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Floris

Floris, Treatment of Anal Furunculosis  with Long Dan Xie Gan Tang and Si Miao San

Abstract

A dog with severe anal furunculosis (AF) was treated with two Chinese Herbal Medicine formulas: Long Dan Xie Gan Tang and Si Miao San. Conventional treatment with  Cyclosporine is cost-prohibitive for some dog owners, as it was in this case. Chinese Herbal Medicine is shown to be an affordable, safe and effective alternative. Biochemical actions of the individual herbs and the formulas are discussed

Introduction

Anal furunculosis (AF), is a disease characterised by inflammation and ulceration with fistula formation of the perineal tissues. Cyclosporine, an immunosuppressive drug, has been successfully used to treat AF. The effectiveness of cyclosporine in the treatment of AF points towards an immune mediated pathogenesis. Many Chinese herbal formulas have immune modulating and anti-inflammatory properties and this case describes succesfull treatment using Chinese herbs as an alternative to conventional treatment.

Case history

On the 13th October 2010, Floris, a 7 yr old Dutch Shepherd crossbred was presented. Body weight 33 kg. He is a castrated male. He was first presented to his regular vet on the 12th of February 2010 with an open abces in his right anal gland. The lesions were explored under general anaesthesia by the regular vet in March 2010. Despite conventional treatment, this had further developed  into AF in the course of 8 months. Cyclosporine treatment, suggested by the regular vet was declined by the owner. She could not afford cyclosporine treatment. At the time of presentation Floris was in so much discomfort that euthanasia was discussed as an option with the owner, and to be considered if there wasn’t a quick improvement of the condition. His owner is an elderly lady, but Floris gets three one hour walks a day. She feeds him a combination of meat and vegetables. Most of the time this is a commercial mix made according to BARF principles. Dogs on fresh food diets often defecate only once a day, because of the high digestibility of their diet. Defecation is extremely painful for Floris, he sits down trying  to defecate about 8 times every walk and cries out loud before he actually passes faeces. About once a week he is constipated for 2 or 3 days because passing faeces is too painful.

Western examination

His perineal region has an offensive odour and one can smell Floris from meters away. There are multiple fistulae around the anus that are draining a  thin brownish/yellowish malodorous fluid. There is redness, oozing and ulceration of the perineal skin. The lesions are very painful, he constantly licks his perineal region. Floris has had halitosis for years and licking his perineal region does not improve his bad breath. Floris is depressed and in constant pain. He is panting almost continuously. He seems to be feeling very hot, but his body temp has always remained normal at around 38.5°C. He does play anymore with other dogs or the owner, nor does he ask for attention like he used to.

Chinese medical exam and case interpretation

On the first examination the tongue was red, wet and swollen. The femoral pulse was fast, slippery and forceful.  It was hard to properly asses because he was so afraid of anyone coming near his very painful perineal region, he gets very stressed and tries to get away while taking the pulse. He was very hot to the touch, wouldn’t lie down long in one spot but soon gets up and looks for a new cool place to lie down, preferably on the cold floor. He does not tolerate any heat and he does not like warm weather. He has been castrated in the past year because of aggressive behavior towards other male dogs. Aggression is a sign of Liver Yang rising. This may have been caused by Liver Qi stagnation due to constant pain. His halitosis is a Dampness sign. He drinks a lot but had moderate appetite, consistent with Damp-Heat. TCM Diagnosis is Damp Heat in the Liver Channel progressing to Toxic Heat. Damp Heat is characterized by the severe inflammation, Toxic Heat by the ulceration, fistulae and abces formation.

Treatment

He had been treated with Rimadyl (Caprofen 75 mg b.i.d.) and several courses, of up to 6 weeks, of Metronidazole 750 mg b.i.d. and  Amoxycillin 350 mg b.i.d, since February 2010. The Amoxycillin caused diarrhea and loss of appetite 7 days into the course. These side-effects were intermittent and mild throughout the whole 6 weeks course of antibiotics. Amoxycillin and Metronidazole transiently mildly improved his condition, but did not resolve the lesions. Cyclosporine, an immunosuppressive drug, has been used successfully to treat AF. Cyclosporine treatment, suggested by the regular vet, was declined by the owner in this case. She could not afford the cyclosporine treatment. Long term or lifelong medication with cyclosporine is often necessary, since dogs tend to relapse after discontinuing cyclosporine treatment.

