choroid plexus [10,11]. Specific information on mechanisms of antiHIV nucleosides entry into cells is sparse. Two anti-HIV nucleosides, zidovudine (azidothymidine; AZT) and Y-deoxythymidine-2'-ene (d4T), have been shown to enter cells by non-facilitated diffusion [12,13]. AZT entered human erythrocytes and lymphocytes by non-facilitated diffusion, and accordingly, without use of the nucleoside transporter [12]. This result was attributed to the lipophilicity of AZT imparted by the azidomoiety at the Y-position. Similar studies were undertaken to demonstrate that d4T enters the human lymphocyte cell in H9 by non-facilitated diffusion [13]. Other 3'-deoxy-3'-substituted nucleosides [14,15] have also been shown to

J.M. Gallo/Advanced Drug Delivery Reviews 14 (1994) 19~209

b y p a s s the nucleoside t r a n s p o r t e r , a n d all have greater lipophilicity t h a n the n a t u r a l p a r e n t nucleoside e n a b l i n g n o n - f a c i l i t a t e d u p t a k e . T h e excellent w o r k o f Collins et al. [16] on the u p t a k e o f p y r i m i d i n e d i d e o x y r i b o n u c l e o s i d e s into m o n k e y C S F suggests t h a t e n t r y o f these c o m p o u n d s into the C N S is c a r r i e r - m e d i a t e d since there was no c o r r e l a t i o n between C S F p e n e t r a tion a n d lipophilicity a n d the fraction o f u n b o u n d d r u g in p l a s m a . C S F u p t a k e was m o r e closely associated with the nucleoside (i.e. t h y m i d i n e > cytidine) t h a n the sugar moiety. F u r t h e r , it s h o u l d be a p p r e c i a t e d that c o m p l e t e c h a r a c t e r i z a t i o n o f BBB a n d b l o o d - C S F b a r r i e r nucleoside t r a n s p o r t systems in m o n k e y s a n d m a n is difficult due to p r o b l e m s in m e a s u r i n g b r a i n p a r e n c h y m a concent r a t i o n , a n d use o f a wide range o f doses. The use o f b r a i n m i c r o d i a l y s i s has been a p p l i e d to investigate a n t i - H I V b r a i n d i s t r i b u t i o n in r a b b i t s a n d

201

m o n k e y s [17-19], M e a s u r e m e n t o f b r a i n interstitial fluid d r u g c o n c e n t r a t i o n s p r o v i d e s a u n i q u e tool to c h a r a c t e r i z e b r a i n disposition, a n d thus allow for the e v a l u a t i o n o f the n a t u r e o f the transp o r t processes.

3. CNS uptake of anti-HIV nucleosides 3.1. Zidovudine

T a b l e 1 p r o v i d e s a s u m m a r y o f studies that have investigated z i d o v u d i n e d i s t r i b u t i o n into the C N S . D a t a are presented f r o m single dose a n d s t e a d y - s t a t e experiments; in the f o r m e r case, the index o f C N S u p t a k e is time-averaged. Z i d o v u dine u p t a k e into the C S F , excluding K l e c k e r et al. [20] d a t a , ranges f r o m 0.15 to 0.28. K l e c k e r et al. [20] o b t a i n e d a time a n d d o s e - a v e r a g e C S F /

Table 1 Summary of zidovudine uptake into the central nervous system (CNS) Species

Dose:Route

Index of CNS uptake~

Human-adult

CSF/plasma SS CR

0.60 ± 0.44

Klecker et al. [20]

Human-children

2-15 mg/kg:multiple i.v. or oral dose 0.5 1.8 mg/kg/h:i.v, infusion

CSF/plasma SS CR

0.20 ± 0.04

Balis et al. [21]

Monkey

80 mg/kg:i.v.

CSF/plasma AUC ratio

0.21 ± 0.05

Collins et al. [16]

Dog

20 mg/kg/d:i.v, infusion

CSF/serum SS CR brain/serum SS CR

0.15 ± 0.05 0.21 ± 0.05

Gallo et al. [22]

Rabbit

10 mg/kg:i.v. 17.2 mg/kg:i.v.

