The antipruritic effect of a 5-HT3 receptor antagonist (tropisetron) is dependent on mast cell depletion – an experimental study

The background of this study is that 5-HT3 receptor antagonists are reported to have an antipruritic effect in uremic and cholestatic pruritus. Recently, we could not confirm such an effect in healthy subjects under experimental conditions. Therefore, it was the aim of the present study to further evaluate a possible antipruritic effect of a 5-HT3 receptor antagonist (tropisetron) on serotonin- and histamine-induced itch before and after skin mast cell depletion in 10 healthy subjects. The results were compared to serotonin and histamine iontophoresis in non-pretreated and pretreated skin with an orally applied antihistamine (cetirizine). Skin mast cell depletion was performed by iontophoretical application of compound 48/80. Wheals and flares were planimetrically evaluated. Itching and burning sensations were rated on an analog scale over a 24-min period. The test protocol also comprised alloknesis, defined as induction of perifocal itch sensations by a mechanical stimulus. When serotonin was iontophoretically applied after mast cells had been depleted before, oral tropisetron resulted not only in significantly lower whealing, itching and alloknesis but also reduced flares. In contrast, after oral pretreatment with tropisetron histamine-induced reactions before and after mast cell depletion did not significantly change. Our study demonstrates that in this model, tropisetron as a 5-HT3 receptor antagonist does not effect histamine-induced itch but has a measurable effect in serotonin-induced reactions when mast cells were depleted before. From these data evidence now exists why tropisetron is to some extent effective in certain types of pruritus such as uremic pruritus, known for increased histamine liberation and increased serotonin levels as well as degranulated and diffusely spread mast cells in the skin.     

Effect of topical capsaicin on the cutaneous reactions and itching to histamine in atopic eczema compared to healthy skin

Abstract Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is thought to produce analgesic and possibly also antipruritic effects when applied topically. Capsaicin 0.05% was applied three times daily over a 5-day period to the same infrascapular region. The effects of the pretreatment upon the pruritogenic and wheal and flare reactions to subsequent histamine iontophoresis (20 mC) were evaluated on the following day. The antipruritic effects of the pretreatment were compared with the effects of placebo pretreatment and no pretreatment. Wheal and flare areas were evaluated planimetrically. Itch or pain were rated every minute over a 24-min period. The areas of alloknesis, i.e. the induction of perifocal itch sensation by usually nonitching (e.g. mechanical) stimuli, were also evaluated. In control subjects, but not in atopic eczema (AE) patients, capsaicin pretreatment significantly reduced the flare area. Compared with control subjects, AE patients showed a lack of alloknesis or significantly smaller areas of alloknesis in pretreated and nonpretreated skin. In control subjects, capsaicin pretreatment significantly reduced itch sensations compared with nonpretreated skin, whereas in AE patients no differences were seen. Itch sensations in capsaicin-pretreated skin were significantly lower in control subjects than in AE patients. We conclude that capsaicin does effectively suppress histamine-induced itching in healthy skin but has less effect in AE. The diminished itch sensations and the absence of alloknesis in atopic individuals indicate that histamine is not the key factor in itching in AE. Received: 24 July 1997     

Lack of efficacy of topical capsaicin in serotonin-induced itch

Capsaicin (CAP) has been demonstrated to be an effective topical inhibitor of cutaneous vasodilatation, pain and pruritus induced by a variety of chemical and physical stimuli. In a previous study, we showed a significantly inhibitory effect of topical CAP treatment on histamine-induced itch and cutaneous vascular reactions in healthy subjects compared to atopic eczema patients. As serotonin is proposed to play a pathophysiological role in some types of pruritus (e.g. uremic and hepatic pruritus) and CAP has been described to be successful in hemodialysis-related pruritus, we investigated the antipruritic effect of topical CAP on serotonin-induced reactions in 10 healthy volunteers in comparison to untreated skin (UPS) and placebo substance (vehicle)-treated skin (VS). On the first day, serotonin iontophoresis was performed in untreated skin. One week later, the treatments started, using either CAP 0.05% liniment or a placebo liniment (vehicle) 3 times daily over a 5-day period. On day 6, serotonin was applied by iontophoresis within the pretreated skin. After another 1-week break, the treatments were performed vice versa on the corresponding infrascapular region. Weal and flare areas were planimetrically evaluated. Itch sensations were documentated by the volunteer on a scale over a 24-min follow-up period. The examination also comprised alloknesis, which stands for induction of perifocal sensations by usually non-itching stimuli. In CAP-treated skin, serotonin-induced wheals were significantly larger post-application compared to non-pretreated skin. Wheals were significantly larger in VS than in UPS. Comparison of serotonin-induced flares in the different study arms did not reveal any significant differences. Itch sensations were not significantly reduced by topical CAP application. The areas of alloknesis were smaller in capsaicin-treated skin compared to VS and UPS, but did not reach significant value. In conclusion, topical CAP application is not effective in serotonin-induced itching in healthy volunteers. Serotonin is most unlikely to play a role in the mechanism of action of CAP.     