For years Floris had been getting dexamethasone injections and tablets from time to time, for an itch that was not further defined and investigated, but suspected to be due to flea infestations. At the time of presentation he was not getting any medication beside Carprofen.

Chinese herbal prescription

Long Dan Xie Gan Tang 1 gram twice daily, this is 60 mg/kg divided in two daily doses. This is a low-normal dose for a dog.

Long Dan Xie Gan Tang belongs to the formulas that Clear Heat and Drain Damp. It treats Damp Heat in the Liver and Gallbladder.

After 3 weeks Si Miao San was added to the prescription at a dose of 1 gram once a day, this is 30 mg/kg s.i.d.. This combination of herbal formulas is used to prevent Long Dan Xie Gan Tang possibly causing diarrhea or loss of appetite. Both formulas have strong anti-inflammatory properties. At the first visit Floris had a marked inflammatory response, allowing the use an aggressive anti-inflammatory formula without adverse effects being likely. While Floris was starting to feel better the risk of adverse effects from long term use of Long Dan Xie Gan Tang increased, since the formula is extremely “cooling” and Floris was getting less “hot”. Combining Long Dan Xie Gan Tang with Si Miao San does not diminish the formula’s strong anti-inflammatory effect but is does make diarrhea and inappetence less likely to occur. Si Miao San has a strong antidiarrheal activity from the herbs in the formula.

He remains on Carprofen  75 mg s.i.d.. for additional pain relief. Liquid Paraffin will be mixed through his food, to soften faecal consistency, without altering gastro-intestinal motility, in order to make defecating less painful for him.

Outcome

Three weeks after starting Long Dan Xie Gan Tang, he became more playful and active and his perineal region less prominently malodorous. Floris seemed to be feeling better and was no longer panting constantly.There was reduction in swelling and redness of the lesions, and discharge from the fistulae seemed slightly less. Defecation was still so painful he would have multiple attempts to pass faeces every walk, and sometimes be constipated for a day. After 6 weeks of Long Dan Xie Gan Tang combined with Si Miao San treatment he defecates at least once a day, at the first attempt. He still cries out while passing faeces. He is showing much more self initiated behavior, wanting to get attention and play.It is obvious to everybody who knows this dog that he is feeling much better, and he does no longer seem to be depressed. After 9 weeks several fistulae can still be seen on visual inspection of the perineal region, but the ulcers are healing and dry. The skin is pink, not red and fistulae are no longer oozing. He displays no coldseeking behavior anymore.

After 3 weeks of herbal treatment the pulse became wiry, slightly rapid and tongue bright pink. On later rechecks the pulse has remained slippery, moderate strength. The tongue is pink. As his condition improves and inflammation subsides he becomes less and less stressed about taking the femoral pulse or visual inspection of the perianal region. Since his anal furunculosis continues to improve, the prescription is not altered, even though his pulse and tongue remain the same and show no further improvement.

Pathogenesis of Anal furunculosis

Research has shown that the cytokine mRNA profile in AF lesions is consistent with T cell mediated inflammation. Cyclosporine inhibits IL-2.  IL-2 mRNA expression was significantly reduced in residual disease tissue, following cyclosporine therapy. The absence of a correlation between T cell cytokine expression and the severity of disease suggests that tissue destruction observed in AF might be a consequence of other inflammatory mediators or downstream effects of T cell activation (Tivers MS, Catchpole B, Gregory SP, House AK, 2008).

Defective pattern-recognition receptors (PRRs) have been implicated in the pathogenesis of AF. Defective PRR function has been implicated in several infectious  and immune-mediated conditions in humans. Comparing PRR responses in blood derived monocytes/macrophages from healthy blood-donor dogs with those from Anal Furunculosis affected German Shepherd dogs, showed a dysfunctional NOD2 response in the latter. This implies dysfunctional macrophage and monocyte responses may be part of the pathogenesis of AF, beside the T cell mediated immune responses mentioned above (House AK, Gregory SP, Catchpole B, 2008).

Discussion on Long Dan Xie Gan Tang

Long Dan Xie Gan Tang, has the following characteristics: gentiana, scutellaria and gardenia clear Heat from the Liver and Heart while drying Damp in the Lower Burner. Bupleurum and scutellaria guide the formula to the Triple Burner and Gallbladder channels, while bupleurum  and angelica prevent Qi and Blood Stasis, either from the intense drying cooling action of the formula, or from the intense Heat of the pathology. Rehmannia cools Blood and protects Yin damaged by Heat and the drying action of the formula. Plantago, alisma and poria drain Damp from the Lower Burner and cool the Upper Burner.

