Dose-response related efficacy in orthostatic hypotension of a fixed combination of D-camphor and an extract from fresh Crataegus Berries and the contribution of the single components. (Review).
Independent, double-blinded, randomized, placebo-controlled studies using sublingual/oral administration of D-camphor, an extract from fresh crataegus berries, and a combination of the two (CCC) yielded the following results:
Both the D-camphor and the extract from fresh crataegus berries, the components of CCC, contribute to the pressoric effects of the combination. The underlying hemodynamic mechanisms can be attributed to an increase in total peripheral resistance induced by an increased tone of the arterioles with both components and the effect of crataegus is intensified by an additional direct positive action on cardiac performance. Conceivably, the D-camphor component is the main factor in inducing the rapid initial effect, whereas the extract from fresh crataegus berries adds a long-lasting effect. For CCC, a dose-dependent increase in supine blood pressure and prevention of orthostatic fall in blood pressure following tilt table-induced orthostasis in patients with orthostatic dysregulation was demonstrated as well. The effect revealed a very rapid onset of action within 1 min following administration, confirming the traditional use in emergency situations such as orthostatic (pre)syncope. Thus, these studies show that CC C, depending on the pressoric activity of its two mono-components, exerts a significant effect that counteracts an orthostatic fall in blood pressure and thereby provides a rationale for its application that reemphasizes the decades-long usefulness of this phyto-combination.
Key words: Blood pressure, camphor, crataegus berry extract, hypotension, orthostatic hypotension, tilt table, total peripheral resistance
Frequently observed complaints such as palpitations, weakness, dizziness, fainting, and--as an extreme variation--syncope with or without generalized convulsions that occur in the upright position and are mostly short-lived after a shift from the supine position represent the most obvious symptoms of orthostatic hypotension (Lamarre-Cliche and Cusson, 2001).
The underlying cause of this severely disabling disorder results from the pooling of blood in the lower part of the body in the upright. When changing from the supine to the standing position, a volume of almost 11 of blood shifts, according to gravity, downward to the legs and the abdominal venous system. Within seconds, the subsequent decrease in venous return to the heart activates pressure receptors located in heart, lungs, carotid sinus, and aortic arch that instantly induce an increase in sympathetic outflow (Lamarre-Cliche and Cusson, 2001). This leads to an immediate (1) increase in cardiac output, followed by (2) contraction of arterioles and venous capacitance vessels. Normally, the orthostatic blood shifts are antagonized within 1 min and blood pressure is stabilized. In the further course of orthostatis, other mechanisms such as activation of the renin-angiotensin-aldosterone system support neuronal ones. In orthostatic hypotension, however, these mechanisms are compromised to a varying degree.
In addition to the symptoms described above, recent epidemiologic studies have revealed orthostatic hypotension to be not only an acute disorder or symptom but also to be a significant prognostic marker of all cause mortality in the elderly. Orthostatic hypotension in this context has been arbitrarily defined as a fall in systolic blood pressure (BPS) by at least 20 mmHg or in diastolic blood pressure (BPD) by at least 10 mmHg after 3 min of standing upright or on a tilt table (Masaki et al. 1998; Raiha et al. 1995, Consensus statement 1996). A prevalence rate of 4 to 33% in the elderly demonstrates that orthostatic hypotension is not a rare but a common phenomenon (Alli et al. 1992; Applegate et al. 1991; Atkins et al. 1991; Mader, 1989; Masuo et al. 1993; Rutan et al. 1992). The Honolulu-Study revealed that with each orthostatic drop in BPS by 10 mmHg, the overall mortality in elderly men increased by 18% (Masaki et al. 1998), a pattern also found in other populations (Raiha et al. 1995). According to the ARIC study, orthostatic hypotension is also a predictor for stroke and coronary heart disease (Eigenbrodt et al. 2000; Rose et al. 2000).
Analogous to many other cardiovascular risk factors, this observation suggests that a drug-induced action against orthostatic hypotension may lower morbidity and mortality. In addition, orthostatic fall in blood pressure to the point of orthostatic syncopes are to be considered an acute disorder that considerably impairs quality of life. Among available antihypotensive drugs, only few orally administered preparations suitable for treatment have the desired effect (Oldenburg et al. 1999). In addition, diverse contraindications, restrictions of application, interactions, and at times significant adverse reactions must be taken into account for instance in the drug treatment with mineralocorticoids or sympathomimetics.
