Journal of Neuroimmunology, 22 (1989) 69-76 69 Elsevier

JNI 00733

Cimetidine as an immunomodula tor in the treatment of herpes zoster

Ariel Miller 1, Dan Harel 1, Arie Laor 2 and Nitza Lahat 3

1 Department of Neurology, 2 Department of Internal Medicine, and 3 Cellular Immunology Laboratory, Lady Davis Carmel Hospital, Haifa, Israel

(Received 17 May 1988) (Revised, received 12 August 1988)

(Accepted 12 August 1988)

Key words: Herpes zoster infection; Histamine; Neuroimmunology

Summary

As there is evidence of a possible immunoregulatory role for H2-histamine receptor antagonists, we carried out a prospective randomized trial to evaluate the in vivo and in vitro effect of cimetidine, an HE-blocker, in the treatment of herpes zoster infection. Cimetidine treatment shortened the median interval until the first decrease in pain, the median interval until the complete resolution of pain and promoted faster complete healing of skin lesions than symptomatic treatment. The immunological trends observed in vitro support an important role for histamine in the induction of immunosuppression, as measured by the response to the mitogen phytohemagglutinin. This effect of histamine was antagonized by cimetidine.

Introduction

Herpes zoster infection is associated with a decline:in cellular immunity in people with no identifiable underlying disease. Cellular immune deficiency may explain its particularly high frequency among the elderly and among patients with lymphoproliferative malignancies or after transplantations (Hope-Simpson, 1965; Shimpff et al., 1972; Becker, 1979; Miller, 1980).

A growing body of evidence suggests that sup- pressor T-ceUs carrying histamine H2-receptors

Address for correspondence: Dr. Ariel Miller, Department of Neurology, Lady Davis Carmel Hospital, 7 Michal St., 34362 Haifa, Israel.

may play an important immunoregulatory role in the execution of the immune response (Plaut et al., 1976; Rocklin, 1976). The suppressor cell function seems to be mediated through the release of a soluble factor induced by histamine, histamine-in- duced suppressor factor (HSF), which modulates lymphocyte proliferation and antigen-induced lymphokine production (Rocklin and Greinder, 1979). This enhanced activity of suppressor T-cells was shown to be reversed by cimetidine in vitro, in cases of common variable hypogammaglobulin- ernia, chronic cutaneous candidiasis and cancer (Jorizzo et al., 1980; Talpaz et al., 1982; White and Ballow, 1985). Preliminary data on uncon- trolled restricted cases of patients with herpes zoster infection (HZI) point to a beneficial effect of cimetidine on the clinical course of the disease

0165-5728/89/$03.50 © 1989 Elsevier Science Publishers B.V. (Biomedical Division)

70

(Van Der Spuy and Lavy, 1980; Hayne and Marcer, 1983; Mavligat and Talpaz, 1984). The purpose of this study was to correlate effects in vivo of cimetidine with in vitro function of sup- pressor cells in cases of HZI.

Materials and methods

Patients with clinically diagnosed varicella zos- ter infection, later confirmed serologically by indi- rect immunofluorescence antibody titers (FAMA), were eligible for our study (Table 1). Patients with cutaneous lesions that had been present for longer than 72 h and patients with malignant conditions were excluded. Informed consent was obtained from all patients prior to randomization. The ex- perimental protocol was approved by our institu- tional Helsinki committee.

Patients were assigned according to a random number sequence to receive either cimetidine (Tagamet, Smith-Kline, RIT) 1200 mg, in three divided doses generally at 7 a.m., 3 p.m. and 11 p.m., or Algolysin (propoxyphene and paraceta-

TABLE 1

CHARACTERISTICS OF PATIENTS WITH HERPES ZOS- TER INFECTION AT ENTRY

Characteristic Treatment groups

Cimetidine Symptomatic (N =10) ( N = 6 )