Comparative efficacy of cetirizine and levocetirizine in chronic idiopathic urticaria

H1 receptor antagonists are the mainstay of treatment for chronic idiopathic urticaria. Newer hydroxyzine derivatives such as cetirizine and levocetirizine have been found to be equally efficacious in preclinical studies in patients with chronic idiopathic urticaria. In this study, the clinical efficacy of cetirizine and levocetirizine has been studied sequentially in individual patients. Fifty chronic idiopathic urticaria patients received 10 mg of levocetirizine daily for 6 weeks. Some 45 patients out of these showed reasonably good clinical efficacy on a visual analog scale to qualify for comparison with levocetirizine. A total of 30 patients completed the study period of 6 weeks each of cetirizine and levocetirizine sequentially. Thus, the clinical efficacy of cetirizine and levocetirizine was comparable with a marginal advantage of better antipruritic effect with levocetirizine, probably at the cost of increased sedation.     

Pruritus in the elderly

Pruritus is an unpleasant sensation leading to the desire to scratch. It is the most common symptom in dermatology, and various skin and systemic diseases can be associated with the presence of itching. Pruritus may also be provoked by numerous drugs. Although the exact epidemiologic data are still absent, it is generally accepted that elderly people frequently suffer from pruritus, and the problem of itching in this population remains a challenge for clinicians. The elderly often complain of numerous comorbidities that complicate the determination of the cause of pruritus, as well as its treatment. Physical and mental deprivation may complicate proper assessment of pruritus severity and negatively impair compliance with complex antipruritic therapies. Taking also into account heterogeneity of possible causes of pruritus, every patient with pruritus must be handled individually, regarding the diagnostic procedures and antipruritic therapy.     

