Zinopin® - the rationale for its use as a food supplement in traveller's thrombosis and motion sickness

PHYTOTHERAPY RESEARCH
Phytother. Res. 18, 687–695 (2004)
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ptr.1575
REVIEW
Zinopin® – the Rationale for its Use as a Food
Supplement in Traveller’s Thrombosis and
Motion Sickness
J. H. Scurr1 and O. P. Gulati2*
1The Lister Hospital, Chelsea Bridge Road, London, UK
2Horphag Research, Avenue Louis-Casaï 71, Geneva, Switzerland
Venous thrombo-embolism (VTE) has been associated with periods of prolonged immobility during air, sea
and road travel. Motion sickness (MS) has also been reported during both long and short journeys. Current
prophylactic therapies for both these indications are generally associated with side effects.
Physiological profiles of Pycnogenol® and Standardized Ginger Root Extract (SGRE) representing active
constituents of Zinopin® have been described and reviewed in relation to their activities involved in the patho-
physiology of VTE (Traveller’s Sickness) and MS and their safe use as food supplement, in traveller’s throm-
bosis and motion sickness. The patho-physiology of VTE and MS is discussed in light of epidemiological data
and risk factors associated with these conditions.
Rationale of development of Zinopin® and its mechanism of action are discussed based on physiological
synergy of Pycnogenol® and SGRE. Conclusions are made in light of preliminary clinical findings obtained in
an open controlled clinical trial. Further clinical study on Zinopin® on these lines is suggested. Copyright
2004 John Wiley & Sons, Ltd.
Keywords: review; clinical trial; herbal food supplement; Zinopin®; Pycnogenol®; efficacy; traveller’s thrombosis; motion sickness.
correspond to more than 12 h flight (Clerel and Caillard, INTRODUCTION
1999). The incidence rate as recorded at the airports ofParis was 0.5 per million of passengers, with an import- Venous thrombo-embolism (VTE) has been associated ant prevalence in females (Clarel and Caillard, 1999).
with prolonged immobility during travel involving aero- Out of 11 in-flight deaths from pulmonary embolism planes, buses, trains and cars. The recognition that VTE there were ten with an incidence of thrombo-embolism was associated with prolonged flight or travel was first reported by Homans in 1954. This was then described Simulated or real long flights have been reported to as ‘Economy Class Syndrome’ in 1988 (Cruikshank et al., bring about blood changes including high fibrinogen 1988). Seventeen to twenty-five percent of patients with levels, haemo-concentration and low fibrinolytic activ- VTE admitted to two Honolulu hospitals had had a ity (Sarvesvaran, 1986, Kraaijenhagen et al., 2000). It recent history of air travel (Eklof et al., 1996; Mercer has been shown in healthy subjects that 1 h sitting and Brown, 1998). Others have looked at this associ- position, there appears a net diminution of flow to legs, ation in relation to travel by car, bus, truck or train 30% increase in haematocrit and 40% increase in plasma (Tardy et al., 1993; Ferrari et al., 1999). The mean dura- proteins (Kraaijenhagen et al., 2000). Other factors in- tion of trip was 14.2 h and the first symptom occurred cluding dehydration (Carruthers et al., 1976) stress, clim- in less than a week after the journey in 75% of the atic change, and activation of blood clotting (Simon cases (Tardy et al., 1993). Prolonged travel in the seated and Krol, 1996) may contribute additional risk factors position causes venous stasis, and it is venous stasis to venous stasis in the development of VTE. Immobil- that is associated with VTE. This is consistent with ity, hypoxia and a decrease in atmospheric pressure Virchow’s classic postulate that venous stasis contrib- was shown to alter fibrinolytic activity and cause release utes to VTE. The present evidence regarding air travel of venous wall factors leading to deep vein thrombosis is circumstantial, and could be misleading given that (Gertler et al., 1993; Landgraf et al., 1994; Bendz et al., VTE is a very common disorder, with an annual incid- 2000). In an independent study in healthy volunteers, ence of 1 per 1000 population suffering with a deep hypoxia and decrease in pressure has been demon- vein thrombosis (Ferrari et al., 1999).
strated to raise clotting factors (Bendz et al., 2000).