Age (years) Median Range

Sex Male 6 Female 4

Dermatomal rash distribution at entry

65 61 45-73 26-78

Cranial 4 2 Cervical 1 - Thoracic 4 3 Lumbar 1 1 Sacral - - Generalized - -

Days from onset of rash to entry 2.4 2.3

Severity of pain at study entry 3 3 Days from onset of pain to entry 5.1 4.0

mol, Zori) three tablets a day for 10 days, blindly for patients and physicians. They were studied either as out-patients or as in-patients in our Neurological Department . The following factors were assessed prospectively in all patients at study entry (day 0), daily up to and including day 10, on days 15, 20, 25, 30, weekly thereafter until disap- pearance of complaints, and monthly thereafter for 6-months, when discharged from follow-up: day and intensity of pain on entry (pain in the area of cutaneous involvement was graded by the pa- tients as none (0), mild (1), moderate (2) or severe (3); first decrease in pain (the first of 3 consecu- tive days during which the patient reported pain of lesser grade than the maximum noted by the patient; resolution of pain (the absence of pain sustained for the duration of follow-up; post- herpetic neuralgia (dermatomal pain that persisted for 30 days or more after the start of treatment); day of rash and dermatomal distribution on entry," cutaneous or visceral dissemination," 50% healing (the loss of the crust in 50% of the maximum number of lesions); complete healing (the loss of the crust in all lesions).

Reagents Histamine, cimetidine and mitomycin C for in

vitro studies were obtained from Sigma (Sigma Chemical Co., St. Louis, MO, U.S.A.). Ap- propriate dilutions were prepared for immediate use in RPMI-1640 (Beit Haemek, Israel). Fetal calf serum (FCS) and antibiotics (penicillin, streptomycin, neomycin) were obtained from Beit-Haemek. Phytohemagglutinin-P (PHA) was purchased from Difco (Detroit, MI, U.S.A.). 96- well U-bot tomed culture plates were obtained from Nunc (Nunc Intermed, Denmark). [3H]- Thymidine (specific activity 25 C i /mmol ) was ob- tained from Amersham (Amersham, U.K.).

Mononuclear cell preparation and culture technique Peripheral blood mononuclear cells (PBMC)

were isolated from fresh heparinized blood on a Ficoll-Hypaque density gradient according to Boyum (1968). The PBMC were suspended in RPMI-1640 plus 10% heat-inactivated FCS and 1% antibiotics (complete medium) and cultured for suppressor cell generation according to Rock- lin et al. (1981). Briefly, the PBMC were divided

into induced-suppressor control cells and indica- tor cells. Induced suppressors were cultured in complete medium at a concentration of 5 x 10-7 M histamine with or without cimetidine (10 -4 M) for 18 h, whereas control cells were cultured in complete medium only. Indicator cells were cul- tured at 106//1Td in 96-well culture plates, in trip- licate, 0.1 ml/well. The next day, both induced- suppressor and control cells were treated with mitomycin C (50 /~g/ml) for 45 min and then washed 3 times with complete medium and added at 106//ml, 0.1 ml/well to the indicator cells. The cell mixture was then stimulated with 10 /xg/ml PHA and cultured for an additional 72 h. 18 h prior to termination, 1/~Ci/well of [3H]thymidine was added. Incorporation of [3H]thymidine into cellular DNA was determined by harvesting the cultures in a semi-automatic Linca Harvester (Linca, Tel Aviv, Israel) and the radioactivity re- corded by liquid scintillation spectroscopy. The mean cpm (___ SD) was determined from triplicate wells. The percentage suppression of [3H]thymi- dine uptake was determined by the following for- mula:

% Suppression

Mean cpm in the presence of histamine = l -

Mean cpm in the absence of histamine

x 100

The change in suppressor cell activity caused by cimetidine was calculated on the basis of the percentage of suppression obtained in the pres- ence of cimetidine compared to that in its absence by the following formula:

% change in suppressive activity (SA)

SA untreated - S A treated 1 - SA untreated

x 100

The suppression induced by histamine and the effect of cimetidine were measured in the patients at diagnosis, after 10 days' treatment with cimeti- dine or 10 days of symptomatic treatment.

Stat&tical analys& Analysis of variance was used for univariate

comparisons. Medians were compared by chi-

71

square test. Discriminant analysis was used for multivariate comparisons. A stepwise method was used to determine the variables contributing most to the discrimination. The classification formulae were used for classification of cases in predicted groups. Correlations between clinical and im- munological variables were found by computing Pearson's correlation coefficient and Spearman's rho correlation coefficient. The statistical analysis was performed by using the SAS procedure.

Results

Subjects Twenty-two patients were entered into the

study; ten with HZI were treated with cimetidine, six with HZI were treated with Algolysine and six cases of PHN were treated with cimetidine.

Clinical diagnoses were confirmed serologically in all cases of HZI. There were no significant differences in age, sex, dermatomal distribution or duration of illness at study entry. Routine blood tests, urine tests and X-rays revealed no signifi- cant findings. The characteristics of the two treated groups of HZI are shown in Table 1.