Recent studies of cutaneous nociception in atopic and non-atopic subjects

Itching reflects a distinct quality of cutaneous nociception elicited by chemical or other stimuli to neuronal receptors at the superficial layers of the skin and muco-cutaneous orifices. Although recent experimental studies of the conduction and perception of itch have yielded deeper insight into the physiology of this sensory quality, little is known about the neuromechanisms involved in pruritus accompanying many inflammatory skin diseases, in particular, in atopic eczema. Previous case-control studies of our research group with patients suffering from atopic eczema (AE) revealed significantly diminished itch perception after iontophoretic application of different doses of histamine as well as substance P (i.c. injected). Further experiments using acetylcholine (ACh, i.c.) clearly demonstrated that ACh elicits pruritus instead of pain in patients with AE. The first part of the present review deals with the results of our most recent case-control studies on histamine-induced itch perception in atopics devoid of eczema as well as in patients with urticaria or psoriasis compared to atopics with or without manifest eczema. We demonstrated that both focal itch and perifocal alloknesis (i.e., itch elicited by a slight mechanical, otherwise non-itching stimulus) were significantly reduced in eczema-free atopics yet were normal in non-atopics suffering from urticaria or psoriasis. In further studies using ACh i.c. injected into the uninvolved skin of patients with AE, lichen ruber, psoriasis, type IV contact eczema, or non-specific nummular eczema (n = 10/each group), all the atopics and 6/10 psoriatics felt itch instead of burning pain, but none of the others did. Different doses of vasoactive intestinal peptide (VIP) i.c. applied to the controls and the atopics with or without eczema did not markedly increase the intensity of nociceptive sensations. However, ACh induced pain in the controls, pure pruritus in the atopics with acute eczema, and a 'mixture' of pain and itch in the atopics just free from eczema. Obviously, the quality of sensations evoked by ACh and VIP depends on the inflammatory or non-inflammatory state of the atopic skin. In a placebo-controlled, double blind study on histamine-induced focal itch and alloknesis with healthy subjects (n = 15) using naltrexone (opioid receptor antagonist) and cetirizine (H1-blocking agent), naltrexone was found to significantly reduce both itching and alloknesis. Cetirizine reduced focal itch but failed to influence the alloknesis phenomenon. The wheal and flare reaction was suppressed only by cetirizine. These different effects point to a mainly CNS-based activity of naltrexone but a peripheral level effect of cetirizine. Due to long-lasting experience with group sport as a supporting adjuvant for inpatients with AE, we evaluated, by clinical, psychometric, and physiological studies, the therapeutic efficacy of controlled physical exercise in addition to otherwise equal anti-eczematous therapy for both voluntary participants and non-participants in sports by performing several case-control studies, one followed-up to 6 months after the patients' discharge from the hospital. Regular moderate exercises neither deteriorated nor impeded the recovery from AE, ameliorated the participants' scratch controlling ability and significantly their depressed emotional mood. The non-participants failed to achieve these aims. Sweating-induced itch was inhibited in almost all participants if simple skin care (clearing by warm shower, ointment) and short-term rest were used by informed patients. In conclusion, there are several indications that itching is elicited in individuals inclined to cutaneous atopy, regardless of their eczematous or just eczema-free state, by a different physiological pathway from that in non-atopic individuals. Therefore, antipruritic agents influencing the centrally altered nociception of atopics are needed and may be expected in near future. (ABSTRACT TRUNCATED)     

Neurophysiological and neurochemical basis of modern pruritus treatment

Abstract:  Chronic pruritus of any origin is a frequent discomfort in daily medical practice, and its therapy is challenging. Frequently, the underlying origin may not be identified and symptomatic therapy is necessary. Conventional treatment modalities such as antihistamines often lack efficacy, and hence new therapeutic strategies are necessary. The neuronal mechanisms underlying chronic pruritus have been partly identified during the past years and offer new therapeutic strategies. For example, mast cell degranulation, activation of neuroreceptors on sensory nerve fibres and neurogenic inflammation have been identified to be involved in induction and chronification of the symptom. Accordingly, controlling neuroreceptors such as cannabinoid receptors by agonists or antagonists showed high antipruritic efficacy. Pruritus is transmitted to the central nervous system by specialized nerve fibres and sensory receptors. It has been demonstrated that pruritus and pain have their own neuronal pathways with broad interactions. Accordingly, classical analgesics for neuropathic pain (gabapentin, antidepressants) also exhibit antipruritic efficacy upon clinical use. In summary, these recent developments show that highlighting the basis of pruritus offers modern neurophysiological and neurochemical therapeutic models and the possibility to treat patients with refractory itching of different origin.     

Expression of serotonergic receptors in psoriatic skin

Psoriasis appears to be influenced by stress, which causes release of adrenal hormones. Serotonin, or hormonal actions on serotonin and serotonin receptors, may have a role in psoriasis. Distribution of serotonin receptors was studied in involved and noninvolved skin in patients with psoriasis and compared to normal skin, by using immunohistochemistry and antibodies to 5-HT1A, 5-HT2A and 5-HT3 receptors (R). There was a decreased (P<0.001) number of 5-HT1AR positive cells, the majority being tryptase positive, in involved and noninvolved psoriatic papillary dermis, compared to normal skin. 5-HTlAR expression was also found in the upper part of the epidermis, on vessel walls and on melanocytes. 5-HT2AR expressing papillary mononuclear cells, CD3 positive, were increased (P<0.001 and P<0.01, respectively) in involved and noninvolved psoriatic skin, compared to normal skin, an increase (P<0.01) also being found in the involved compared to noninvolved skin. Expression of 5-HT3R could be found in the basal epidermal layer of noninvolved but not in the involved skin of psoriasis, where it was only found in the acrosyringium. The present findings are compatible with the 5-HT1A and 5-HT2A receptors having antagonistic functions, and raise the possibility of using receptor specific drugs in the treatment of psoriasis.     

