Therapeutic Efficacy of a Mixed Formulation of Conventional and PEGylated Liposomes Containing Meglumine Antimoniate, Combined with Allopurinol, in Dogs Naturally Infected with Leishmania infantum

ABSTRACT The treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote a marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP plus Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg of body weight/dose) at 4-day intervals plus allopurinol at 30 mg/kg/12 h per os (p.o.) during 130 days (LCP+Allop); LC plus Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) plus allopurinol during 130 days (LC+Allop); Allop, treated with allopurinol only; and a nontreated control. Parasite loads were evaluated by quantitative PCR in liver, spleen, and bone marrow tissue and by immunohistochemistry in the ear skin, before treatment, just after treatment, and 4 months later. The LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen, and bone marrow 4 months after treatment compared to the pretreatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin in comparison to the control group. On the basis of clinical staging and parasitological evaluations, the LCP formulation exhibited a more favorable therapeutic profile than the LC one, being therefore promising for the treatment of canine visceral leishmaniasis.

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Mixed Formulation of Conventional and Pegylated Meglumine Antimoniate-Containing Liposomes Reduces Inflammatory Process and Parasite Burden in Leishmania infantum-Infected BALB/c Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00962-17 ◽

2017 ◽

Vol 61 (11) ◽

Cited By ~ 10

Author(s):

Levi Eduardo Soares Reis ◽

Rory Cristiane Fortes de Brito ◽

Jamille Mirelle de Oliveira Cardoso ◽

Fernando Augusto Siqueira Mathias ◽

Rodrigo Dian Oliveira Aguiar Soares ◽

...

Keyword(s):

T Cells ◽

Leishmania Infantum ◽

Inflammatory Process ◽

Parasite Burden ◽

T Cell Subsets ◽

Content Type ◽

Meglumine Antimoniate ◽

First Choice ◽

Ifn Γ

ABSTRACT Pentavalent antimonial has been the first choice treatment for visceral leishmaniasis; however, it has several side effects that leads to low adherence to treatment. Liposome-encapsulated meglumine antimoniate (MA) arises as an important strategy for chemotherapy enhancement. We evaluated the immunopathological changes using the mixture of conventional and pegylated liposomes with MA. The mice were infected with Leishmania infantum and a single-dose treatment regimen. Comparison was made with groups treated with saline, empty liposomes, free MA, and a liposomal formulation of MA (Lipo MA). Histopathological analyses demonstrated that animals treated with Lipo MA showed a significant decrease in the inflammatory process and the absence of granulomas. The in vitro stimulation of splenocytes showed a significant increase of gamma interferon (IFN-γ) produced by CD8+ T cells and a decrease in interleukin-10 (IL-10) produced by CD4+ and CD8+ T cells in the Lipo MA. Furthermore, the Lipo MA group showed an increase in the IFN-γ/IL-10 ratio in both CD4+ and CD8+ T cell subsets. According to the parasite load evaluation using quantitative PCR, the Lipo MA group showed no L. infantum DNA in the spleen (0.0%) and 41.4% in the liver. In addition, we detected a low positive correlation between parasitism and histopathology findings (inflammatory process and granuloma formation). Thus, our results confirmed that Lipo MA is a promising antileishmanial formulation able to reduce the inflammatory response and induce a type 1 immune response, accompanied by a significant reduction of the parasite burden into hepatic and splenic compartments in treated animals.

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Neutrophils, eosinophils, and mast cells in the intestinal wall of dogs naturally infected with Leishmania infantum

Revista Brasileira de Parasitologia Veterinária ◽

10.1590/s1984-296120180085 ◽

2018 ◽

Vol 27 (4) ◽

pp. 430-438 ◽

Cited By ~ 1

Author(s):

Diogo Tiago da Silva ◽

Maria Luana Alves ◽

Júlio Cesar Pereira Spada ◽

Rita de Cássia Viveiros da Silveira ◽

Trícia Maria Ferreira de Sousa Oliveira ◽

...