When travel times are greater than 12 h there was a These blood changes may contribute to the develop- greater incidence of thrombo-embolism – 76.5% cases The majority of clots are asymptomatic, with only those extending into the femoral and pelvic veins * Correspondence to: Dr O. Gulati, Horphag Research, AvenueLouis-Casaï 71, Geneva, Switzerland.
giving rise to classic symptoms of pain and swelling.
Asymptomatic DVT occurs in 3–10% of air travellers.
Copyright 2004 John Wiley & Sons, Ltd.
Phytother. Res. 18, 687–695 (2004)
Copyright 2004 John Wiley & Sons, Ltd.
Scurr and his colleagues (2001) demonstrated ‘ultra- sengers with no risk factors can also develop deep vein sound detected thrombus’ in up to 10% of people travel- thrombosis. With 7–10% of the population suffering ling long distance. Patients with known risk factors from a thrombophilia, often unknown and undiag- had already been excluded. Only a few go on to de- nosed, it is not difficult to see why up to 10% of people velop swelling of the legs, or signs and symptoms of travelling will develop an asymptomatic deep vein pulmonary embolism including death. The development of a deep vein thrombosis is generally associated with Frequency of travel and duration of travel are also risk factors. The more risk factors, the greater is the chance of developing a deep vein thrombosis. The con-dition is not confined to people with cardiovasculardisease, or even previous thrombo-embolic episodes,but can affect young healthy people. Many people who CURRENT TREATMENT AND PROPHYLAXIS
have suffered a deep vein thrombosis had no obvious FOR VENOUS THROMBO-EMBOLISM
risk factors other than travel. Any deep vein thrombo-sis is potentially life threatening. The development of a Most of the studies relate to hospitalised patients.
DVT will predispose to a future DVT, and larger DVTs Mechanical methods of prophylaxis including elastic are associated with an increased risk of pulmonary compression stockings and intermittent pneumatic com- embolism. Small clots cause difficulty in breathing. Large pression have been proven to reduce the incidence of deep vein thrombosis (Tardy et al., 1993; International Although asymptomatic DVTs may resolve, valvular Consensus Statement, 1997; Anonymous, 2000; Belcaro damage may occur, predisposing people to further epi- et al., 2001). By extrapolation reduce the incidence of sodes of deep vein thrombosis and the development of deep vein thrombosis is thought to reduce the risk of pulmonary embolism. A number of pharmacological The LONFLIT study (Belcaro et al., 2001) demon- approaches have been evaluated, including low dose strated 3% of travellers developing clots on long flights, unfractionated heparin, low molecular weight heparin, most are silent or asymptomatic, but still potentially low dose Warfarin, and aspirin. There are many studies posing a threat of recurrent deep vein thrombosis. With looking at the effects on reducing deep vein thrombo- US Airlines carrying 600 million passengers, 50% mak- sis, and un-fractionated low dose heparin, low molecu- ing journeys over 4 h with up to 10% developing clots, lar weight heparin, low dose Warfarin, and aspirin have this would suggest that up to 1.8 million travellers de- been seen to have some beneficial effects. Currently, velop deep vein thrombosis. In studies where patients low molecular weight heparin is the treatment of choice.