Pharmacologically Long Dan Xie Gan Tang is strong anti-inflammatory and anti-bacterial formula and it also has immune modulating properties. Several of the herbs in Long Dan Xie Gan Tang have demonstrated immune enhancing and immune modulating properties.

Long Dan Xie Gan Tang has anti-bacterial action. Experiments show that Long Dan Xie Gan Tang can inhibit in vitro micrococci and the following bacteria: Staphylococci aureus, Staphylococci epidermidis, E. coli, Proteus vulgaris and Shigella flexneri (Gao Ling Ling et al,1998).

Long Dan Xie Gan Tang has anti-inflammatory action. At dosages of 2.5g/kg, 5g/kg, and 10g/kg, Long Dan Xie Gan Tang can inhibit increases in capillary permeability in mice and egg albumin-induced edema in rats (Tan Yu Zhi et al, 1991).

Long Dan Xie Gan Tang can inhibit passive skin allergic reaction in rats. The formula is also effective in protecting guinea pigs from death due to anaphylactic shock  (Tan Yu Zhi et al,1991).

Long Dan Xie Gan Tang has immune enhancing properties. Administered to young mice by intraperitoneal injection at the daily dosage of 50g/kg for six consecutive days, Long Dan Xie Gan Tang is shown to increase the weight of the subjects’ thymus gland. The formula is also shown to increase macrophages’ phagocytic capacity, raising both the phagocytic rate and index, and promote lymphocyte transformation (Wu He SuaN  et al, 1984).Furthermore, experiments show that the formula has a dose-dependent inhibitory effect on induced intra-macrophage formation of NO (Feng Yi Yin et al, 2000).

The pharmacological actions of the individual herbs in Long Dan Xie Gan Tang are as follows

Radix et Rhizoma Gentiana– Long Dan Cao has anti-inflammatory action at an oral dose of 10-100 mg/kg, due to suppression of IL-6 and TNF-α (Wie-Jong Kwak et al, 2005). The plants of this genus have broad bioactivities such as anti-fungal and anti-inflammatory activity as well as a liver protective effect (Wang C, Wang Z, Wang W, Peng X, 2009)

Radix Scutellariae – Huang Qin contains the flavone Baicalein. This was found to regulate molecular mediators and immune cells that are functionally associated with atopic dermatitis in mice. Atopic dermatitis is what cyclosporine is most commonly prescribed for in dogs (Yun MY et al, 2010). Baicalin inhibits the expression of genes encoding inflammatory molecules induced by IL-17 exposure. IL-17 is a potent inflammatory cytokine and mediates leukocyte infiltration and tissue destruction. It is produced by Th 17 cells. Th 17 cells are  CD4+IL17+T-cells. Baicalin decreases the expression of pro-inflammatory cytokine IL-6, thus reducing Th 17 numbers. Other IL-17 related mediators, like IL-22, IL-1, TNF-α are also inhibited by baicalin, thus potentially reducing the recruitment of Th1, Th2 or other effector cells in vivo (Yang J, Yang X, Chu Y, Li M, 2011).

Fructus Gardeniae – Zhi Zi. Glycoprotein 27 kDa has shown to inhibit the expression of the inflammation-related cytokines TNF-α and IL-6 in cadmium chloride-exposed mice (Lee J, Lim KT, 2011). Crocin, a carotenoid isolated from Gardenia, has dual inhibitory effect against the COX-1 and COX-2 enzymes and to inhibit prostaglandin E(2) production. It has shown to decrease swelling of xylene-induced ear edema in mice and carrageenan-induces paw edema in rats (Xu GL et al, 2009). Gardenia also showed significant dose-dependent reduction of symptoms in cerulin induced pancreatitis in mice, by decreasing the levels of TNF- α and IL-1β. In this study a trend was shown towards suppression of IL-6 but the difference was not significant (Won-Seok Jung et al, 2008).

Radix Angelicae Sinensis – Dang Gui has immune modulating abilities, protecting mice from lethal experimental sepsis via inhibition of the novel inflammatory cytokine High Mobility Group Box 1 protein (HMGB1) (Alleva LM, Cai C, Clark IA, 2009). It contains polyynes that have antibacterial activities, in this study these were demonstrated against Mycobacterium tuberculosis (Shixin Deng et al, 2009).