Tropisetron via α7 nicotinic acetylcholine receptor suppresses tumor necrosis factor‐α‐mediated cell responses of human keratinocytes

Tropisetron is a serotonin receptor (5‐HT‐R)‐modulating agent and approved as an antiemetic for patients undergoing chemotherapy. In the gut, it acts via specific serotonin receptors, 5‐HT₃‐R, to elicit its beneficial effects against nausea. We investigated whether tropisetron can affect inflammatory cell responses of human primary epidermal keratinocytes (NHK) which are key cells in the regulation of skin homoeostasis. Tropisetron significantly and dose‐dependently suppressed tumor necrosis factor (TNF)‐α‐mediated mRNA expression and protein secretion of interleukin (IL)‐6 and IL‐8 in these cells. This effect of tropisetron was independent of p65/NF‐κB as shown by various NF‐κB signal transduction read‐outs. Importantly, the anti‐inflammatory tropisetron effect on NHK was neither mediated by 5‐HT₃‐R nor 5‐HT₄‐R since these receptors were absent in NHK. In contrast, NHK expressed α7 nicotinic acetylcholine receptors (α7nAchR) which previously were found to bind tropisetron. The α7nAchR antagonist α‐bungarotoxin neutralized, whereas AR‐R17779, a specific α7nAchR agonist, mimicked the suppressive effect of tropisetron on TNF‐α‐mediated IL‐6 and IL‐8 expression in NHK. Our findings suggest that tropisetron and probably other α7nAchR‐activating agents could be useful for the future therapy of inflammatory skin diseases.     

Behandlung von Pruritus als Symptom von Hauterkrankungen mit dem Serotonin‐Rezeptorantagonisten Ondansetron

Background: Pruritus is often a stressing symptom and a therapeutic challenge. We report our experience with the serotonin receptor antagonist ondansetron in the symptomatic treatment of pruritus accompanying various skin diseases. Patients and Methods: The influence of ondansetron (8 – 12 mg orally per day) on pruritus was assessed in twelve patients with various skin disorders. The intensity of pruritus was quantitated daily by a visual analogue scale over the time period of one week before, during, and one week after treatment. Results: Ondansetron decreased pruritus intensity in prurigo simplex (four patients), asteatotic eczema (two patients), parapsoriasis en plaques, and pruritus of unknown origin (one patient each). One of two patients with atopic dermatitis experienced relief, whereas no benefit was observed in urticaria factitia and notalgia paraesthetica (one patient each). Conclusions: Ondansetron may ameliorate the concomitant pruritus of some dermatologic diseases.     

A randomized,placebo-controlled,double-blind trial of ondansetron in renal itch

BACKGROUND: Renal itch is a relatively common and distressing problem for patients with chronic renal failure. Ondansetron, a serotonin type 3 receptor antagonist was developed for relief of chemotherapy induced nausea. Recently, anecdotal reports describe relief of renal itch with ondansetron. OBJECTIVES: We performed a double-blind randomized placebo-controlled trial to objectively assess the effectiveness of ondansetron in renal itch. PATIENTS AND METHODS: With approval from the local ethical committee, 24 patients on haemodialysis were enrolled in the trial. On a random basis 14 patients were blindly allocated to the ondansetron-placebo sequence and 10 to the placebo-ondansetron sequence. Baseline values for itch were obtained for 7 days before the treatment period and there was a 7-day washout between the treatment periods. During the treatment patients received either 8 mg of ondansetron three times a day or a placebo tablet three times a day for 2 weeks. Patients were asked to record the severity of their pruritus on a visual analogue scale (VAS) twice a day. At the end of the study patients were asked blindly which treatment they had preferred. RESULTS: Seventeen patients completed the trial. Pruritus decreased by 16% (95% CI: 0.5-32%) during active treatment and by 25% (95% CI: 9-41%) during treatment with placebo. The change in VAS scores during treatment with ondansetron (P = 0.04) and placebo (P = 0.01) were both significant. Eleven patients expressed a preference, seven for placebo and four for ondansetron. CONCLUSIONS: Our results show that ondansetron is no better than placebo in controlling renal itch.     