presenting with deep vein thrombosis and pulmonary Studies using unfractionated heparin, and more recently, embolism were studied, up to 66% had a deep vein low molecular weight heparin, have demonstrated a thrombosis attributed to air travel (Simon and Krol, reduction in the incidence of pulmonary embolism 1996). A similar figure of around 50% has been (Belcaro et al., 2001; Cesarone et al., 2002; Belcaro obtained by Mercer and Brown (1998). In Honolulu, et al., 2002; Scurr, 2002). There are as yet few properly Eklof et al. (1996) found 254 patients with deep vein controlled clinical studies looking at the effect of thrombosis, of whom 20% had developed clots during prophylaxis on air travel. Several studies have shown air travel. The incidence of deep vein thrombosis a beneficial effect of wearing compression stockings was found to be 6% in a study made by Ferrari et al. in both preventing asymptomatic and the symptoms of (1999) in Nice. There is a considerable range, and the true incidence of deep vein thrombosis following air Aspirin has some proven benefits in the arterial cir- travel remains unknown. Further studies by the WHO culation, but the effects on the venous circulation re- addressing the epidemiology of venous thrombosis will main controversial with an associated increased risk of gastrointestinal bleeding, making it difficult to recom-mend aspirin on a routine basis (Llyod and Bochner,1996; International Consensus Statement, 1997). Thusresearch investigators are encouraged to develop new RISK FACTORS
anti-platelet agents that are equivalent or superior toaspirin, but with less or no adverse effects. Currently, In the absence of properly controlled clinical studies, for most passengers, DVT prophylaxis consists of ad- most of our information relating to risk factors comes vice, exercises before, during, and after the flight, the from hospital-based studies, looking at patients admitted avoidance of excessive alcohol and sleeping tablets, and to hospital to undergo surgical treatment (Lowe et al., advice to report symptoms at an early stage. None of 1992; Scurr et al., 1998). Immobility, a past history of these methods of prophylaxis have yet been scientific- deep vein thrombosis, recent surgery or injury, and an underlying thrombophilia remain the most importantfactors. Cancer, chronic heart disease, diabetes, andobesity are also included as risk factors. Pregnancy,oestrogen-containing oral contraceptives, and women PATHOPHYSIOLOGY OF VENOUS STASIS
on hormone replacement therapy, are also thought to OEDEMA AND CHRONIC VENOUS
have an increased risk. No single risk factor is likely INSUFFICIENCY
to cause a deep vein thrombosis, but a combinationof several risk factors increases the risk. Identifying risk Venous stasis and the inability to reduce venous pres- factors will identify passengers who are at increased sure during exercise give rise to chronic venous insuffi- risk during periods of travel. Unfortunately other pas- ciency with increased capillary permeability (Wenner Copyright 2004 John Wiley & Sons, Ltd.
Phytother. Res. 18, 687–695 (2004)
et al., 1980). An experimental model using the rat tail the blood flow, with the development of intravascular (Nordmann and Gulati, 1980; Nordmann et al., 1982) thrombosis. Thrombokinase is released from micro- has been used to assess the effects of hydroxyethylruto- thrombi converts prothrombin to thrombin. Thrombin sides (Paroven®) in chronic venous insufficiency. These converts fibrinogen to fibrin, forming the basic skele- models were validated using plethysmography, thermo- ton of a clot. As platelets and red blood cells get graphy, fluorescence angiography and radioactive micro- spheres techniques. Paroven was a venotonic drugshowing significant inhibition of the oedemogenic re-sponse in the acute and chronic phases of experiment-ally induced chronic venous insufficiency.
PATHOPHYSIOLOGY OF MOTION SICKNESS
It is postulated that venous stasis leads to endothelial damage, the incorporation of inflammatory cells, with a Motion sickness (MS) is an illness triggered by sensory release of oedemogenic and/or inflammatory mediators.
conflicts involving the vestibular system, occurring when Endothelial damage leads to increased venous perme- sensory inputs regarding body position in space are ability in the post-capillary venules (Gulati et al., 1983a; contradictory or different from those predicted from 1983b). The same group showed oedemogenic medi- ators, including histamine, leukotriene C and leukotriene Gastric dysrhythmias (tachygastria) has been associ- D and inflammatory mediators like cytokines, prostag- ated with the patho-physiology of motion sickness (Stern landins, causing increased vascular permeability lead- et al., 1987; 1989). Quantitative analyses showed that ing to fluid leaving the intravascular compartment for tachygastria index correlated with intensity of nausea, the extra-cellular spaces. This process was further aided which in turn, correlated positively with plasma vaso- by increased venous pressure, in particular, the ability pressin levels (Koch et al., 1990). Vasopressin is re- to be unable to reduce it. The accumulation of fluid in leased from neurohypophysis during motion sickness, the extra-cellular compartment has an osmotic effect which mediates nausea. Elevated plasma vasopressin increasing oedema further. With increased local in- levels demonstrate a close temporal relationship with flammation of the veins, red blood cells leave the the development and resolution of nausea evoked by circulation and form part of the process ultimately circular vection (Koch et al., 1990; Xu et al., 1993; Kim giving rise to lipodermatosclerosis.
et al., 1997; Koch, 1999). Elusory self-motion or vectionevokes nausea, dysrhythmia and vasopressin release inmotion sicknes-susceptible subjects via cholinergic –prostaglandin independent pathways (Kim et al., 1997).