Keyword(s):

Mast Cells ◽

Visceral Leishmaniasis ◽

Leishmania Infantum ◽

Parasite Burden ◽

Inverse Correlation ◽

Muscle Layer ◽

Intestinal Wall ◽

Control Group ◽

Cell Hyperplasia ◽

Cell Counts

Abstract Visceral leishmaniasis (VL) is a disease caused by the protozoa Leishmania infantum and can cause an inflammatory reaction in the gastrointestinal tract, however the role of granulocytic cells (neutrophils, eosinophils, and mast cells) in the intestine of dogs infected is not fully understood. We performed a quantitative analysis these cells in the intestinal wall of dogs with canine visceral leishmaniasis (CVL). Twenty dogs were assigned to one of three groups: group 1 (G1, n=8), dogs with CVL and L. infantum amastigotes in the intestine; group 2 (G2, n=9), dogs with CVL but without intestinal amastigotes; and group 3 (G3, n=3), uninfected dogs (control group). Granulocytic cells were counted in the crypt-villus unit (mucosa), submucosa, and muscle layer of the intestinal mucosa. Cell counts were higher in the intestinal wall of dogs from G2 followed by G1 and G3 (p≤0.05). In G1, there was a low inverse correlation between parasite burden of the small intestine and granulocyte counts (r= -0.1, p≤0.01). However, in G2 dogs, mast cell and eosinophil numbers showed positive correlation (r=0.85, p≤0.01). The granulocytic cell hyperplasia observed in the intestine of L. infantum-infected dogs suggests that these cells may be involved in the cell-mediated immune response for parasite elimination.

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Licochalcone a Exhibits Leishmanicidal Activity in vitro and in Experimental Model of Leishmania (Leishmania) Infantum

Frontiers in Veterinary Science ◽

10.3389/fvets.2020.00527 ◽

2020 ◽

Vol 7 ◽

Author(s):

Julia M. Souza ◽

Érica A. A. de Carvalho ◽

Ana Carolina B. B. Candido ◽

Rafael P. de Mendonça ◽

Maria Fernanda da Silva ◽

...

Keyword(s):

Experimental Model ◽

Leishmania Infantum ◽

Parasite Burden ◽

Negative Control Group ◽

Negative Control ◽

Control Group ◽

Licochalcone A ◽

Leishmanicidal Activity ◽

Visceral Leishmaniosis

The efficacy of Licochalcone A (LicoA) and its two analogs were reported against Leishmania (Leishmania) amazonensis and Leishmania (Leishmania) infantum in vitro, and in experimental model of L. (L.) infantum in vitro. Initially, LicoA and its analogs were screened against promastigote forms of L. (L.) amazonensis. LicoA was the most active compound, with IC50 values of 20.26 and 3.88 μM at 24 and 48 h, respectively. Against amastigote forms, the IC50 value of LicoA was 36.84 μM at 48 h. In the next step, the effectivity of LicoA was evaluated in vitro against promastigote and amastigote forms of L. (L.) infantum. Results demonstrated that LicoA exhibited leishmanicidal activity in vitro against promastigote forms with IC50 values of 41.10 and 12.47 μM at 24 and 48 h, respectively; against amastigote forms the IC50 value was 29.58 μM at 48 h. Assessment of cytotoxicity demonstrated that LicoA exhibited moderate mammalian cytotoxicity against peritoneal murine macrophages; the CC50 value was 123.21 μM at 48 h and showed about 30% of hemolytic activity at concentration of 400 μM. L. (L.) infantum-infected hamsters and treated with LicoA at 50 mg/kg for eight consecutive days was able to significantly reduce the parasite burden in both liver and spleen in 43.67 and 39.81%, respectively, when compared with negative control group. These findings suggest that chalcone-type flavonoids can be a promising class of natural products to be considered in the search of new, safe, and effective compounds capable to treat canine visceral leishmaniosis (CVL).

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Efficacy of Combined Therapy with Liposome-Encapsulated Meglumine Antimoniate and Allopurinol in Treatment of Canine Visceral Leishmaniasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00208-12 ◽

2012 ◽

Vol 56 (6) ◽

pp. 2858-2867 ◽

Cited By ~ 35

Author(s):

Sydnei M. da Silva ◽

Izabela F. G. Amorim ◽

Raul R. Ribeiro ◽

Erly G. Azevedo ◽

Cynthia Demicheli ◽

...

