scholarly journals Lymphatic Targeting of Anti-Human Immunodeficiency Virus Nucleosides: Pharmacokinetics of G′-Deoxy-2′,3′-Didehydrothymidine after Intravenous and Oral Administration of Dipalmitoylphosphatidyl Prodrug to Mice

1997 ◽  
Vol 8 (5) ◽  
pp. 409-415 ◽  
Author(s):  
KK Manouilov ◽  
Z-S Xu ◽  
LS Manouilova ◽  
FD Boudinot ◽  
RF Schinazi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Lymph Nodes ◽  
Extended Release ◽  
Lymphatic System ◽  
Parent Compound ◽  
Equimolar Dose ◽  
Lipophilic Prodrug ◽  
Immunodeficiency Virus ◽  
Intravenous And Oral Administration ◽  
Therapy Strategies

The lymphatic system is a primary target for early anti-human immunodeficiency virus drug therapy. Strategies are currently being sought to enhance the delivery of nucleoside analogues such as 3′-deoxy-2′,3′-didehydrothymidine (stavudine; d4T) toward the lymph and lymph nodes. The purpose of this study was to synthesize dipalmitoylphosphatidyl-d4T (DPP-d4T) as a lipophilic prodrug of d4T and to evaluate the lymphatic distribution of d4T following administration of d4T and DPP-d4T to mice. The pharmacokinetics of d4T were characterized following administration of a single intravenous or oral dose of 50 mg kg−1 d4T and an equimolar dose (214 mg kg−1) of DPP-d4T. Concentrations of d4T in serum and lymph nodes were determined by HPLC. Following administration of d4T, the distribution of d4T into lymph nodes was rapid with maximum concentrations observed within 5 min after dosing. The AUC and half-life values of d4T in three groups of lymph nodes were similar to those in serum. Administration of DPP-d4T resulted in significantly lower concentrations of d4T in serum and lymph nodes. Approximately 67% of the intravenously administered DPP-d4T was biotransformed to parent compound. The apparent oral bioavailability of DPP-d4T was low. While the phospholipid prodrug did not increase d4T concentrations in the lymph nodes, it did provide an extended release of the parent nucleoside, resulting in sustained concentrations of d4T.

Lymphatic Targeting of anti-HIV Nucleosides: Distribution of 3′-azido-3′-deoxythymidine (AZT) and 3′-azido-2′,3′-dideoxyuridine (AZdU) after Administration of Dipalmitoylphosphatidyl Prodrugs to Mice

1995 ◽  
Vol 6 (4) ◽  
pp. 230-238 ◽  
Author(s):  
K. K. Manouilov ◽  
I. I. Fedorov ◽  
F. D. Boudinot ◽  
C. A. White ◽  
L. P. Kotra ◽  
...  
Keyword(s):  
Oral Administration ◽  
Lymph Nodes ◽  
Lymphatic System ◽  
Parent Compound ◽  
Mesenteric Lymph Nodes ◽  
Therapeutic Benefits ◽  
Mesenteric Lymph ◽  
Immunodeficiency Virus ◽  
Intravenous And Oral Administration ◽  
Anti Hiv

Human immunodeficiency virus appears to be proliferating within the lymphatic system throughout the period of clinical latency. Targeting of anti-HIV compounds to the lymphatic tissue may therefore provide therapeutic benefits. The purpose of this investigation was to determine the distribution of 3′-azido-3′-deoxythymidine (AZT) and 3′-azido-2′,3′-dideoxyuridine (AZdU) in lymph nodes in a mouse model after administration of the lipophilic prodrugs dipalmitoylphosphatidyl-azidodeoxythymidine (DPP-AZT) and dipalmitoylphosphatidyl-azidodideoxyuridine (DPP-AZdU). Mice received 50 mg kg−1 of parent nucleoside and 164 mg kg−1 of DPP-AZT (equivalent to 50 mg kg−1 AZT) intravenously or orally and 180mg kg−1 DPP-AZdU (equivalent to 50 mg kg−1 AZdU) orally. Serum, neck, axillary and mesenteric lymph nodes were collected at selected times and AZT and AZdU concentrations were determined by HPLC. The disposition of AZT and AZdU in serum and lymph nodes was significantly altered after intravenous and oral administration of DPP-AZT and oral administration of DPP-AZdU when compared to that after administration of parent nucleoside. Lower peak concentrations of AZT and AZdU were observed in serum and lymph nodes after administration of the phospholipid prodrugs. However, DPP-AZT and DPP-AZdU produced consistently higher concentrations of AZT and AZdU, respectively, 2-3 h after prodrug administration. Half-life values for both nucleosides in serum and lymph nodes were significantly greater after prodrug administration. Greater AUC values for nucleosides were noted in neck (AZT and AZdU) and mesenteric (AZT) lymph nodes after administration of prodrugs compared with values obtained for parent drugs. Furthermore, relative lymph node exposure to AZT and AZdU in the lymph nodes was greater after administration of prodrug than after administration of parent compound. Thus, DPP-AZT and DPP-AZdU show potential as useful prodrugs for the delivery of AZT and AZdU to the lymphatic system.