CSF/plasma AUC ratio CSF/blood CR brain/blood CR CSF/plasma SS CR CSF/plasma AUC ratio thalamus/plasma AUC ratio

0.15 ± 0.28 ± 0.51 ± 0.19 ± 0.18 ± 0.069 ±

0.08 ± 0.06 0.15 ± 0 . 0 2 0.023 ± 0.018c

1 mg/kg/h:i.v, infusion 5-30 mg/kg:i.v. Rat

50 mg/kg:multiple i.v. doses 6.7 mg/kg:i.v.

brain/serum SS CR CSF/plasma CR brain/plasma CR

Mouse

50 mg/kg:i.v, 250 mg/kg:i.v,

brain/serum CR brain/serum CR

Extent of CNS uptake

0.02 0.10 0.23 0.003 0.015

Reference

Hedaya and Sawchuk [23] Brewster et al. [24] Sawchuk and Hedaya [25] Wong et al. [17]

0.017 b

0.06 ± 0.02 0.28 ± 0.64

aSS = steady state; CR - concentration ratio; AUC - area under the concentration time curve. bThalamus concentrations obtained by microdialysis and represent extracellular fluid concentrations. CCorrected for blood contribution to total brain concentration.

Gallo et al. [26] Galinsky et al. [27] Doshi et al. [28]

202

J.M. Gallo/Advanced Drug Delivery Reviews 14 (1994) 199 209

plasma concentration ratio of 0.60 _+ 0.44 with one subject having a ratio of 1.35, certainly a prime source of variability and the high mean ratio. Indices of brain uptake of zidovudine range from 0.023 to 0.51, again time-averaged parameters being considered where appropriate. A critical point to consider is that not all reported brain concentrations have not been corrected for the vascular or blood concentration o f zidovudine causing an inflated index o f brain uptake. Depending on the species and method of brain collection and analysis, vascular space corrections may range from about 1% to 20% [22]. The magnitude of the corrections of total brain zidovudine concentrations, yielding a brain parenchyma concentration, will also depend on the value of the zidovudine blood concentration or time of the sample. A critical question that has been raised is: Does AZT, and implicitly other dideoxynucleosides, cross the BBB, or are brain parenchyma concentrations a result of diffusion of drug from CSF across the ependymal surface? Terasaki and Partridge [29] suggest A Z T does not pass the BBB via the nucleoside transport system because an extremely low ( < 1 % ) percentage of the administered dose was measured in rat brain. The use of anesthetized rats and a first-pass brain extraction method raises concern as to the authors' assessment. A recent study by Wong et al. [17], utilizing microdialysis techniques to assess A Z T rabbit CNS distribution, found A Z T extracellular thala-

mic concentrations, although less than CSF (see Table 1), paralleled the latter, supporting direct BBB passage of AZT. The authors also demonstrated that A Z T ' s CNS distribution was dose-independent based on extracellular thalamic, CSF and plasma A Z T concentrations. This observation provides partial support that A Z T brain uptake is more intimately linked to its lipophilicity, allowing for passage diffusion across the BBB, rather than its affinity for a nucleoside transporter. In a second study by Wong et al. [18], an active transport system for the efflux of A Z T from the extracellular fluid to blood and from the CSF to blood was found in rabbits. These transport sytems were sensitive to inhibition by probenecid. Application of the microdialysis technique to monkeys found brain interstitial fluid concentrations of A Z T and 3'-fluoro-3'-deoxythymidine to be greater than those required to inhibit H I V replication in vitro. Since a range of doses was not evaluated, information on saturable transport processes was not obtained. It is probably accurate to state that brain parenchyma zidovudine concentrations are not greater than CSF zidovudine concentrations collected from the same study, and brain concentrations are a function of BBB transport and diffusion from the CSF across the ependymal surface. Finally, excluding human A I D S subjects, there do not appear to be species differences in zidovudine CNS uptake, and thus a variety of animals

Table 2 Summary of 2',3'-dideoxyinosine (ddl) uptake into the central nervous system (CNS) Species