Radix Rehmanniae –Di Huang was shown to inhibit TNF-α secretion by inhibiting IL-1 secretion in Lipopolysaccharide stimulated asterocytes (Kim et al, 1999). Topical application of Rehmannia in allergen induced atopic dermatitis in mice reduced the expression of cytokines IL-4 and TNF-α, chemokines and adhesion molecules, thus significantly reducing the development of atopic lesions (Sung YY et al, 2011).

Radix Bupleuri – Chai Hu Administration of bupleurum  to mice enhanced phagocytic functions of macrophages, and inhibited lipopolysacharride-induced production of nitrous oxide (NO) and pro-inflammatory cytokines IL-1β, IL-6 and TNF- α. These data suggested that, at least part of the traditional beneficial effects of bupleurum on inflammatory diseases, could be ascribed to the immunomodulatory effects of bupleurum polysaccharides on macrophages (Cheng XQ et al, 2010).

Semen Plantaginis – Che Qian Chi exerts a considerable anti-inflammatory effect, significantly reducing carrageenan induced paw edema in rats. The author suggest this could be through inhbition of  COX-2. As known COX-2 is the major source of prostanoids formed in inflammation. It also was found to be a anti-oxidant thus having hepatoprotective activity in CCl4 induced liver toxicity (Idris Türel et al, 2009). In contrast, Vigo E et al found that Plantago Lanceolata exerts anti-inflammatory action by decreasing Nitrous Oxide(NO) production, possibly due to inhibitory effects on inducible NO-synthase (iNOS) gene expression or due to NO-scavenging activity. These researchers found no modification of COX-2 mRNA expression or Prostaglandin E levels in LPS/TNF-α stimulated murine macrophages, pretreated with Plantago extracts (Vigo E, Cepeda A, Gualillo O, Perez-Fernandez R, 2005). According to Chen and Chen, 2004, p. 392 all Plantago species have similar activities and can be used interchangeably.

Rhizoma Alismatis – Ze Xie contains Alisol A 24 acetate, 13beta,17beta-epoxy alisol A and Alisol B 23 –acetate which are all protostan type triterpenoids having immunosuppressive actions on mouse lymphocytes (Zhang C, Zhou A,  Zhang M, 2009)

Poria cocos– Fu Ling inhibits  phospholipase A(2), 5-lipoxygenase and elastase. Pachymic and Dehydrotumolosic acids were shown to inhibit leukotriene B(4) release. These result indicate that Poria cocos could be potentially valuable in the management of skin pathologies involving chronic inflammation (Prieto JM et al, 2003). Polysaccharides in Poria enhance the secretion of both immune stimulators and suppress the secretion of immune suppressors thus potentiating the immune response. The triterpenes have inhibitory effect on phospholipase A, while triterpenoids have immune modulating activity demonstated in immune mediated disease like psoriasis, rheumatoid arthritis and auto-immune uveitis (Rios JL, 2011)

Radix et Rhizoma Glyccirhizae – Gan Cao has anti-inflammatory action through inhibition of both 5-lipoxygenase and COX-2 activity (Herold A et al, 2003)

Discussion on Si Miao San

From a TCM perspective Si Miao San belongs to the formulas that Drain Damp and Clear Heat. Si Miao San consists of Cang zhu which tonifies the Spleen and drains Damp, Huang bai clears Heat and dries Damp, Yi yi ren drains Damp and supports the Spleen while Huai niu xi moves blood and astringes.

From a Western point of view  Si Miao San has strong anti-inflammatory properties.

Modified Si Miao San, with Codonopsis Pilosi substituted for Achrysanthis, in order to increase anti-inflammatory effect, suppressed IKKβ activation and down-regulated TNF-α and IL-6 gene over-expression, demonstrating its anti-inflammatory activity in hepatocytes (Liu K et al, 2011).

Modified Si Miao San, with Codonopsis Pilosi substituted for Achrysanthis, significantly inhibits the excessive production of Nitrous Oxide, TNF-α and IL-6 and the over expression of relative genes in lipopolysacharride-stimulated macrophages, thus exhibiting an anti-inflammatory effect (Fan J et al, 2010)

 

The pharmacological actions of the individual herbs in Si Miao San are as follows