Antagonism of the serotonin pathway – a novel antifibrotic approach?

The neurotransmitter serotonin (5‐Hydroxytryptamin, 5‐HT) has been implicated in the pathogenesis of scleroderma and scleroderma‐like skin changes for years. In particular, a role of serotonin has been suggested as an important vasoactive mediator of the Raynaud's phenomenon in patients with systemic sclerosis. Accordingly, anti‐serotoninergic therapies have been utilized clinically to treat Raynaud's phenomenon. There is also recent evidence that multiple cell types of the skin have the capacity to synthesize serotonin. The biological effects of serotonin are mediated by at least 15 different 5‐HT‐receptor subtypes. One of them is the 5‐HT3‐receptor, which binds the 5‐HT‐antagonist tropisetron. Here we investigated the effect of tropisetron on transforming growth factor‐beta1 (TGF‐beta1)‐mediated collagen synthesis in human dermal fibroblasts (HDF) in vitro. In addition, we elucidated the impact of tropisetron on activation of SMAD, a signaling transduction pathway implicated in TGF‐beta1‐mediated collagen synthesis. Tropisetron at non‐cytotoxic doses significantly suppressed TGF‐beta1‐mediated collagen type I (alpha1 and 2) and type III (alpha1) expression at RNA level in HDF as shown by real‐time PCR analysis. This effect of tropisetron was paralleled by reduced amounts of intracellular collagen type I protein as evidenced by Western immunoblotting. In addition, tropisetron significantly decreased secreted procollagen‐I‐C‐peptide as demostrated by ELISA. In contrast, tropisetron alone did not have any detectable effect on collagen expression. Analysing the SMAD pathway we could further show that tropisetron in contrasts to TGF‐beta1 neither affects SMAD3 phosphorylation, nuclear translocation of SMAD2/3 nor SMAD3/4‐dependent promoter activity in HDF. Our results for the first time demonstrate a potent suppressive effect of tropisetron on TGF‐beta1‐induced collagen synthesis in vitro. Regardless of the molecular mechanism of TGF‐beta1 antagonism by tropisetron, these findings should be of special relevance towards the exploitation of tropisetron and related agents as a novel treatment for patients with fibrotic diseases.     

Mouse model of touch-evoked itch (alloknesis)

Lightly touching normal skin near a site of itch can elicit itch sensation, a phenomenon known as alloknesis. To investigate the neural mechanisms of alloknesis, we have developed an animal model. Low-threshold mechanical stimulation of the skin normally does not elicit any response in naive C57/BL6 mice. Following acute intradermal (i.d.) injection of histamine in the rostral back, mechanical stimulation 7 mm from the injection site elicited discrete hindlimb scratch bouts directed toward the stimulus. This began at 10 minutes and peaked 20-40 minutes post histamine injection, declining over the next hour. Histamine itself elicited bouts of scratching not associated with the mechanical stimulus, which ceased after 30 minutes. Histamine- and touch-evoked scratching was inhibited by the μ-opiate antagonist naltrexone. Touch-evoked scratching was observed following i.d. 5-HT (5-hydroxytryptamine), a protease-activated receptor (PAR)-4 agonist, and an MrgprC11 agonist BAM8-22, but not chloroquine or a PAR-2 agonist. The histamine H1 receptor antagonist terfenadine prevented scratching and alloknesis evoked by histamine, but not 5-HT, a PAR-4 agonist or an MrgprC11 agonist. In mice with experimental dry skin, there was a time-dependent increase in spontaneous and touch-evoked scratching. This animal model appears to be useful to investigate neural mechanisms of itch and alloknesis.     

Neurophysiology of pruritus: cutaneous elicitation of itch

Itching is defined as an unpleasant cutaneous sensation leading to the desire to scratch. It serves as a physiological self-protective mechanism as do other cutaneous sensations like pain, touch, vibration, cold, and heat to help defend the skin against harmful external agents. Pruritus can be evoked in the skin directly by mechanical and thermal stimuli or indirectly through chemical mediators. It may also be generated in the central nervous system independently of peripheral stimulation. Single-nerve-fiber recordings have shown that histamine-evoked itch is transmitted by selective slow-conducting subpopulations of unmyelinated C-polymodal neurons. Recent experimental studies using improved methods have demonstrated which of the suspected chemical itch mediators such as histamine, neuropeptides, prostaglandins, serotonin, acetylcholine, or bradykinin act pruritogenically on C-fibers. Moreover, investigations have revealed new receptor systems such as vanilloid, opioid, and cannabinoid receptors on cutaneous sensory nerve fibers that may modulate itch and thereby represent targets for antipruritic therapy. This review focuses on the peripheral generation of itch, including neurotransmitters, neuropeptides, and inflammatory mediators.     

