Effects of selective dopamine-1 receptor activation on intraocular pressure in man

The lack of specific agonists and antagonists has, until recently, precluded investigation of a role for dopamine receptors in the control of intraocular pressure. In the present study, we have examined the effects of fenoldopam, a novel selective dopamine1 (DA1) receptor agonist, on intraocular pressure, in eight healthy human volunteers. Fenoldopam, infused intravenously at 0.5 micrograms kg-1 min-1, increased intraocular pressure from 14.6 +/- 0.9 to 17.6 +/- 1.4 mmHg (P less than 0.05) while a control saline infusion had no effect. Pupil diameter and blood pressure did not change. In the same subjects, i.v. norepinephrine or angiotensin II both increased intraocular pressure--from 13.8 +/- 1.4- to 17.6 +/- 1.4 mmHg and from 13.4 +/- 1.3- to 17.5 +/- 1.7 mmHg respectively (P less than 0.05), and mean arterial pressure by about 20 mmHg. These data suggest that: (1) DA1 receptor activation can modulate intraocular pressure; (2) the intraocular pressure effects of the DA1 receptor agonist, fenoldopam, are independent of changes in systemic blood pressure, in contrast to those of norepinephrine or angiotensin II where intraocular and systemic blood pressures increase in parallel; (3) the ability of a DA1 receptor antagonist to lower intraocular pressure merits investigation.     

Aminophylline targeting to lung: optimization of the size and drug loading of albumin microspheres.

Aminophylline, a bronchodilator, was considered a suitable drug for targeting to the lung to treat emphysema. Factorial concept was utilized to optimize the size and drug loading of microspheres suitable for targeting. Aminophylline-loaded albumin microspheres were prepared by heat denaturation adjusting the manufacturing variables, namely albumin concentration, drug concentration, water-oil phase ratio and stirring rate at low and high levels. For two levels of the four variables the experimentation was performed in 16 batches. A good yield of well-defined microspheres of the size range, 2-30 microns, were obtained from all the batches. The drug loading was found maximum (36.33 per cent) in batch XV of microspheres prepared with low albumin concentration, high drug concentration, low water-oil phase ratio and low stirring rate. The least number (13 per cent) of microspheres of batch XV were below 7 microns and the remaining 87 per cent were above this size. Considering the payload and size, microspheres of batch XV were found suitable for targeting to the lung.     

Characterization of solid-state forms of celecoxib.

This study deals with the generation and characterization of various solid-state forms of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor. The drug was subjected to polymorphic screen using different solvents to explore the possibility of existence of different solid forms. N,N-Dimethyl acetamide (DMA) and N,N-dimethyl formamide (DMF) yielded solvates in 1:1 stoichiometric ratio. Quench cooling of the melt resulted in amorphous form of the drug. All these solid-state forms were characterized by thermoanalytical (DSC, TGA, HSM), crystallographic (XRD), microscopic (polarized, SEM), spectroscopic (FTIR), and elemental analysis techniques. Solubility and van't Hoff studies were carried out for their thermodynamic interpretation. Influence of morphology of different solid-state forms on flow behavior was also investigated. Molecular modeling studies were used to elucidate the interaction between solute and solvent molecules in the solvate.     

Characterization of GP110, a neutrophil surface protein.

Localized juvenile periodontosis is associated with a defect of neutrophil chemotaxis that is characterized by selective depletion of a surface protein with a molecular mass of 110 kDa (GP110). Data on partial characterization of GP110 suggest that it is a glycoprotein which is enriched in Lys, Glu, His, Leu, and Ala residues.     

Clinical profile of AIDS: a study at a referral hospital

The present study describes the clinical and epidemiological features of 74 patients with human immunodeficiency virus (HIV) infection who presented to a referral hospital. Sixty two patients (83.7%) were diagnosed to have acquired immune deficiency syndrome (AIDS). Mean age of the patients was 34.9 +/- 12 years and male to female ratio was 3:1. Majority of patients (80%) were from lower socio-economic class. Multiple unprotected heterosexual contact with commercial sex workers in metropolitan cities of India, mainly Mumbai, was major risk factor in 82.1% male patients while most of the females (66.6%) had acquired infection from HIV positive husbands. Blood transfusion was the risk factor in 9(12.1%) patients. Sixty eight patients were infected with HIV 1, one with HIV 2, and five patients with both HIV 1 and HIV 2. Fever and weight loss were the commonest presenting symptoms. Tuberculosis, oropharyngeal candidiasis, and interstitial pneumonitis were present in 54.8%, 40.3% and 20.9% patients, respectively. Fourteen patients (22.5%) had generalised lymphadenopathy. Herpes zoster, cryptococcal meningitis, and peripheral neuropathy were infrequent. Response to standard antifungal and antitubercular treatment was satisfactory. Kaposi's sarcoma, lymphoma, and CNS toxoplasmosis were not found. The clinical manifestations of AIDS patients are strikingly different from that in the Western countries. It, thus, necessitates setting up of different guidelines for the clinical diagnosis and management of AIDS in India.     