Efficacy Cimetidine was significantly effective in cuta-,

neous healing and resolution of pain (Table 2). As compared to the controls, cimetidine significantly accelerated the median period until complete heal- ing of cutaneous lesions (12 vs. 21 days; P = 0.014). Cimetidine also shortened the time until the first decrease in pain (3 vs. 6 days; P = 0.031) and the median time to resolution of pain (14 vs. 26 days; P =0.012). Postherpetic neuralgia oc- curred in one control group patient with lumbar rash (aged 53 years). Generalization of cutaneous rash, visceral dissemination or relapse of herpes zoster did not occur in either group in the follow- up period of 12 months. Severity of disease course was not correlated to dermatomal involvement.

Toxicity Cimetidine was well tolerated and no symp-

toms, signs or laboratory abnormalities that may have been caused by treatment were noted (Table 2).

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TABLE 2

CLINICAL EFFECTS OF T R E A T M E N T IN PATIENTS WITH HERPES ZOSTER INFECTION

Variable Treatment group P-value a

Cimetidine Symptomatic ( N = 1 0 ) ( N = 6 )

Median No. of days b

Pain First decrease in pain 3 6 Resolution of pain 14 26

Cutaneous lesions 50% healing 5 5 Complete healing 12 21

Postherpetic neuralgia 1 Toxicity

0.031 0.012

N . S .

0.014

a Chi-square test. b Related to day 1 of therapy.

Suppression of cell activity in vitro An inhibi tory activity of h is tamine on

lymphocyte proliferative response to the mitogen PHA was observed in the study groups. In nor- mals, histamine at a concentration of 10 -3 M depressed the response to PHA by 17%, at 10 -5 M by 9% and at 10 - 7 M by 3% (Fig. 1A and B). Patients with HZI had, at diagnosis, significantly enhanced histamine-induced suppression at the three concentrations used, 34%, 28%, 22% at 10 3 M, 10 -5 M, 10 -7 M, respectively (Fig. 1A, P < 0.05). However, following 10 days of treatment with cimetidine, histamine-induced suppressor ac- tivity was 17.5%, 2.5%, 0%, and did not differ from the healthy controls (Fig. 1B, P = N.S.). In patients with HZI who were treated symptomati- cally, significant enhanced suppressor cell func- tion was still present, although a trend towards reduced induction of suppression was still per- ceived, 25%, 20% and 14% respectively (Fig. 1B).

In patients with chronic PHN, histamine re- duced lymphocyte response to PHA by 21%, 15%, and 6%, at 10 -3 M, 10 -5 M, 10 -7 M, respec- tively. Following 10 days of treatment with cimetidine, no change was noted in the suppressor cell activity.

We calculated the proliferative response to PHA of lymphocytes derived from patients with H Z I as a percentage of the normal response. A significant

reduction in the response to PHA was observed in patients with HZI at diagnosis: 66% of normal response (Fig. 2(I)A) ( P <0.05). In the cimeti- dine-treated group, after ten days of treatment, an 80% response was noted (Fig. 2(I)A) compared to 74% of normal response in the control group (Fig. 2(II)A). This difference in response after 10 days of treatment in the two groups did not reach statistical significance ( P = 0.063). No effect was observed after 10 days of treatment with cimeti- dine in the postherpetic neuralgia (PHN) group (Fig. 2(III)A) ( P = N.S.).

The effect of incubation in vitro with cimeti- dine on the response to PHA was measured as a percentage of the normal response (Fig. 2(1, II, Ill)B). In cases of HZI, at diagnosis, incubation in vitro with cimetidine elevated the response to PHA from 66% to 77% (Fig. 2(1, II)B) ( P = N.S.). How- ever, in the cimetidine-treated HZI group follow- ing 10 days of treatment, incubation in vitro with cimetidine further augmented the response to 100% of the control normal response (Fig. 2(I)B). At the same time, after 10 days in the control group,

~_ 100%

c 9 0 -

#-

8 0 - "6

70

60

Y i I i i i i

10 3M 10 5M IO-IM 10-3M IO-'~M 10 ZM

Fig. 1. Histamine-induced suppressor cell activity. Mono- nuclear cells were cultured with histamine (10 -3 M, 10 -5 M and 10 -7 M) for 24 h, washed and co-cultured with PHA- stimulated indicator cells. His tamine caused a dose-dependent suppression of proliferation. A: at entry; B after 10 days; (A) herpes zoster treated with cimetidine; (111) post herpetic neu- ralgia treated with cimetidine; (e) herpes zoster treated symp-

tomatically; (°) normal controls.