Dose:Route

Index of CNS uptake a

Extent of CNS uptake

Reference

Human

0.2 3.2 mg/kg:multiple i.v. infusion

CSF/plasma CR

0.21 _+ 0.03

Hartman et al. [30]

Rats

125 mg/kg/h:i.v, infusion

CSF/plasma SS C R brain/plasma SS CR

Anderson et al [3 I]

12.4 and 32 mg/kg/h:i.v

CSF/plasma SS CR brain/plasma

0.015 0.047 0.007 b 0.019 0.049

93.9 mg/kg/h ddA c i.v. infusion

CSF/plasma SS C R

0.10 _+ 0.01

Wientjes et al. [23]

Dog

"SS - steady-state; CR - concentration ratio. hCorrected for blood contribution to total brain concentration. ~2',3'-Dideoxyadenosine (ddA) was administered.

Hoesterey et al [32]

J.M. Gallo/AdvancedDrug Delivery Reviews 14 (1994) 199~09 may serve as appropriate models for anti-HIV nucleoside CNS distribution.

3.2. 2',3'-Dideoxyinosine (ddl) Uptake of ddI into CSF varied considerably between rats and humans (see Table 2), AIDS subjects exhibiting greater ratios with CSF ddI concentrations about 20% of those obtained in plasma. A similar tendency towards enhanced CNS uptake was observed for zidovudine in AIDS patients. As with most human investigations, the CSF data are limited, and conclusions concerning factors influencing CNS uptake are tenuous. The species difference in ddI CNS uptake may be due to inherent differences in ddI's membrane transport or due to the AIDS disease.

3.3.2',3'-Dideoxycytidine (ddC) Similar to ddI, ddC does not attain the same extent of CNS uptake as does zidovudine (see Table 3). Interestingly, as with zidovudine and ddI, somewhat greater CSF/plasma ratios are attained in AIDS subjects compared to animals. The brain/ plasma concentration ratios for ddC in mice appear greater than expected based on the CSF/plasma concentration ratios. However, bear in mind that these values were estimated graphically and were not corrected for plasma concentrations of ddC.

203

3.4. Other anti-HIV nucleosides The limited data (see Table 4) indicate that other anti-HIV nucleosides enter the CNS to a similar extent, between 10% and 30%, as zidovudine, ddI and ddC. Species differences and the possibility of non-linear CNS transport cannot be evaluated with the available data.

4. Experimental approaches to enhance anti-HIV nucleoside CNS delivery Based on the data presented in Section 3, a simple, yet important, deduction is that CNS uptake of anti-HIV nucleosides is less than optimal. Exact requirements for optimal CNS therapy with nucleosides cannot be specified until the pharmacodynamics are defined, and the potential effects of drug treatment on the development of HIV-resistant strains are evaluated. However, based on the chronic nature of AIDS, one could assume that effective CNS therapy most likely requires maintenance of constant CNS HIV-inhibitory concentrations of anti-HIV nucleosides. This assumption has not been systematically evaluated, yet treatment regimens producing less than inhibitory CNS nucleoside concentrations for a substantial period of time will undoubtedly be unacceptable. CNS drug delivery strategies for the anti-HIV nucleosides consist of the use of prodrugs, pumps, CNS effiux inhibitors, liposomes, and in-

Table 3 Summary of 2',Y-dideoxycytidine(ddC) uptake into the central nervous system (CNS) Species

Dose:Route

Index of CNS uptakea

Extentof CNS uptake

Reference

Human

0.03~.25 mg/kg:multiple i.v. infusions

CSF/plasmaSS CR

0.20

Yarchoan et al. [34]

Monkey

20 mg/kg:i.v. 27 mg/kg:i.v.

CSF/plasma CR CSF/plasma AUC ratio

0.01 0.033 _+ 0.007

Collins et al [16] Kelley et al. [35]

Mouse

100 mg/kg:i.v. 2 mg/kg/h:i.p, infusion

Brain/plasma CR Brain/plasma SS CR

0.24b

Kelley et al. [35]

0.25 b

aSS - steady-state; CR ~ concentration ratio; AUC - area under the concentration-time curve. bEstimated from the data and uncorrected for blood contribution to total brain concentration.