PATHOPHYSIOLOGY OF DEEP VEIN
The effect is centrally mediated and not peripheral THROMBOSIS
action of vasopressin. Selective vasopressin antagonistshave been shown to abolish symptoms of motion sick- Virchow (1856) noted that venous stasis, combined with ness in primates (Cheung et al., 1994).
damage to the venous endothelium, plus changes in the Nausea associated with motion sickness is unpleas- blood’s ability to coagulate, would predispose to the ant. Current anti-motion sickness medication includes development of a deep vein thrombosis. In actual antimuscarinics and antihistamines. These agents pro- situation, following long travels by air, bus car, truck or duce incomplete symptom control and elicit significant train, the mechanisms include tendency to clot forma- side effects such as dry mouth, lethargy and drowsiness.
tion in the legs secondary to the reduced venous returninduced by the sitting position with direct compressionof popliteal and femoral veins, and secondary to dehy-dration and haemoconcentration (Tardy et al., 1993).
BIOLOGICAL PROFILE OF PYCNOGENOL®
Immobility remains an important factor. Damage causedto the endothelial lining by oxidative stress, and changes Biological profile of Pycnogenol® and its clinical activi- in the ability of the blood to coagulate, are not only ties have been reviewed by Packer and his co-workers important in the process of forming a deep vein (1999) and Rohdewald (1999; 2002). For the purpose thrombosis (Gertler et al., 1993; Landgraf et al., 1994; of this review we will consider those studies, which are Bendz et al., 2000), but also important because we can relevant to the product Zinopin® in context with the influence these changes, reducing the risk of deep vein thrombosis. Platelets are the smallest cellular compon- The most obvious feature of Pycnogenol® is its strong ents in the blood stream existing as a a-nuclear disc- antioxidant activity owing to the basic chemical struc- shaped cells in their resting state and they travel singly ture of its components procyanidins and phenolic as discoidal particles. (Rao, 1993; Rao and Rao, 1994).
acids. Various studies have addressed its antioxidant Any insult to the vascular endothelium will make it capacity in simplified assay systems in vitro, cultured thrombogenic, with platelets binding to fibrinogen, cell models (Rong et al., 1995; Wei et al., 1997; Virgili aggregating to the area and among themselves giving et al., 1998a; Bayeta et al., 2000), in vivo in animals rise to microthrombi. The microthrombi release platelet (Blazso et al., 1994; 1995; 1997) and in clinical studies activating factors (PAFs, including adenosine diphosph- (Devraj et al., 2002). The antioxidant activity of ate (ADP) and serotonin. ADP and arachidonic acid two major metabolites [σ-(3, 4 dihydroxyphenyl)-γ- (AA) metabolite act as endogenous platelet activator, valerolactone] and [σ-(3-methoxy-4 hydroxphenyl)-γ- thromboxane A (TxA ), intensifying the extent of valerolactone] of Pycnogenol® has also been shown in platelet aggregation. These substances act in positive an independent in vitro study (Grimm et al., 2004).
feedback loops, producing a vicious circle (Llyod and Interestingly Nelson et al. (1998) studied the capacity Bochner, 1996). Venous stasis leads to slowing of of Pycnogenol® to protect the low density lipoprotein Copyright 2004 John Wiley & Sons, Ltd.
Phytother. Res. 18, 687–695 (2004)
(LDL) fraction of human plasma from copper-inducedoxidation and have reported a dose-dependant decreasein lipid peroxide. Pycnogenol® exhibited a concentra-tion dependent inhibition of oxidative burst triggeredby zymosan in murine macrophages in vitro. Further-more, it significantly minimized the cleavage of DNAcaused by hydroxyl radicals, induced by exposure ofpBR 322 plasmid DNA to iron/ascorbic acid systemand measured by agrose gel electrophoresis (Nelsonet al., 1998). Chida and his co-workers (1999) studiedPycnogenol® among different known antioxidants andfound Pycnogenol® to be many fold more potent thanvitamin C, E and grape seed extract in the lipidperoxidation model using bovine retinal cell model.