Keyword(s):

Bone Marrow ◽

Visceral Leishmaniasis ◽

Drug Combination ◽

Combined Therapy ◽

Combined Treatment ◽

Parasite Load ◽

The Other ◽

Sand Flies ◽

Content Type ◽

Meglumine Antimoniate

ABSTRACTAn innovative liposomal formulation of meglumine antimoniate (LMA) was recently reported to promote both long-term parasite suppression and reduction of infectivity to sand flies in dogs with visceral leishmaniasis. However, 5 months after treatment, parasites were still found in the bone marrow of all treated dogs. In order to improve treatment with LMA, the present study aimed to evaluate its efficacy in combination with allopurinol. Mongrel dogs naturally infected withLeishmania infantumwere treated with six doses of LMA (6.5 mg Sb/kg of body weight/dose) given at 4-day intervals, plus allopurinol (20 mg/kg/24 hper os) for 140 days. Comparison was made with groups treated with LMA, allopurinol, empty liposomes plus allopurinol, empty liposomes, and saline. Dogs remained without treatment from day 140 to 200 after the start of treatment. The drug combination promoted both clinical improvement of dogs and significant reduction in the parasitic load in bone marrow and spleen on days 140 and 200 compared to these parameters in the pretreatment period. This is in contrast with the other protocols, which did not result in significant reduction of the bone marrow parasite load on day 200. Strikingly, the combined treatment, in contrast to the other regimens, induced negative quantitative PCR (qPCR) results in the liver of 100% of the dogs. Both xenodiagnosis and skin parasite determination by qPCR indicated that the drug combination was effective in blocking the transmission of skin parasites to sand flies. Based on all of the parasitological tests performed on day 200, 50% of the animals that received the combined treatment were considered cured.

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Hepatotoxicity of Pentavalent Antimonial Drug: Possible Role of Residual Sb(III) and Protective Effect of Ascorbic Acid

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01499-13 ◽

2013 ◽

Vol 58 (1) ◽

pp. 481-488 ◽

Cited By ~ 27

Author(s):

Kelly C. Kato ◽

Eliane Morais-Teixeira ◽

Priscila G. Reis ◽

Neila M. Silva-Barcellos ◽

Pascal Salaün ◽

...

Keyword(s):

Ascorbic Acid ◽

Side Effects ◽

Protective Effect ◽

Peroxidase Activity ◽

Hepatic Uptake ◽

Control Group ◽

Content Type ◽

Meglumine Antimoniate ◽

Effective Strategies

ABSTRACTPentavalent antimonial drugs such as meglumine antimoniate (Glucantime [Glu; Sanofi-Aventis, São Paulo, Brazil]) produce severe side effects, including cardiotoxicity and hepatotoxicity, during the treatment of leishmaniasis. We evaluated the role of residual Sb(III) in the hepatotoxicity of meglumine antimoniate, as well as the protective effect of the antioxidant ascorbic acid (AA) during antimonial chemotherapy in a murine model of visceral leishmaniasis. BALB/c mice infected withLeishmania infantumwere treated intraperitoneally at 80 mg of Sb/kg/day with commercial meglumine antimoniate (Glu) or a synthetic meglumine antimoniate with lower Sb(III) level (MA), in association or not with AA (15 mg/kg/day), for a 20-day period. Control groups received saline or saline plus AA. Livers were evaluated for hepatocytes histological alterations, peroxidase activity, and apoptosis. Increased proportions of swollen and apoptotic hepatocytes were observed in animals treated with Glu compared to animals treated with saline or MA. The peroxidase activity was also enhanced in the liver of animals that received Glu. Cotreatment with AA reduced the extent of histological changes, the apoptotic index, and the peroxidase activity to levels corresponding to the control group. Moreover, the association with AA did not affect the hepatic uptake of Sb and the ability of Glu to reduce the liver and spleen parasite loads in infected mice. In conclusion, our data supports the use of pentavalent antimonials with low residue of Sb(III) and the association of pentavalent antimonials with AA, as effective strategies to reduce side effects in antimonial therapy.

