Prenylation inhibitors to treat proliferative renal disease

CORRESPONDENCE

Prenylation inhibitors to treat proliferative renal disease Sir—Arif Khwaja and colleagues (Feb 26, p 741) 1 postulate that prenylation inhibitors could be used to treat proliferative renal diseases. These investigators also discuss pravastatin’s ability to decrease acute and chronic rejection in organ transplantation and suggest that these effects “are due to inhibition of Ras and Rho prenylation with subsequent inhibition of the proliferation of vascular smooth muscle, which is an essential histological feature of chronic rejection”. Indeed, the ability of status to inhibit vascular smooth muscle proliferation (at high concentrations) may contribute to its chronic-rejection prevention properties. Also, statins and other prenylation inhibitors may inhibit acute and chronic rejection by suppressing T-cell activation and function. We have shown that pravastatin inhibits T-cell proliferation in vitro and that this effect is abrogated by addition of farensyl pyrophosphate but not cholesterol.2 This finding confirms our hypothesis that prenylation inhibitors suppress T-cell activation and function by interfering with protein isoprenylation. We have also shown that perillyl alcohol, a naturally occurring prenylation inhibitor, inhibits acute rejection, Th1 cytokine expression, and alloantibody production in a rat cardiac transplant model.3 Perillyl alcohol also interfered with T-cell activation, motility, and normal polarity. 4 Furthermore, we showed that perillyl alcohol preferentially induced apoptosis in activated T cells. Our findings, along with the well-documented roles of Ras GTPases in T-cell activation and function confirm our hypothesis that isoprenylation inhibitors (the Ras inhibitors), are effective antirejection agents. Hence, given our experience with isoprenylation inhibitors in allograft rejection and the disordered cellular proliferation caused in part by an imbalance of the normal cytokine profile that is central to the pathophysiology of many proliferative kidney diseases, we feel that the hypothesis put forth by Arif Khwaja and colleagues deserves further experimental and clinical testing. Ming-Sing SI, *David K Imagawa UCI Medical Center, Division of Transplantation, Building 26, Room 1001, 101 The City Drive, Orange CA 92868, USA

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Khwaja A, O’Connolly J, Hendry BM. Prenylation inhibitors in renal disease. Lancet 2000; 355: 741–44. Imagawa DK, Si M, Maggard M, Ke B, Busuttil RW. p21ras inhibitors: a new class of immunosuppressive drugs?; Annual Meeting of the American Society of Transplant Surgeons, May, 1998; Chicago, Illinois, USA (http://www.asts.org/abstracts/asts981151.htm) Si M, Wei X, Imagawa DK, et al. Isoprenylation inhibitors pravastatin and perillyl alcohol as immunosuppressive agents. Transplantation 2000 (in press). Wei X, Si M, Imagawa DK, Ji P, Tromberg BJ, Cahalan M. Perillyl alcohol inhibits TCR-mediated [Ca2+]i signaling, alters cell shape and motility, and induced apoptosis in T lymphocytes. Cell Immunol 2000 (in press).

Although not 100% effective, NAT screening narrows the infectious window and exponentially reduces the HBV load detectable by serological screening. We advocate NAT screening for HBV in appropriately sized donated blood pools after routine serological screening. *Kazuo Otake, Kusuya Nishioka *Blood Services Department, and Japanese Red Cross NAT Screening Research Group, Japanese Red Cross Society, Minatoku, Tokyo 105-8521, Japan 1

Sacher RA, Schreiber GB, Kleinman SH. Prevention of transfusion-transmitted hepatitis. Lancet 2000; 355: 331–32.

Nucleic acid amplification testing of hepatitis B virus

Dopamine-transporter density in patients with ADHD

Sir—In their Jan 29 commentary 1 Ronald Sacher and colleagues say that the effect of screening by nucleic acid amplification testing (NAT) on transmission of hepatitis B virus (HBV) is complex and that during the infectious period HBV seems to be present at a low titre. NAT screening for HBV, HCV, and HIV-1 was started in July, 1999, by the Japanese Red Cross Society. This is not only to narrow the infectious window in the early stage of acute HBV infection, but also to detect HBV-DNA in persistently infected individuals with the extremely low concentrations of HBV antigen and antibody often observed in HBV mutants. Up to February, 2000, we used a multiplex HBV/HCV/HIV-1 reagent developed by Roche Diagnostics (Tokyo, Japan) and Roche Molecular Systems (CA, USA) to test 420 770 units of blood donated voluntarily at Japanese Red Cross blood centres all over Japan that had screened negative after pooling 50 units into one. We identified five units with wild-type HBV of subtype adr and genotype C samples and two units with precore mutant of subtype adr and genotype C. HBV DNA content in the five wildtype samples per mL was 5·8⫻103, 5·7⫻10 3, 5·4⫻10 3, 4·0⫻10 2, and 3·1⫻102 and that of precore mutants was 4·0⫻102 and 2·3⫻102, respectively. All these units of blood were found to be negative for HB-core and HBsurface antibodies, IgM, and HB-core and HB-surface antigens by overnight enzyme immunoassay with Auszyme II (Abbott, IL, USA). Thus, serologically negative, but HBV-DNA positive units were detected by 50 pool NAT screening with MPX and some of the units were precore mutants.

Sir—Darin Dougherty and colleagues (Dec 18/25, p 2132) 1 state that patients were excluded from their study of patients with attentiondeficit-hyperactivity disorder (ADHD) if they were on “drugs which affect the dopamine system within 1 month before participation”. They probably are referring to the amphetamines— methylphenidate (Ritalin), d-, 1amphetamine (Adderall), and damphetamine (Dexedrine). Brown and colleagues2 have shown such a theory to be simplistic and invalid, accentuating that it cannot be said of any drug, or class of drugs, that they are known to act exclusively on any one set of chemical transmitters, or, that it is known exactly how they act. If the investigators are speaking of other types of psychotropic drugs, it cannot be assumed (no mention is made of what the drugs were or how long the patients had been on them) that there would be no drug effect capable of altering the single photon emission computed tomography (SPECT) testing, 1 month after the patients stop taking whatever drug it was they were on. Because it was six adult patients with ADHD that were studied, it is likely that they had been on psychotropic therapy long-term, and were more likely to have been on stimulant therapy than other psychotropic drugs. But again, none of these details are given. Surely, the investigators make no claim that their patients with ADHD were wholly drug-naïve, that is, that they had used no drugs at all, at any time in their lives, and that their ADHD behaviour was the sole variable. The fact that patients were apparently on some psychotropic

THE LANCET • Vol 355 • April 22, 2000