Increase in antioxidative enzyme system (GSH reduc-tion enzymes, SOD and catalase) has been demon-strated in two independent studies in vitro (Wei et al.,1997; Maritim et al., 2003).
Figure 1. Dose response effects of single Pycnogenol® adminis-
Interestingly, a strong correlation between anti- tration on platelet reactivity index in 19 smokers. Statistical oxidant activity in vivo and anti-inflammatory activity significant difference to basline (0 mg Pycnogenol®) was in vivo has been demonstrated indicating the role of achieved with 100 mg or more Pycnogenol®. (Reproduced from oxidative stress in inflammation and anti-inflammatory Watson, 2003; with permission from the author) mechanism of Pycnogenol® working through its anti-oxidant activity (Blazso et al., 1994).
500 mg of acetylsalicylic acid (aspirin) or 100 mg of Anti-inflammatory activity of Pycnogenol® is well Pycnogenol®. The anti-platelet-reactivity effects were documented (Blazso et al., 1994; 1995; 1997). One of shown to be dose dependent (Fig. 1). At a dose of 200 mg the molecular features of the UV induced inflam- of Pycnogenol® the inhibitory effect on platelet reactiv- matory response is the activation of the transcription ity and decreased thrombaxane levels in smokers factor NF-κB which in turn, regulates the expression (Araghi-Nicknam et al., 1999). The authors suggest that of different inflammatory cytokines and triggers the this activity of Pycnogenol® is related to its nitric oxide inflammatory response. Pycnogenol® has been shown releasing capacity from the endothelial cells (Minuz to significantly inhibit this activation (Peng et al., 2000).
et al., 1995; Fitzpatrick et al., 1998), which in turn would Furthermore, Pycnogenol® dose dependently inhibited inhibit the synthesis of thrombaxane A-2. In a clinical tumour necrosis factor-α (TNF-α) – induced activation study with 60 patients meeting the diagnostic criteria of of NF-κB and inhibited TNF-α – induced release of coronary heart disease, it was reported that Pycnogenol® superoxide and hydrogen peroxide ions from human administered for four weeks inhibited the adhesion vascular endothelial cells in vitro. Adhesion molecules and aggregation of platelets, enhanced the capillary are needed for penetration of inflammatory cells into diameter and improved the microcirculation (Wang tissues. At the transcriptional level, the expression et al., 1999). The cardiovascular profile of Pycnogenol® of the adhesion molecule (iCAM-1) is inhibited by has been reviewed by Watson (1999, 2003). Interest- pre-incubation of Pycnogenol® in human vascular ingly, Pycnogenol® has been shown to decrease the endothelial cells (Peng et al., 2000). Pycnogenol® re- levels of thrombaxane in an independent clinical study duces production of reactive oxygen and nitrogen species in activated immune cells (Virgili et al., 1998a;1998b). The oxidative burst of macrophages releasingsuperoxide and hydroxyl radical including hydro-gen peroxide is inhibited by Pycnogenol® in vitro BIOLOGICAL PROFILE OF GINGER ROOT
(Virgili et al., 1998a; Nelson et al., 1998). Furthermore the production of the pro-inflammatory interleukin-1βis inhibited by Pycnogenol® in the same cell system Ginger root extract has been shown to have anti- (Cho et al., 2000). Pycnogenol® down regulates platelet aggregation activity in vitro (Guh et al., 1995; Interferon-γ – induced adhesion of T cells to human Venkateshwarlu, 1997; Nurtjahja-Tjendraputra et al., keratinocytes by inhibiting inducible ICAM-I expres- 2003) and ex vivo in humans (Verma et al., 1993). In sion (Bito et al., 2000). Pycnogenol® has been shown to addition to inhibiting platelet aggregation, it also re- provide protection against UV induced damage to skin duces platelet thrombaxane synthesis both in vitro and in vitro as well as in vivo in animals and in humans in vivo (Srivastava, 1984; 1986; 1989; Thomson et al., (Guochang, 1993; Saliou et al., 2001; Sime and Reeve, 2002). Ginger inhibits thrombaxane synthesis and stimulates synthesis of prostacyclin (Backon, 1986).