J.M. Gallo/Advanced Drug Delivery Reviews 14 (1994) 199-209

204

Table 4 Summary of other anti-HIV nucleoside uptake into the central nervous system (CNS) Species

Compound a

Dose:Route

Index of CNS uptake b

Extent of CNS uptake

Reference

Monkey

d4T FDT

60 mg/kg:i.v, and oral doses 60 mg/kg:i.v, and oral doses

CSF/serum C R CSF/serum C R

0.15 + 0.04 0.14 + 0.03

Schinazi et al. [36]

Mouse

AZDU

50 mg/kg:i.v. 250 mg/kg:i.v. 25 mg/kg:oral

Brain/serum C R Brain/serum C R Brain/serum C R

0.23 + 0.28 0.28 + 0.79 0.13 _+ 0.15 c

Doshi et al. [28]

d4T

Russell et al. [37]

a A Z D U = 3'-azido-2',3'-dideoxyuridine; d4T = 2',3'-didehydro-3'-deoxythymidine; F D T = 3'-fluoro-3'-deoxythymidine. bCR -- concentration ratio. CEstimated from the data.

trathecal administration. Table 5 summarizes the available CNS data for these techniques.

4.1. Direct CSF administration Intrathecal or intra-CSF administration bypass the two barriers, i.e. the BBB and blood-CSF barrier, responsible for the limited CNS access of the nucleosides. Three AIDS subjects received 50 mg of AZT every 12 hours by bolus injections into the CSF for periods of 3-5 months [44]. The patients tolerated the treatment well with improved mental status and no hematological toxicity. Direct CSF administration (i.e. infused over 25 min) of a liposomal encapsulated ddC was administered to rats [43]. Total ddC CSF concentrations, including encapsulated and free ddC, were greater than ddC concentrations achieved by administration of free ddC, although it was difficult to estimate the magnitude of the increase over the 68-hour study period. The liposomes serve as a reservoir for ddC since apparently the liposomes themselves are not rapidly cleared or degraded by CSF. Upon ddC's release from the liposomes it appeared to follow the same kinetics as when ddC was given in solution. Larger, controlled trials seem warranted based on these early findings. Questions on how systemic nucleoside treatment should be altered, what is the optimum CSF regimen (i.e. bolus vs. constant rate infusion and administration of free or encapsulated drug), and what are the pharmacokinetics of the intra-CSF treatment regimens remain to be evaluated. Of particular importance

will be how brain parenchyma and CSF nucleoside concentrations compare. Without systemic therapy, brain parenchyma concentrations will be primarily a function of drug diffusion across the ependymal membrane. The use of carrier systems administered intra-CSF, such as the liposomal dosage form, that "lock-in" the nucleoside in the CNS offer exciting possibilities for this treatment mode.

4.2. Inhibition of CNS efflux Probenecid effectively inhibits the CNS effiux of AZT and ddI in the rabbit and rat, respectively [18,23,25,38]. This process is distinct from the production of increased CNS nucleoside concentrations by elevated plasma nucleoside concentrations due to inhibition of renal clearance. Analogous to probenecid's inhibitory effect on active secretion of organic acids in renal tubules, probenecid inhibits active transport of the nucleosides from brain to blood and from the CSF to blood by competitive inhibition. This mechanism is consistent, in a general sense, with in vitro investigations characterizing active transport of nucleosides at the choroid plexus. In vivo investigations elucidating transport parameters (i.e. Bmax, Kd, Ki) for probenecid and AZT or ddI remain to be completed. This information would be useful in designing clinical treatment regimens for these agents, assuming a rat or rabbit model may be extrapolated to humans. Based on the study by Galinsky et al. [38], it