Features of diagnostics of the peripheral lymph nodes tuberculosis

2020 ◽  
Vol 22 (4) ◽  
pp. 43-46
Author(s):  
G. S. Balasaniantc ◽  
V. V. Dantsev ◽  
M. S. Matinina ◽  
B. V. Zarecky ◽  
R. D. Muchaidze
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mycobacterium Tuberculosis ◽  
Lymph Nodes ◽  
Deoxyribonucleic Acid ◽  
Lymphatic System ◽  
Molecular Genetic ◽  
Biopsy Material ◽  
Genetic Studies ◽  
Peripheral Lymph ◽  
Immunodeficiency Virus

The analysis of the features of diagnostics of peripheral lymph nodes tuberculosis in modern conditions is carried out. For this 28 case histories of patients suffering from tuberculosis of peripheral lymph nodes were studied and 85,7% of them had a combination of tuberculosis and infection caused by the human immunodeficiency virus. All patients were undergoing biopsies or surgery of lymph nodes, and the material was examined using microbiological molecular, genetic and histological methods. 85,7% of patients had relapses with different periods of time, on average, 34 years, and repeated periods of tuberculosis activation. At all patients the lymph nodes were enlarged, mainly cervical (71,4%) and axillary (67,9%), the sizes of nodes varied from 1 to 5 cm, on average, 2,21,6 cm. In 78,6% cases tuberculosis of peripheral lymph nodes was characterized by fluctuation of nodes and the discharge of 30 to 80 ml of odorless creamy pus. It was found that tuberculosis of peripheral lymph nodes is part of a widespread tuberculous lesions especially at patients with tuberculosis associated with an infection caused by the human immunodeficiency virus. Tuberculosis of peripheral lymph nodes develops simultaneously with a specific lesion of other groups of lymph nodes intrathoracic (75%), intra-abdominal (57,1%), which allows to generalized tuberculosis of the lymphatic system. Fibrobronchoscopy showed in 35,7% patients residual bronchial tuberculosis changes, at 14,3% an active fistulous form of bronchial tuberculosis. Microscopy of biopsy material was negative at 78,6% of cases, while cultural examination revealed Mycobacterium tuberculosis in 100% and molecular genetic studies deoxyribonucleic acid of Mycobacterium tuberculosis in 64,3% patients.

An Approach towards the Synthesis of Potential Metal-Chelating TSAO-T Derivatives as Bidentate Inhibitors of Human Immunodeficiency virus Type 1 Reverse Transcriptase

1998 ◽  
Vol 9 (5) ◽  
pp. 412-421 ◽  
Author(s):  
C Chamorro ◽  
M-J Camarasa ◽  
M-J Pérez-Pérez ◽  
E de Clercq ◽  
J Balzarini ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Parent Compound ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

Novel derivatives of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-T have been designed, synthesized and tested for their in vitro antiretro-viral activity against HIV. These TSAO-T derivatives have been designed as potential bidentate inhibitors of HIV-1 RT, which combine in their structure the functionality of a non-nucleoside RT inhibitor (TSAO-T) and a bivalent ion-chelating moiety (a β-diketone moiety) linked through an appropriate spacer to the N-3 of thymine of TSAO-T . Some of the new compounds have an anti-HIV-1 activity comparable to that of the parent compound TSAO-T, but display a markedly increased antiviral selectivity. There was a clear relationship between antiviral activity and the length of the spacer group that links the TSAO molecule with the chelating moiety. A shorter spacer invariably resulted in increased antiviral potency. None of the TSAO-T derivatives were endowed with anti-HIV-2 activity.

scholarly journals Disseminated human immunodeficiency virus 1 (HIV-1) infection in SCID-hu mice after peripheral inoculation with HIV-1.

1994 ◽  
Vol 179 (2) ◽  
pp. 513-522 ◽  
Author(s):  
T R Kollmann ◽  
M Pettoello-Mantovani ◽  
X Zhuang ◽  
A Kim ◽  
M Hachamovitch ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Lymph Nodes ◽  
Peripheral Blood ◽  
Interleukin 2 ◽  
Human T Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Human Immunodeficiency Virus 1

A small animal model that could be infected with human immunodeficiency virus 1 (HIV-1) after peripheral inoculation would greatly facilitate the study of the pathophysiology of acute HIV-1 infection. The utility of SCID mice implanted with human fetal thymus and liver (SCID-hu mice) for studying peripheral HIV-1 infection in vivo has been hampered by the requirement for direct intraimplant injection of HIV-1 and the continued restriction of the resultant HIV-1 infection to the human thymus and liver (hu-thy/liv) implant. This may have been due to the very low numbers of human T cells present in the SCID-hu mouse peripheral lymphoid compartment. Since the degree of the peripheral reconstitution of SCID-hu mice with human T cells may be a function of the hu-thy/liv implant size, we increased the quantity of hu-thy/liv tissue implanted under the renal capsule and implanted hu-thy/liv tissue under the capsules of both kidneys. This resulted in SCID-hu mice in which significant numbers of human T cells were detected in the peripheral blood, spleens, and lymph nodes. After intraimplant injection of HIV-1 into these modified SCID-hu mice, significant HIV-1 infection was detected by quantitative coculture not only in the hu-thy/liv implant, but also in the spleen and peripheral blood. This indicated that HIV-1 infection can spread from the thymus to the peripheral lymphoid compartment. More importantly, a similar degree of infection of the hu-thy/liv implant and peripheral lymphoid compartment occurred after peripheral intraperitoneal inoculation with HIV-1. Active viral replication was indicated by the detection of HIV-1 gag DNA, HIV-1 gag RNA, and spliced tat/rev RNA in the hu-thy/liv implants, peripheral blood mononuclear cells (PBMC), spleens, and lymph nodes of these HIV-1-infected SCID-hu mice. As a first step in using our modified SCID-hu mouse model to investigate the pathophysiological consequences of HIV-1 infection, the effect of HIV-1 infection on the expression of human cytokines shown to enhance HIV-1 replication was examined. Significantly more of the HIV-1-infected SCID-hu mice expressed mRNA for human tumor necrosis factors alpha and beta, and interleukin 2 in their spleens, lymph nodes, and PBMC than did uninfected SCID-hu mice. This suggested that HIV-1 infection in vivo can stimulate the expression of cytokine mRNA by human T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

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