Based on long-term medical experience and recent clinical-pharmacological studies a viable alternative to conventional synthetic drug treatment is offered by the phytocombination of natural D-camphor and an extract from fresh crataegus berries (CCC) which for decades has been used successfully in the treatment of hypotonic and/or orthostatic circulatory dysregulation. The present review compiles results of the effects of the mono-components and their combination on blood pressure and hemodynaniics in the supine position, and the dose-effect of this combination in postural orthostatic hypotension.
* Studies with D-camphor
Since ancient times, natural camphor has been extracted from wood of the east Asian camphor tree. In contrast to the synthetic racemate, the natural product exclusively contains the D-isomer (Belz et al. 2000; Franz and Hempel, 2000). For centuries, camphor has been used for the stimulation of heart and peripheral circulation. Recently, the cardiovascular effects of Dcamphor were evaluated and documented in controlled clinical studies (Belz et al. 2000). We conducted a randomized, double-blind, placebo-controlled, two-way cross-over study on the hemodynamic effects of D-camphor (in 60 vol% ethanolic solution) following sublingualloral administration. Sequential doses of 20, 40, 80 and 120 mg with lag-times of 60 mm were applied to supine, resting, healthy volunteers. Blood pressure (Korotkoff phases I and V) and cardiac output (electrical impedance cardiography) were measured non-invasively, while mean arterial pressure and total peripheral resistance (TPR) were calculated according to standard procedures (Be lz et al. 1981; Breithaupt et al. 1990).
Fig. 1 depicts the change in arterial mean blood pressure following sequential administration of 20 to 120 mg D-camphor (in 60 vol% ethanol) compared to equal volumes of a placebo containing 60 vol% ethanol. With D-camphor, a statistically significant dose-dependent increase in blood pressure vs. placebo is clearly demonstrable (ANOVA vs. placebo < 0.05). Though changes in total peripheral resistance (TPR, Fig. 2) did not reach statistical significance vs. placebo, it is obvious that there was a tendency of TPR to increase with D-camphor. This effect may be considered one possible cause of the increase in blood pressure.
* Studies with Extract from Fresh Crataegus Berries
Crataegus extracts have long been used in the treatment of various cardiovascular diseases. However, in contrast to extracts from crataegus leaves and flowers and dried berries (Gabard et al. 1983), only scarce information exists on the pharmacological and hemodynamic mechanisms of an extract from fresh crataegus berries that provide a rationale for the effectiveness of their use (Rietbrock et al. 2001).
In order to demonstrate cardiovascular effects of this phytopharmaceutical preparation in humans, we conducted a randomized study with a cross-over design (washout >4 weeks) (Mang et al. 1997). Fourteen healthy male volunteers received for 28 days a daily dose of an extract from fresh crataegus berries of 9.0 g (1:1,4; 60 vol% ethanol, concentrated to 5:1 with 3% procyanidins and 40 vol% ethanol, preserved with sorbinic acid) or a placebo (40% ethanol and caramel as coloring agent and sorbinic acid as preservative). At the beginning and end of each period, a hemodynamic profile with measurements of blood pressure in the supine position as well as TPR and systolic time intervals was generated (PEP/LVET) (Li and Belz, 1993) and recorded for up to 6 hours after the 1st and the 28th day doses. An ANOVA for repeated measurements was performed.
The following statistically significant effects of the extract from fresh crataegus berries as compared to placebo were seen: on the first day, a rise in arterial mean pressure (p < 0.02, Fig. 3), increase in total peripheral resistance (TPR, p <0.05) and shortening of the cardiac performance parameter PEP/LVET (p < 0.03). On day 28, the effects were similar and increase in blood pressure was intensified (p <0.001, Fig. 4).
The results clearly revealed that acute and chronic administration of extract from fresh berries exerts pressoric and cardiostimulatory (PEP/LVET) effects.