20 mg/kg/d:i.a, infusion

36 mg/kg:i,v,

AZT and probenecid

ddl and probenecid

AZT

AZT

AZT-CDS

AZT-CDS

AZT-CDS AZDU-CDS

AZT-CDS

AZDU-CDS

d4T-CDS

ddC

Rabbit

Rat

Rat

Dog

Rat

Dog

Mouse

Rabbit

Monkey

Mouse

Rat

ddC

d4T

AZDU

AZT

AZT AZDU

AZT

c

CR

3.09 ± 0.89

7.97 ± 2.51

liposomes/ intra-CSF

prodrug

prodrug

prodrug

prodrug prodrug

prodrug

prodrug

Brewster et al. [24] 2.7 ± 1.5 1.88 ± 0.82 0.78 ± 0.43

brainp,l/brain~ CR CSFpa/CSF~ CR CSFpa/CSF c CR

see text

-

6.1 d

Chu et al. [40] Chu et al. [40] brainpdbrain~ A U C 9.3 brainpa/brain~ A U C 5.5

brainpa/brainc CR

Little et al. [39]

2.0 c

CSFpa/CSFc AUC

Kim et al. [43]

Palomino et al. [42]

Chu et al. [41]

Little et al. [39]

brainpd/brain~ A U C 3.0

Gallo et al. [22]

first-pass extraction CSF/serum SS CR 0.13 4- 0.05 brain/serum SS CR 0.25 ± 0.15

Galinsky et al. [38]

Sawchuk and Hedaya [25]

Hedaya and Sawchuk [23]

Reference

Gallo et al. [26]

CSFpb/CSF c SS CR 5.4 brainpbbrainc SS CR 1.5

CSFpb/CSF

CSFvb/CSFc A U C ratio

Extent of CNS uptake

first-pass extraction brain/serum SS CR 0.28 4- 0.12

inhibition of CSF effiux

Inhibition o f CSF effiux

Inhibition of CSF effiux

Index of CNS uptake b

aIn most studies, an equimolar dose of the parent nucleoside was given as a control (c). bpb -- probenecid; c - control; pd - prodrug; CR - concentration ratio; SS = steady-state; AUC - area under the concentration-time curve. CR and A U C CNS indexes based on measurements of delivered drug following experimental drug delivery administration compared to control administration. CBased on 1 animal. aEstimated from the data.

50/~g:intraventricular

25 mg/kg:i.v,

49.2 mg/kg:i.v.

25 mg/kg:i.v.

72.7 mg/kg:i.v. 73.9 mg/kg:i.v.

2.9 mg/kg:i.v.

AZT

AZT

AZT

ddI

125 mg/kg/h:i.v, 30 mg/kg/h:i.v, infusion 4.8 m/d:i.a, infusion

AZT

AZT

Delivered Drug delivery drug method

1 mg/kg bolus plus 3 mg/h infusion: i.v. 15 mg/kg bolus plus 45 mg/h:i.v.

10 mg/kg:i.v. 30 mg/kg bolus plus 30 mg/kg/h infusion i.v.

AZT and probenecid

RAbbit

Dose:Route

Administered ~ compound

Animal

Table 5 Summary of anti-HIV nucleoside CNS delivery by various methods

t~a

&

-e

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J.M. Gallo/Advanced Drug Delivery Reviews 14 (1994) 199-209

appeared the influence of probenecid is selective for directly enhancing CSF ddI concentrations rather than brain parenchyma concentrations. Thus, similar to intra-CDS treatment modalities, CSF efflux inhibitors may not lead to a significant increase in brain parenchyma concentrations. Certainly, additional studies are warranted to evaluate this possibility. 4.3. First-pass brain extraction

Administration of drugs intra-arterially into the carotid artery may result in increased brain concentrations relative to intravenous administration due to first-pass brain extraction. For an organ that does not irreversibly eliminate the drug, as for the nucleosides, the enhancement in brain uptake is predicted by [45]: Rd = 1 + CL/Q,

where CL = total systemic clearance and Q = brain blood flow. Data obtained (see Table 5, [26]) and an estimated Ra for the rat supported the idea that intracarotid pump delivery of AZT may be a viable approach to enhance brain uptake of AZT. Subsequent studies in dogs (see Table 5 and Table 1), however, did not show the same trend as in rats, and predicted Ra values in humans suggested little improvement in intracarotid versus intravenous administration. The studies by Gallo et al. [22] did show that constant CSF and serum AZT concentrations could be achieved via an implantable pump device for a l-month period. Continuous infusion of nucleosides via a pump ensures patient compliance, and offers flexibility in designing novel treatment regimens. In addition to controlling drug doses, programmable pumps allow on-off cycles and alternating drug cycles. These latter attributes may have implications for the development of HIV drug-resistant strains. Although first-pass brain extraction via intra-arterial administration of nucleosides does not seem to be a viable CNS drug delivery technique, use of more lipophilic compounds or prodrugs by this method may result in enhanced brain delivery.