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T lymphocytes and macrophages in the intestinal tissues of dogs infected with Leishmania infantum

Revista Brasileira de Parasitologia Veterinária ◽

10.1590/s1984-29612017039 ◽

2017 ◽

Vol 26 (2) ◽

pp. 159-170 ◽

Cited By ~ 2

Author(s):

Diogo Tiago da Silva ◽

Maria Luana Alves ◽

Júlio Cesar Pereira Spada ◽

Aline Cristine da Silva ◽

Rita de Cássia Viveiros da Silveira ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Cd8 T Cells ◽

Leishmania Infantum ◽

Parasite Burden ◽

Treg Cells ◽

Control Group ◽

Significant Difference ◽

Group 2 ◽

High Parasite

Abstract This study was about a semi-quantitative analysis of T lymphocytes (CD4+ and CD8+, FoxP3+ regulatory T cells), and macrophages in the gut wall of dogs naturally infected with Leishmania infantum. Thirteen dogs were divided into three groups: group 1 (G1, n=5), dogs with canine visceral leishmaniasis (CVL) and infected with L. infantum amastigotes in the intestine; group 2 (G2, n=5), dogs with CVL but without intestinal amastigotes; and group 3 (G3, n=3), uninfected dogs (control group). There was no significant difference (p ≥ 0.05) on CD4+ and Treg cell numbers among the groups, whereas the levels of CD8+ T cells and macrophages were significantly higher in dogs from G1 group than in G2 and G3 (p ≤ 0.05), especially in intestinal segments with high parasite burden. Parasite burden correlated positively with levels of CD8+ T cells and macrophages (p ≤ 0.05), but was inversely correlated to levels of CD4+ T lymphocytes and FoxP3+ Treg cells. In conclusion, in the intestine of dogs with CVL, the increase of CD8+ T cells and macrophages population associated with high parasite burdens, but no changes of CD4+ T cells and FoxP3+ Treg cells suggest a possible immunoregulation by the parasite not dependent on Treg cells.

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Effects on the murine mononuclear phagocyte system of chronic administration of liposomes containing cytotoxic drug or lipid A compared with empty liposomes

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y87-035 ◽

1987 ◽

Vol 65 (2) ◽

pp. 185-190 ◽

Cited By ~ 16

Author(s):

T. M. Allen ◽

L. Murray ◽

Carl R. Alving ◽

James Moe

Keyword(s):

Lipid A ◽

Chronic Administration ◽

Mononuclear Phagocyte ◽

Mononuclear Phagocyte System ◽

Phagocytic Index ◽

Control Group ◽

Large Individual ◽

Particulate Carbon ◽

Liver Uptake ◽

Meglumine Antimoniate

In experiments designed to examine the adverse effects of chronic liposome administration in vivo on the mononuclear phagocyte system (reticuloendothelial system), the presence of drug entrapped in the liposomes may increase the level of reticuloendothelial impairment. We have compared the effects on the mononuclear phagocyte system in mice of chronic administration of empty liposomes with the effects of liposomes containing the anti-leishmanial drug meglumine antimoniate. We have also examined the effect on the mononuclear phagocyte system of continued injections of liposomes containing lipid A, a component of bacterial lipopolysaccharide, which is responsible for macrophage activation. Ten intravenous injections of multilamellar liposomes composed of dipalmitoylphosphatidylcholine and cholesterol (1:0.75 M ratio) were given to ICR mice over a 25-day period. Two individual groups of mice received endotoxin-free liposomes in which meglumine antimoniate was either present or absent. One addition group received liposomes containing lipid A derived from Escherichia coli lipopolysaccharide. A control group received sterile saline injections. In each group, a depression of the phagocytic index, as measured by reduction of uptake of particulate carbon, was observed among some of the individual animals 24 h after the first injection. In many mice a marked splenomegaly was observed. A depressed phagocytic index and splenomegaly were most marked for mice receiving lipid A liposomes. However, there was a large individual variability among mice receiving these preparations and some mice in each group had normal spleen size and a nearly normal phagocytic index. Tissue distribution of liposomes containing [14C]dipalmitoylphosphatidylcholine as a phospholipid marker was examined in all groups in mice 24 h after the last injection. Mice receiving liposomes with entrapped meglumine antimoniate showed decreased liver and increased spleen uptake of radiolabel as compared with controls. This has previously been suggested to be an indication of reticuloendothelial blockade. Mice receiving liposomes without meglumine antimoniate had tissue distributions of liposomes similar to control mice, and mice receiving liposomes containing lipid A had greatly decreased spleen uptake and increased liver uptake of liposomes as compared with control mice and mice receiving endotoxin-free liposomes (an indication of reticuloendothelial stimulation), suggesting that liposomes are being treated differently from particulate carbon in the presence of lipid A.