Another interesting feature of Pycnogenol® is its anti- Arachidonic acid-induced human platelet serotonin thrombosis profile, relevant to the subject matter of release and aggregation is inhibited (Koo et al., this review. Pycnogenol® inhibits platelet reactivity induced by cigarette smoking, without producing any Beneficial effects of ginger 0.5 and 1 g ginger in a adverse effect on the bleeding time that characterises double blind randomised clinical trial has been shown aspirin use (Pütter et al., 1999). Pütter and his collabor- in nausea and vomiting following surgery (Bone et al., ators (1999) have observed that in a group of heavy 1990; Phillips et al., 1993; Arfeen et al., 1995) and in smokers, platelet aggregation was prevented either by morning sickness (Fischer-Rasmussen et al., 1991; Copyright 2004 John Wiley & Sons, Ltd.
Phytother. Res. 18, 687–695 (2004)
Aiken-Murphy, 1998; Keating and Chase, 2002) motion lower leg and ankle (Gulati, 1999). Two independent sickness and sea sickness (Mowrey and Clayson, 1982; studies with 40 patients each confirmed the efficacy of Stewart et al., 1991; Lien et al., 1993; Lanner et al., 1995).
Pycnogenol® in chronic venous insufficiency (Arcangeli, Ernst and Pittler (2000) made a systematic review of 2000; Petrassi et al., 2000). Another blind study com- evidence from six randomized controlled trials for and pared the effects of horse chestnut seed extract and against efficacy of ginger for nausea and vomiting Pycnogenol® by measuring the circumference of the including post-operative patients, subjects with sea sick- lower limb in patients with CVI. A fast onset of action ness, morning sickness and those on the chemotherapy.
was shown by Pycnogenol® with a significant reduction The results from these studies collectively favour ginger in leg circumference as compared to horse chestnut in efficacy over placebo in nausea and vomiting.
Different hypotheses have been put forward: • Ginger improves the effects of motion sickness through its aromatic, carminative, spasmolytic and RATIONALE OF THE DEVELOPMENT OF
possible absorbent properties, which are thought to ZINOPIN®
block gastrointestinal reaction and subsequent nauseafeedback (Lien et al., 1993). Unlike anti-motion sick- Zinopin® is a combination of SGRE and Pycnogenol®.
ness drugs, it does not reduce vestibular optokinetic Pycnogenol® is an anti-oxidant and effective anti- nystagmus (Mowrey and Clayson, 1982; Suekawa oedema anti-inflammatory agent, reducing capillary et al., 1984; Yamahara et al., 1990). The action of permeability, and has an anti-thrombotic effect by in- ginger is peripheral and not central and thus not as- hibiting platelet reactivity. Pycnogenol® is effective in sociated with general side effects such as drowsiness decreasing platelet reactivity like asprin, however, it is common to centrally acting anti-emetics.
devoid of devoid of side effect like bleeding By reduc- • It is thought that ginger may act by increasing ing capillary permeability there is a reduction in oedema gastrointestinal motility reducing the feedback from formation, reduced endothelial damage, and this com- the GI tract to central chemo receptors (Holtman bined with its effect on inhibiting platelet activity, has et al., 1989; Qian and Liu, 1992). Ginger juice pro- been shown in clinical studies to reduce the clinical duce anti-motion sickness by central and peripheral symptoms of heaviness of the legs, ankle swelling and a anti-cholinergic and anti-histaminic effects (Mascolo Pycnogenol® has been combined with SGRE because • Some researchers believe that ginger produces ben- ginger is also known to have anti-platelet aggregation eficial effects in motion sickness by preventing the activity, fibrinolytic activity and it inhibits thromboxane development of gastric dysrhythmias and elevation synthesis. In addition, it is also effective in preventing of plasma vasopressin (Mascolo et al., 1989).