4.4. Prodrug

The most avidly pursued method to increase CNS delivery of the nucleosides has been the use of more lipophilic prodrugs based on the principle ~hat lipophilic compounds will cross the BBB by passive diffusion more readily than the parent nucleoside. A number of 5'-ether derivatives of parent nucleosides have been synthesized, yet only a few have been promoted and tested for the potential to enhance brain uptake of the parent compound in vivo. Some prodrugs have been designed to prolong the apparent elimination halflife of the parent moiety, enhance stability, or to facilitate entry into target HIV cells [46-48]. The extent of CNS delivery (see Table 5) of the parent compounds via the prodrug approach indicates that the prodrug approach is viable, with most indices of CNS delivery greater than one, indicating an advantage over parent drug administration. It should be appreciated that the data are usually based on a small number of animals and time points. The chemical delivery system (CDS) or "Bodor" approach has been used extensively with the premise that the lipophilic dihydropyridine derivatives will be oxidized to the quaternary salt species in the brain followed by a gradual hydrolysis to the parent drug. Additional studies are needed to characterize and define the ultimate use of the CDS approach. Halogenated conjugates of ddI, in particular 6C1-2',3'-dideoxypurine (6-Cl-ddP) have been examined for their ability to avoid gastrointestinal degradation of ddI, and to enhance CNS delivery of ddI. Studies in mice [49] indicated no significant increase in ddI brain concentrations following 6Cl-ddP administration compared to those obtained from ddI administration. However, preliminary results in rats indicated improved CSF and brain delivery of ddI with 6-Cl-ddP and 6-BrddP administration [50]. Future strategies to increase CNS delivery of parent nucleoside may also consider the use of macromolecule-conjugates. These types of carrier systems have been promoted for increasing anticancer drugs and peptides across the BBB by absorptive and receptor-mediated endocytosis [51-53].

J.M. Gallo/Advanced Drug Delivery Reviews 14 (1994) 19~209

5. Conclusions Delivery of a n t i - H I V nucleosides to the C N S is a n active research area that is likely to grow based on the m o d e r a t e C N S u p t a k e of p a r e n t nucleosides a n d the devastating neurological consequences of A I D S . A d d i t i o n a l studies need to be c o n d u c t e d to fully elucidate the t r a n s p o r t m e c h a n isms o f a n t i - H I V nucleosides in a n d out of the CNS, a n d the effect of the disease on C N S uptake. There seems to be a trend towards greater permeability o f the nucleosides in A I D S subjects c o m p a r e d to n o r m a l animals. T r a d i t i o n a l memb r a n e t r a n s p o r t studies on nucleosides find carrier-mediated pathways prevalent, yet non-facilitated diffusion has been n o t e d for some a n t i - H I V nucleosides in red b l o o d cells a n d lymphocytes. A saturable C N S effiux pathway, capable of inhibition by probenecid, has been reported for A Z T in an a n i m a l model. U n d e r s t a n d i n g the C N S antiH I V nucleoside t r a n s p o r t processes will cultivate new strategies of drug delivery. C u r r e n t experimental approaches to increase p a r e n t nucleoside C N S u p t a k e have shown enc o u r a g i n g results. Q u a n t i t a t i v e e v a l u a t i o n of the drug delivery advantages of experimental approaches in whole animals, particularly m o n k e y s , are difficult yet necessary prerequisites of clinical trials. F u r t h e r d e v e l o p m e n t s will u n d o u b t e d l y be seen with prodrug, effiux inhibitors a n d intraC S F techniques. Together, these a n d future strategies will offer tangible m e a n s to i m p r o v e the neurological course of A I D S .

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