* Dose-Effect of the Combination of D-Camphor and an Extract from Fresh Crataegus Berries (CCC)
The combination of D-camphor and an extract from fresh crataegus berries (Korodin Herz-Kreislauf-Tropfen [R]), 100 g solution (1 drop contains 40 mg of CCC) containing 97.3 g extract from fresh crataegus berries, 2.5 g D-camphor, 60 vol% ethanol has been employed for decades in the treatment of hypotonic and/or postural orthostatic circulatory dysregulations. A study was performed to assess the hemodynamic effects of CCC in the supine position. The dose-effects of this combination on blood pressure (BP), heart rate (HR), and cardiac output, were assessed noninvasively and total peripheral resistance was calculated from these measurements (Herrmann et al. 1996).
In a double-blind, randomized, cross-over design, 10 healthy male volunteers received sequential doses of CCC (20,40, 80, 120 drops), applied in intervals of one hour between each dose step, and equal volumes of placebo (60 Vol% ethanol and caramel as coloring agent), respectively. Hemodynamic effects were measured at 1,2,4, 6, 10,20,40 and 60 mm after each dose step.
Mean changes from baseline (delta values) in arterial mean pressure (Fig. 5) and total peripheral resistance (TPR) (Fig. 6) are depicted. CCC dose-dependently increased blood pressure compared to placebo (ANOVA p <0.001) revealing maximum effect at 4 and 6 min after administration of each dose. Furthermore, an increase in basic arterial mean pressure may be observed over the entire measurement period (ANOVA p < 0.001).
TPR displays a similar overall pattern indicating a pressoric effect of CCC via an increase in arteriolar tone. This reaction can thus provide a plausible hemodynamic explanation for the effects traditionally observed when using CCC in the treatment of hypotonic/orthostatic circulatory dysregulations.
* Dose-Effect of CCC on Blood Pressure under Tilt-Induced Orthostasis in Patients with Postural Orthostatic Hypotension
After these studies had shown a pressoric effect of Dcamphor, the extract from fresh crataegus berries, and the combination of the two compounds, an additional study was performed to investigate the effect of the combination (CCC) on blood pressure under orthostasis in patients suffering from postural hypotension. The details of methodology and results have been published previously in this Journal (Belz et al. 2002). From a basic cohort of 519 patients, 48 were recruited. In a screening procedure on a tilt table (3 mm 80 degrees head-up tilt) they had demonstrated a drop in blood pressure of 20 mmHg systolic and/or 10 mmHg diastolic, thereby fulfilling the consensus definition of orthostatic hypotension (Consensus 1996). Individual falls in systolic blood pressure are shown in Fig. 7 for all the subjects included. The design of the study was randomized and double-blind in a 4-fold cross-over. The CCC combination was given in doses of 5, 20, and 80 drops (ingredients as described in the previous chapter). Pla cebo was 20 drops of a 60 vol% ethanol, with 0.2% menthol and caramel as coloring agent.
CCC drops attenuated the orthostatic fall in blood pressure as compared to placebo in a statistically significant dose-dependent fashion (Figs. 8 and 9). A testing of the dose-dependency of the effects as shown in Fig. 9 for arterial blood pressure using Page's exact trend test revealed significant (p < 0.01) results for systolic, diastolic and mean blood pressure as well (Belz et al. 2002).
Mean arterial pressure revealed a very fast onset of action after 1 mm (Fig. 8). These hemodynamic findings demonstrated a rapid stabilizing effect of CCC on blood pressure under orthostasis and thus corroborate the decades-old medical experience with this phytocombination in the indication of postural orthostatic hypotension. Again in this study, placebo exerted a similar effect on blood pressure compared to baseline as the active combination (Fig. 8). It is therefore concluded that the 20 placebo drops may have a pharmacodynamic efficacy beyond the putative placebo effect. Especially the menthol component (0,2%) which had been added for blinding purposes may be responsible for such an effect. If this had triggered a pharmacologic action in the same direction as CCC, it would easily explain difficulties in separating the verum's effects from those of placebo. On the other hand, if placebo was not completely ineffective, the intensity of the CCC effects were systematically under- (and in no case over-) estima ted. That this is probably the case can be inferred from judging the effects of CCC in figures 5 and 8 not with respect to placebo but to the baselines before administration.
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Gustav G. Belz, Center for Cardiovascular Pharmacology ZeKaPha GmbH, Alwinenstr. 16, D-65 189 Wiesbaden, Germany
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|Author:||Belz, Gustav Georg; Loew, Dieter|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||May 1, 2003|
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