100%

90

80

70

60

50

40 1 A

1

..~...

iiii!

B i

C

r

I

i i c

#-

I

'5

100%

90

80

70

60

50

4 0 - 1 1 1 A B C

100%

9 0 -

8 0 -

7 0 -

6 0 -

5 0 -

4 0 -

III

A B C

Fig. 2. Suppressor cell activity as measured by response to PHA. Shaded columns: before treatment (cimetidine or symp- tomatically); open columns: after 10 days treatment. Columns A: proliferative response to PHA; columns B: effect of in vitro incubation with cimetidine on PHA response; columns C: effect of in vitro preincubation with cimetidine on histamine- induced suppressor activity. Suppressor activity: I = HZI treated with cimetidine; II = HZI treated symptomatically;

III= PHN treated with cimetidine.

incubation in vitro with cimetidine resulted in an 80% response (Fig. 2(II)B) ( P = N.S.). In the P H N group the response to PHA remained low both before and after 10 days of treatment with cimetidine, with and without incubation in vitro with cimetidine: 39-41% of normal response (Fig. 2(III)B) ( P = N.S.).

The ability of cimetidine to prevent induction of suppressor activity by exogenous histamine was measured as the proliferative response to PHA of lymphocytes preincubated with cimetidine (10 -4 M) in vitro in the presence of histamine (10-5 M).

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The proliferative response of lymphocytes of HZI patients was measured as a percentage of the normal response (Fig. 2(1, II, Ill)C). At diagnosis there was no difference between proliferative re- sponse to PHA with no additives compared to that of preincubation with cimetidine with hista- mine (Fig. 2 columns A vs. C) ( P = N.S.). Thus, cimetidine seems to neutralize histamine-induced suppressor activity. After 10 days of treatment with cimetidine in vivo, in the presence of hista- mine with lymphocytes preincubated with cimeti- dine also in vitro, the proliferative response rose to 90% of the control value (Fig. 2(I)C), compared to only 76% in the symptomatically treated group (Fig. 2(II)C). Although the difference did not reach statistical significance, one can see that cimetidine has a tendency to block suppressor cell activity induced by histamine.

Discussion

Our results suggest that orally administered cimetidine, a histamine H2-receptor antagonist, significantly accelerated cutaneous healing and pain relief in adults with herpes zoster infection.

Although there were no significant differences in the clinical or immunological characteristics at entry, median first decrease in pain, complete resolution of pain, complete healing of cutaneous lesions and absence of complications such as P H N were significantly different in the cimetidine- treated group of H Z I compared to the symp- tomatically treated patients.

We have also demonstrated that lymphocytes derived from patients with acute herpes zoster had a significantly reduced response to PHA, com- pared to the normal control response. Higher sup- pression of the response to PHA was noted in the presence of exogenous histamine.

Orally administered cimetidine, and in vitro preincubation of lymphocytes with cimetidine re- versed separately and additively the induced sup- pression.

These findings, together with the limited im- provement in immunological and clinical parame- ters in patients treated symptomatically only, point to an enhanced induced suppressor T-cell activity in patients with HZI.

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Moreover, a potential beneficial effect of cimetidine on their immune defense mechanisms, by augmentation of cellular immune response with early control of viral infection is suggested, al- though the difference did not reach statistical sig- nificance. It should be mentioned that a trend towards normalization of the immune parameters was observed in the symptomatically treated group. This is in accordance with previous reports by Neumeyer and Hirsh (1986), who detected inver- sion of T-cell subsets with elevation of suppressor T-cells before clinical HZI and normalization of the T4/T 8 ratio 4 months after the infection sub- sided. Abnormality in T-cell activity may occur during the incubation period as part of the viral effect. Correction of the immune mechanisms may, therefore, be part of the natural history of the recovery. An alternative possibility is that the depressed immune response preceded and may have led to the reactivation of the virus. In either case, suppressor activity appears to antedate clini- cal HZI, as has been observed in recurrent herpes simplex lesions (Jordan, 1984).