Placebo-controlled study of the efficacy of topical antihistaminics against histamine-induced pruritus

2 antipruritic ointments, when compared to placebo, were ineffective against histamine-induced itching applied in 2 volunteers after the intracutaneous injection of histamine. Testing of 11 topical antihistaminics after pretreatment for 30 and 60 min on 12 volunteers showed that some of the preparations reduced the histamine-induced itching significantly, while others were able to inhibit itching only slightly or were very close to placebo. Pain from pin pricks could not be attenuated significantly by pretreatment with the topical antihistaminics at any time.     

The antipruritic effect of a sedative and a non-sedative antihistamine in atopic dermatitis

A double-blind, randomized, cross-over study was carried out on the effect of a sedative and a non-sedative antihistamine on 25 adults with atopic dermatitis. Intensity of itch was recorded using a computerized method for self-assessment (Pain-Track) and using conventional visual analogue scales. The antipruritic effect of 3 days of treatment with the non-sedative H1 antagonist terfenadine (60 mg b.i.d.) and with the sedative antihistamine, clemastine (2 mg b.i.d.) did not differ from that found with the placebo. Our findings support the view that histamine is not of importance in the pathogenesis of itch in atopic dermatitis.     

Endogenous opioids, mu-opiate receptors and chloroquine-induced pruritus: a double-blind comparison of naltrexone and promethazine in patients with malaria fever who have an established history of generalized chloroquine-induced itching

AIMS: Chloroquine induces a severe generalized pruritus, in predisposed Black African patients, during treatment of malaria fever, and also in some Caucasian patients treated for rheumatological diseases. We have previously shown that chloroquine may release endogenous opioids and/or interact with micro-opiate receptors in rats, and that both histamine and malaria parasite blood density, contribute to the itching severity in malaria fever in humans. The aim of our present study was to assess and compare the antipruritic efficacy of the micro-opiate receptor antagonist, naltrexone, and the antihistamine, promethazine, in chloroquine treated patients with malaria fever. METHODS: A double-blind, randomized, parallel group comparison of the chloroquine-induced pruritus intensity and time profile in patients with parasitologically proven malaria fever, who were pretreated with a single dose of either naltrexone 50 mg or promethazine 25 mg orally (six patients each). All patients had an established history of severe pruritus following chloroquine treatment of malaria fever. A self-assessed itching severity score was undertaken at 0, 6, 12, 24, 48 and 72 h after initial chloroquine dosing, and the areas under the pruritus-intensity time curve AUCP0-72 h was determined in each patient and correlated to the malaria parasite density in blood. RESULTS: Both naltrexone and promethazine subjectively reduced itching severity compared with prior historical experience. One patient on naltrexone and two on promethazine never experienced any itching. There was no statistically significant treatment effect, but a significant time effect (P = 0.001, F = 4.77 d.f. 5) by two-way repeated measures ANOVA. The AUCP for naltrexone was 82 +/- 25 units/h, and 57 +/- 34 units/h for promethazine [95% confidence interval for the difference being -73 to 123]. However, the malaria parasite density in the naltrexone group (740 +/- 178 microl(-1)) tended to be higher than in the promethazine group 314 +/- 69 microl(-1) (P = 0.056, 95% confidence interval for the difference being -15 to 866 microl(-1)). Correction of the AUCP for malaria parasite density (parasite pruritogenic index, AUCP. units/h/parasites/microl blood) tended to be lower with naltrexone 9.1 +/- 2.6 than with promethazine 12.2 +/- 7.0 There was a highly significant and positive correlation between the malaria parasite density and the AUCP0-72 h, on naltrexone (r2 = 0.78, P = 0.040) and promethazine (r2 = 0.93, P = 0.008). However, comparison of regressions revealed that the slope of the regression was significantly steeper with promethazine 0.48 than naltrexone 0.12 (P = 0.006, t = 4.2), with the intercepts showing a trend to a difference (P = 0.086). CONCLUSION: Naltrexone exerted an antipruritic action, at least to a similar extent to promethazine in patients with chloroquine-induced itching in malaria fever. However, the relationship between parasite density and resultant pruritus was significantly different between naltrexone and promethazine. Thus, micro-opiate receptors/and or endogenous opioids may contribute to chloroquine itching in malaria fever, in humans, in accord with animal experimental findings. Malaria parasite density in blood is a strong determinant of itching severity in patients predisposed to chloroquine-induced pruritus.     