• Ginger has been shown to produce anti-oxidant It is thought that ginger acts in a peripheral capacity, effects in vitro and in vivo (Cao et al., 1993; Ahmed avoiding the common side effects of centrally acting anti-emetics, which includes drowsiness. Pycnogenol® • Anti-inflammatory actions of ginger have been shown and ginger both are generally recognized as safe in different animal models. Jana et al. (1999) demon- (GRAS) The combination of SGRE and Pycnogenol® strated that ginger (100 mg/kg) was effective as ace- therefore, seems to be an appropriate and safe travel tylsalicylic acid (100 mg/kg) in reducing carrageen in supplement. The proposed rationale and mechanism induced oedema in rats. Similar results have been of action of Zinopin® and its active components reported by Mascolo and his colleagues (Jana et al., Pycnogenol® and SGRE has been shown in Fig. 2. It 1999). The anti-inflammatory action is thought to be seems both components may act in synergy to produce due to inhibition of arachidonic acid metabolism and beneficial effects of Zinopin® in long-haul travel rel- prostaglandin release like other non-steroidal anti- inflammatory drugs, in clinical conditions (Jana et al.,1999).
• Ginger has been shown to increase fibrinolytic activ- ity in human fed with heavy fat diet (Bordia et al., CLINICAL STUDIES OF ZINOPIN®
Zinopin® is currently being taken by travellers that aretravelling for more than 8 h, and who are over 18 yearsof age. There have been no exclusions from this study.
CLINICAL EXPERIENCE WITH
Prior to entering the study, a full medical history is PYCNOGENOL®
obtained, including a history of recent flights and theduration of those flights. Any current medication is Rohdewald (2002) has recently reviewed the clinical noted and passengers are asked to record any use of study data on Pycnogenol®. However, in this review we medication during the study period. No specific advice will focus only on the clinical studies relevant to the about travel was given to any passenger, and the pas- subject matter of this review. Five placebo-controlled, sengers took one Zinopin® tablet the day before flight, double-blind studies involving a total of 149 patients two on the day of flight, and a further tablet on each of and three double-blind, controlled studies in a total of the two following days. On their return, all passengers 231 patients have demonstrated that Pycnogenol® sig- completed a questionnaire looking specifically for leg nificantly improved pain, occurrence of cramps, heavi- and chest symptoms. Passengers took the Zinopin® on ness of legs and significantly reduced swelling in the both the outward bound and the return flights.
Copyright 2004 John Wiley & Sons, Ltd.
Phytother. Res. 18, 687–695 (2004)
Figure 2. Zinopin®: Pycnogenol® and Standardized Ginger Root Extract (SGRE).
lution, in some people, damage to the vein wall remains, predisposing to further thrombosis episodes. A deepvein thrombosis may be associated with risk factors, The study is ongoing and passengers are still being but not always. There are occasional episodes of spon- recruited. No passenger has developed a symptomatic taneous deep vein thrombosis in passengers with no deep vein thrombosis. More than 50% of the passen- obvious risk factors. The deep vein thrombosis may gers taking Zinopin® commented spontaneously that occur two weeks or more after a flight, and may not they had less ankle swelling. This was not objectively be associated with travel. There is no evidence to date measured and is a subjective assessment, but entirely to suggest that travel-related thrombosis is specific to consistent with previous studies using Pycnogenol®.
airline travel, and the current link is simply to one of The results will be analysed on an intention-to-treat basis. It will form the basis of a pilot study, leading to Pycnogenol® has the benefits of aspirin, without a full double-blind study to assess the benefits of taking having the risk of gastrointestinal bleeding. There are additional benefits of Pycnogenol® in terms of the cir-culation, reduction of tissue fluid, and the resultantoedema. SGRE similarly has many effects which couldbe seen to be beneficial in the prevention of venous CONCLUSIONS
thrombosis, and in addition to this, an anti-nauseouseffect, which makes it an ideal ingredient for any travel Deep vein thrombosis is far more common than was supplement. Preliminary studies with the Zinopin® show originally appreciated. Whilst in the majority of cases not only that it is effective; it is well tolerated, and not a deep vein thrombosis will resolve with complete reso- been associated with any significant side-effects.
Copyright 2004 John Wiley & Sons, Ltd.
Phytother. Res. 18, 687–695 (2004)
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