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Potential of Artesunate in the treatment of visceral leishmaniasis in dogs naturally infected by Leishmania infantum: Efficacy evidence from a randomized field trial

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0008947 ◽

2020 ◽

Vol 14 (12) ◽

pp. e0008947

Author(s):

Hacène Medkour ◽

Idir Bitam ◽

Younes Laidoudi ◽

Ismail Lafri ◽

Abdelaziz Lounas ◽

...

Keyword(s):

Field Trial ◽

Leishmania Infantum ◽

Test Group ◽

Public Health Problem ◽

Control Group ◽

Neglected Diseases ◽

Meglumine Antimoniate ◽

Antibody Titers ◽

Antibody Levels

Leishmaniasis is among the world’s most neglected diseases. Dogs are the main reservoirs/hosts of Leishmania infantum, causative agent of both canine and human visceral leishmaniosis. Canine leishmaniasis (CanL) represents a public health problem as one of the most prevalent zoonotic diseases worldwide. Current therapeutics present drawbacks; thus, there is a need for more effective, safer, and cheaper drugs. The aim of this study was to evaluate and to compare the efficacy of oral administration of artesunate or meglumine antimoniate/allopurinol in dogs with clinical leishmaniasis. Forty-two dogs with naturally occurring clinical leishmaniasis were included in this open-label, simple randomized positive-control clinical field trial with 6 months of follow-up. Dogs received meglumine antimoniate 100 mg/kg/day and allopurinol 30 mg/kg/day for 28 days (control group, n = 26) or artesunate 25 mg/kg/day for 6 days (test group, n = 16). The animals were evaluated for their clinical evolution, parasite load (by qPCR) and humoral response at different time points: 0, 30, 90, and 180 days after treatment. Data analyses showed a significant improvement in both groups in clinical scores, parasitemia and antibody titers after treatment. Compared to the control group, the artesunate group showed significantly lower clinical score (P = 0.0001), lower parasitemia (P = 0.0001) and antibody titers after 6 months of follow-up. Compared to baseline values, a rapid, significant reduction (P < 0.012) in antibody levels, 2.28- versus 3.04-fold for the control versus artesunate groups, respectively, was observed 30 days after treatment. Antibody levels continued to decrease further in the artesunate group, where 58% of cases became seronegative at the 6-month follow-up. All qPCR-positive dogs were negative after treatment with artesunate, while 14.3% remained positive with the appearance of two new cases in the control group. Artesunate was well tolerated, and no side effects were recorded. Treatment failures were similar in both groups with 27.27% (6/22), including 18.18% (4/22) mortality in the control group, versus 26.66% (4/15), including 13.33% (2/15) mortality in the artesunate group. This is the first report showing the potential of artesunate in the treatment of dogs with clinical leishmaniasis. Artesunate showed higher efficacy than the current first-line treatment for CanL without any adverse effects. It could be a good alternative chemotherapy for CanL, and may be considered for further studies in human leishmaniases. Further clinical trials are needed to confirm these findings, to determine if there are relapses after treatment and if dogs remain infective to sandflies, to define the ideal therapeutic dosage and duration of treatment with artesunate.