Changes in plasma serotonin concentration and acceleration plethysmograms in patients with Raynaud's phenomenon after long-term treatment with a 5-HT2 receptor antagonist

High blood serotonin concentrations have been reported in patients with Raynaud's phenomenon and a relationship has been suggested. Because of the difficulty in evaluating Raynaud's phenomenon objectively, a possible correlation between blood serotonin concentrations and clinical findings has not yet been evaluated. We measured plasma serotonin concentrations and acceleration plethysmograms (APG) before and one year after administration of a serotonin receptor antagonist. Twenty-seven patients with either collagen disease or diseases associated with Raynaud's phenomenon were given a combined 5-HT2 and serotonin receptor antagonist, sarpogrelate hydrochloride. Plasma serotonin concentrations were determined before and after administration and the APG d/a value was measured as an index of peripheral hemodynamics. These values were compared with the clinical symptoms of the patients. After one year of treatment, the subjective symptoms improved in 59.3% of patients who has Raynaud's phenomenon. The pretreatment plasma serotonin concentrations of the study patients were significantly higher than those of the normal controls, but became significantly decreased following 5-HT2 administration. However, there was no clear-cut relationship with the clinical symptoms. The pre-treatment APG d/a value of the patients was significantly lower than that of the normal controls, although there was no significant difference after administration when analyzed as an entire group or in a subset of patients whose symptoms did not subjectively improve or worsened after one year of treatment. In the subset in whom the subjective symptoms improved, however, the value significantly increased following administration, suggesting an improvement in peripheral hemodynamics. These results suggest the possibility that APG can be used as an objective index of peripheral hemodynamics.     

Opioid-induced pruritus: an update

Pruritus is an unpleasant sensation leading to scratching. It can be a feature of numerous skin or systemic diseases, and may also be a side-effect of various drugs. Opioids are one of the best-known medicines evoking pruritus. The pathogenesis of opioid-induced pruritus is still not fully known, but two different mechanisms have been proposed: peripheral and central. Several treatment options have been tested for opioid-induced pruritus, but none has been completely satisfactory. Opioid antagonists seem to be the most potent antipruritic drugs, but they also decrease analgesia, which limits their usage. Many other treatments have been tried, but to date, the data are conflicting or only limited studies have been performed to confirm their efficacy. Further studies are still needed to better elucidate the mechanism of opioid-induced pruritus and to develop more effective treatment options.     

A comparison of cetirizine and terfenadine in the management of solar urticaria.

Many solar urticaria patients may benefit from the use of antihistamines. Historically, the value of such therapy was limited by sedation. Newer agents such as terfenadine and cetirizine that are relatively non-sedating appear to be better tolerated by patients. The latter drug, in addition to its antihistamine effect, also appears to inhibit eosinophil migration, which terfenadine and other potent H1 antagonists do not significantly affect. Eosinophils have been reported as early migrating cells in induced solar urticaria, raising the possibility that the dual action of cetirizine may provide a greater potential benefit in the management of solar urticaria. Six patients with idiopathic solar urticaria were entered into a double-blind, phototest study to compare cetirizine and terfenadine. Using the minimal urticarial dose as a phototest end-point, both drugs were equally effective in raising the threshold of sensitivity in 4 patients. Two patients failed to respond to either therapy, which is in keeping with the known variable response to histamine blockade in solar urticaria. At the dosage used, cetirizine therapy appears to be no more effective than terfenadine.