Patients with chronic postherpetic neuralgia were found to have very low PHA responsiveness, which suggests T-cell immune deficiency. In these patients, however, the effect of exogenous hista- mine which was minimal and the failure of cimetidine to augment the diminished response to PHA, support the possibility of other mechanisms for immunodeficiency in these patients (Miller et al., 1985).

In accordance with the literature (McGregor et al., 1977; Freston, 1982), no immunostimulant effect was noted in immunocompetent subjects treated in vivo, such as patients treated for peptic ulcer, or treated in vitro with cimetidine.

No correlation was found between immunologi- cal or clinical parameters of HZI patients, at entry, and the natural history of the disease or the characteristics of PHN patients. Therefore, neither a prediction of clinical prognosis, mainly PHN, according to clinical or immunological markers at the beginning of the infection, nor a choice of high-risk candidates who may derive most benefit from cimetidine treatment, could be made. Larger studies are probably necessary for establishing such correlations.

Both latency and reactivation of varicella zoster

virus are brought about by mechanisms not yet understood (Hope-Simpson, 1965), and we can only speculate about the relationship of cellular immunity to the human disease. The importance of cell-mediated mechanisms in the body's defence against HZI is supported by the susceptibility to HZI in elderly individuals (Burgoon et al., 1957; Becker, 1979; Miller, 1980), patients with malig- nant disease (Sokal and Firat, 1965; Shimpff et al., 1972; Arvin and Polards, 1978) and cardiac transplant patients (Rocklin, 1976), which are cor- related closely with a depressed cellular immune response.

It is not unreasonable to expect that the corollary may also apply, viz. that a rapid recovery from HZI may be related to an augmentation of the cellular immune response (Malvigat and Talpaz, 1984; White and Ballow, 1985).

Although the improvements in vivo and in vitro in our study support the hypothesis of an im- munomodulative effect of cimetidine, when this is considered together with the reports that raniti- dine, a specific H2-antagonist , has a molar potency 4-8 times higher than cimetidine, but no en- hancing effect on the T-cell immunoresponse, this suggests that some of the immunomodulatory ef- fect of cimetidine may not be mediated by classi- cal Hz-receptors (Peden et al., 1982; Zeldis et al., 1983).

It should be emphasized that in order to appre- ciate the real and potential role of immunomodu- lators, one needs to understand the nature of the specific immunological defect in the disease and to take into account the human immunoregulatory network. The clinical consequences of an im- munostimulator are not easy to predict (Fauci, 1987).

Among the other mechanisms that may be sug- gested for the clinical improvement of an anti- histamine as analgesic is one which should be taken into account. Recently, direct proof for histaminergic pathways involved in nociception has been reported (Diamond et al., 1981; Pollard and Schwartz, 1987) and antihistaminergic drugs can modulate their responses either centrally or peripherally (Rumore and Schlichting, 1976).

Our study population consisted entirely of pa- tients who could be regarded as otherwise normal adults. In patients with malignant disease who had

undergone either intensive chemotherapy or bone marrow transplants, patients who were at high risk of developing a severe disseminated HZI, the treatment of choice is considered to be acyclovir (Whitley et al., 1982; Portenoy et al., 1986; Shepp et al., 1986). This antiviral agent has been shown to shorten the course of dermatomal HZI in nor- mal adults too, but after the drug was discon- tinued, neuralgia worsened (Bean et al., 1982; Balfour et al., 1986; Portenoy et al., 1986) and none of the substances with the acyclovir formula- tion have yet been shown to reduce the overall incidence or severity of PHN. The limited benefit of acyclovir does not appear to offset the incon- venience and expense of hospitalization for paren- tal chemotherapy and its associated side effects in the majority of the patients with HZI. Since early studies using orally administered antiviral agents, that can be used on an out-patient basis produced inconclusive results (McKendrick et al., 1984; Bal- four, 1986), the possibility that a substance such as cimetidine with well-known pharmacokinetics and low toxicity may be an effective immunomod- ulator is promising. To these one should add the possibility of its administration in ambulatory care units. Details regarding dosage and duration of therapy have to be established more precisely. Further investigations are required to delineate subgroups of patients in whom this treatment is reasonable.

On the basis of the data in our study and the other cases reported, we believe that a subset of patients with immunoregulatory disorder char- acterized by excessive suppressor-cell activity, either malignant or viral disease, may respond to treatment with cimetidine. However, the precise mechanism of action of cimetidine and other antagonists to histamine H2-receptors on the im- mune response remain to be elucidated.

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