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Modulation effects of hexamethylene bisacetamide on growth and differentiation of cultured human malignant glioma cells

Journal of Neurosurgery ◽

10.3171/jns.1996.84.5.0831 ◽

1996 ◽

Vol 84 (5) ◽

pp. 831-838 ◽

Cited By ~ 13

Author(s):

Xiao-Nan Li ◽

Zi-Wei Du ◽

Qiang Huang

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Malignant Glioma ◽

Culture Media ◽

Morphological Changes ◽

Control Group ◽

Cell Cycle Distribution ◽

Content Type ◽

Hexamethylene Bisacetamide ◽

Human Malignant Glioma

✓ The modulation effects of hexamethylene bisacetamide (HMBA), a differentiation-inducing agent, on growth and differentiation of cells from human malignant glioma cell line SHG-44 were studied. At cytostatic doses (2.5 mM, 5 mM, 7.5 mM, and 10 mM for 15 days), HMBA exerted a marked inhibitory effect on cell proliferation. Exposure to HMBA (5 mM and 10 mM for 12 days) also resulted in an accumulation of cells in G0/G1 phase and a decrease of cells in S phase as analyzed by flow cytometry. The reversible effects of 7.5 mM HMBA and 10 mM HMBA on cell proliferation and 10 mM HMBA on disruption of cell cycle distribution were observed when HMBA was removed from culture media on Day 6 and replaced with HMBA-free media. Colony-forming efficiency (CFE) in soft agar was remarkably decreased by HMBA (2.5 mM, 5 mM, 7.5 mM, and 10 mM for 14 days), and in 7.5 mM HMBA— and 10 mM HMBA—treated cells, the CFEs were reduced to 25% and 12.5%, respectively, of that in untreated cells. Cells treated with HMBA (5 mM and 10 mM for 15 days) remained tumorigenic in athymic nude mice, but the growth rates of the xenografts were much slower than those in the control group. The effects of HMBA on cell proliferation, cell cycle distribution, CFE, and growth of xenografts were dose dependent. A more mature phenotype was confirmed by the morphological changes from spindle shape to large polygonal stellate shape and remarkably elevated expression of glial fibrillary acidic protein in cells exposed to HMBA (5 mM, 10 mM for 15 days). Our results showed that a more differentiated phenotype with marked growth arrest was induced in SHG-44 cells by HMBA.

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Evaluation of genotoxicity of pan masala employing chromosomal aberration and micronucleus assay in bone marrow cells of the mice

Toxicology and Industrial Health ◽

10.1177/0748233709345939 ◽

2009 ◽

Vol 25 (7) ◽

pp. 467-471 ◽

Cited By ~ 7

Author(s):

BN Mojidra ◽

K. Archana ◽

AK Gautam ◽

Y. Verma ◽

BC Lakkad ◽

...

Keyword(s):

Bone Marrow ◽

Chromosome Aberration ◽

Chromosomal Aberration ◽

Bone Marrow Cells ◽

Micronucleus Assay ◽

Control Group ◽

Genotoxic Potential ◽

Polychromatic Erythrocytes ◽

Significant Difference ◽

Marrow Cells

Pan masala is commonly consumed in south-east Asian and other oriental countries as an alternate of tobacco chewing and smoking. Genotoxic potential of pan masala (pan masala plain and pan masala with tobacco known as gutkha) was evaluated employing chromosome aberration (CA) and micronucleus (MN) assay in vivo. Animals were exposed to three different doses (0.5%, 1.5% and 3%) of pan masala plain (PMP) and gutkha (PMT) through feed for a period of 6 months and micronucleus and chromosomal aberrations were studied in the bone marrow cells. Induction of mean micronuclei in polychromatic erythrocytes (MNPCE) and normochromatic erythrocyte (MNNCE) was higher in both types of pan masala treated groups with respect to control group. Both pan masala plain and gutkha treatment significantly induced the frequency of MNPCE and MNNCE in the bone marrow cells, indicating the genotoxic potential. Furthermore, slight decline in the ratio of polychromatic erythrocytes to normochromatic erythrocytes was also noticed, suggesting the cytotoxic potential even though the ratio was statistically non significant. A dose-dependent, significant increase in chromosome aberration was observed in both types of pan masala treated mice with respect to control. However, no significant difference in micronucleus and chromosomal aberration induction was noticed between two types of pan masala exposed (PMP and PMT) groups. Results suggest that both types of pan masala, i.e. plain and gutkha, have genotoxic potential.

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