Cortex Phellodendri – Huang Bai  contains berberine which effectively inhibited IL-6 and TNF- α production in hepatocytes in a concentration dependent manner, thus demonstrating an anti-inflammatory effect (Lou T et al, 2010). The methanol extract of Phellodendron decreased the infiltration and release of inflammatory mediator in Lipopolysaccharide (LPS) induced acute airway inflammation in mice (Mao YF et al, 2010). It was also found to attenuate LPS-stimulated increase in production of TNF-α, IL-1β and NO in a mouse microglia cell line (Park YK et al, 2007). Berberine was found to inhibit LPS induced induced Nitrous Oxide Synthase (iNOS) gene expression thus reducing the production of NO. Both Berberine and Baicalin were found not to not affect expression of COX-2 genes (Kim KW et al, 2007). In contrast, Kuo CL et at, found that berberine inhibits an anti-inflammatory effect by reducing the production of Prostaglandin E2 (PGE2) in a dose-dependent way. They found berberine does reduce COX-2 protein but does not reduce enzyme activity (Kuo CL, Chi CW, Liu TY, 2004). The

Rhizoma Atractylodis lancea et chinensis – Cang Zhu contains Atractylenolide I (AO-I) was was able to inhibit LPS-induction in macrophages of TNF-α, IL-1β and NO production in a dose-dependent manner (Wang C, He L, Wang N, Liu F, 2009). Atractenolide III (AO-III) inhibits the secretion and expression of IL-6 and release of histamine in stimulated human mast cells. Thus it could control immunological reactions by regulating cellular functions of IL-6 in mast cells (Kang TH, Han NR, Kim HM, Jeong HJ, 2011). Atractylodes Japonica was found the have antibacterial activity against Methicillin resistent Staphylococcus areus (Jeong SI et al, 2010)

Coix lacryma-jobi – Yi Yi Ren exerts an anti-inflammatory effect by downregulation of the expression of iNOS and COX-2 proteins in LPS stimulated macrophages. It also has anti-oxidative properties through free radical scavenging. It are the phenolic components that are particularly related to these activities (Huang DW et al, 2009). The methanolic extract of Coix inhibits COX-2, but not COX-1, expression. It reduces PGE(2) levels in serum of mice (Huang WX, Chang HC, 2003). The crude coix hull acetone extract was found to directly act upon the Zona Fasciculata-Reticularis of the adrenal cortex to diminish corticosterone release, by inhibiting corticosterone synthesis enzymes (Chang LL et al, 2006)

Radix Achrysanthis Bidentata – Huai Niu Xi Chen and Chen, 2004, p.651 cites research published in Chinese showing Achrysanthis has marked analgesic and anti-inflammatory effects in laboratory animals. No English extract could be found on this article.

Conclusion

Due to the high cost of cyclosporine in dogs, suffering from AF, some owners will decline  treatment. Chinese Herbal Medicine offers alternatives that are in comparison less expensive, have fewer side effects and may be just as effective or more effective in treatment of anal furunculosis. Further investigation into the pharmacological actions, of both Long Dan Xie GanTang and Si Miao San, would be interesting since these herbal formula has not been subject to much research yet. Scutellaria and phellodendron have well documented anti- inflammatory actions but many of the other herbs in both Si Miao San and Long Dan Xie Gan Tang need further research, in order to determine their pharmacological actions on the immune system. Despite Long Dan Xie Gan Tang having a reputation for causing GI side-effects these did not occur in this case, possibly due to combining the formula with Si Miao San. Despite yi yi ren having a reputation for use in acne in humans no research was found on this subject. Since both acne and furunculosis both are deep bacterial skin infections, further investigation on the pharmacological properties of coix would be interesting since this is relatively mild herb that is well tolerated long term by most patients.

 

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Interpretation of signs and symptoms  according to traditional Chinese medicine (TCM) principles

Signs and Symptoms TCM interpretation
Anal fistulae and anal furunculosis Damp Heat and Toxic Heat
Ulceration/tissue destruction Toxic Heat
Aggression Liver Yang Rising
Feeling hot to the touch, preference for cool surfaces, panting a lot Damp Heat
Increased thirst and moderate appetite Damp Heat
Halithosis Dampness, Damp Heat, Stomach Fire
Reddish pink tongueSwollen tongue Damp HeatDampness and/or Qi stagnation
Slippery pulseForceful pulse

Fast pulse

Dampness, Damp HeatExcess pattern

Damp Heat, Toxic Heat, Fire

Painful lesions Localised Qi and Blood Stasis
Diarrhea from antibiotics Spleen Qi deficiency
Depression Liver Qi stagnation
Corticosteroid injections Yin Tonic, tendency to further increase Dampness
Perineal area Belongs to Liver/Gallbladder channels
Bright pink tongue Mild Heat
Wiry pulse Qi stagnation

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