Hepatic microsomal cytochrome P450 system during experimental hookworm infection

Experimental infection of golden hamsters with the hookworm, Ancylostoma ceylanicum, caused a profound decline in the hepatic microsomal cytochrome P450 content. Concomitant decrease was also noticed in aminopyrine N-demethylase and benzo[a]pyrene hydroxylase activities. However, aniline hydroxylase activity was only marginally elevated during the infection. Microsomal markers, viz., cytochrome b5, NADH-cytochrome-c reductase, and glucose-6-phosphatase, were not significantly altered. Hepatic tissue exhibited an accumulation of lipids, especially phospholipids, triglycerides, and cholesterol, resulting in fatty necrosis around the central vein region. Isolated hepatic microsomes showed a decrease in phosphatidylcholine content. Impairment in hepatic mixed function oxidase (MFO) activities was further confirmed by prolongation in hexobarbital sleeping time and zoxazolamine-induced paralysis. The hepatic MFO system of A. ceylanicum-infected hamsters responded qualitatively and quantitatively in a manner similar to that of control hamsters, upon stimulation with selective chemical inducers like phenobarbitone and 3-methylcholanthrene. Kinetic and in vitro substrate binding studies revealed that for aminopyrine the substrate affinity and the maximum enzyme activity (Vmax) were decreased, while for aniline the binding affinity was decreased and the binding capacity was enhanced. Results indicate specific/selective impairment of the hepatic microsomal cytochrome P450 system during hookworm infection and may have many practical implications in toxicology and pharmacology.     

Characterisation of the differences between hepatitis C virus genotype 3 and 1 glycoproteins

Sequence variation in the envelope E1 and E2 glycoproteins of hepatitis C virus (HCV) could account for differences in disease pathogenesis in patients infected with different genotypes. A cDNA encoding the structural region of the hepatitis C polyprotein was constructed to match the majority sequence of viral RNA extracted from a patient infected with genotype 3a (designated strain HCV3a-Gla). The principal differences predicted between E2 of HCV3a-Gla and the corresponding H77c genotype 1a protein were that the former contained six more amino acids (361 vs. 355), but it had one fewer glycosylation site. Expression studies showed that, in common with the H77c glycoproteins, E1 and E2 from HCV3a-Gla localised to the endoplasmic reticulum (ER) membrane in both Huh-7 and BHK tissue culture cells and interacted to form native complexes. Analysis of the cross-reactivity of antibodies raised against glycoproteins of genotype 1a strains showed that three of five monoclonal antibodies that recognise linear epitopes were able to detect E2 from strain HCV3a-Gla. However, neither conformational E2 antibodies nor antibodies raised against E1 were able to detect the HCV3a-Gla glycoproteins. In receptor binding assays, E2 of HCV3a-Gla consistently failed to bind CD81, a putative cell receptor for HCV. Absence of binding to CD81 and lack of recognition by most antibodies raised to genotype 1a glycoproteins indicate important differences between these glycoproteins representative of genotypes 3a and 1a. These may be pertinent to the differences in response to interferon therapy and the prevalence of steatosis reported in patients infected with these genotypes.     

Validity of self-report of recent opiate use in treatment setting

Self-report validity of recent drug use among heroin abusers depends on many factors including the population being studied and the setting in which the study is carried out. This study was conducted by the treating physicians to assess the self-report validity of recent heroin use by heroin dependent patients in the outdoor setting using 'thin layer chromatography' (TLC) and two highly sensitive methods of urinalysis viz. 'gas liquid chromatography' (GLC) and 'high performance liquid chromatography' (HPLC). Out of seventy-six heroin dependent patients who entered the study, 64 provided urine sample on the same day. Patients' self-report about recent opiate use was found to have a moderate agreement with urinalysis report. However, it is important to validate it with urinalysis during the treatment process because a substantial proportion of patients fails to report recent opiate use. It is recommended that all drug dependence treatment centres should be equipped with a sensitive urinalysis facility. Otherwise, the outcome of the treatment process should be considered with caution.     

Stimulation of human monocytes by anti-CD3 monoclonal antibody: Induction of inflammatory mediator release via immobilization of Fc receptor by adsorbed immunoglobulin and T-lymphocytes

Human monocytes released superoxide anion, prostaglandin E₂, leukotriene B₄, IL-1, and TNF when exposed to plastic surfaces coated with murine anti-CD3 monoclonal antibody, OKT 3. Stimulation of mediator release by OKT 3 was dependent on the amount of antibody immobilized onto wells of plastic tissue culture plates. Soluble antibody or antibody adsorbed to monocytes and reacted with an aggregating (cross-linking) second antibody failed to induce mediator release. Monocytes armed with OKT 3 formed rosettes with T cells in a fashion indistinguishable from that seen between monocytes and T cells sensitized with OKT 3. Monocytes with adsorbed OKT 3 antibodies released IL-1 and TNF- when exposed to unsensitized T cells, although increased superoxide release could not be detected. OKT 4a, a murine IgG_2a antibody that reacts with a different T cell epitope (CD4), failed to induce cytokine release from monocytes when cross-linked by T cells or a CD4+ T cell line, even in the presence of IL-2 or IFN-. These data indicate that certain antibodies bound to Fc receptors (FcR) of monocytes may trigger monocyte function when reacting with cells bearing the appropriate target antigens. FcR-mediated signaling resulting in mediator release may be involved in initiating or regulating the immune response. Furthermore, systemically administered monoclonal antibodies may induce inflammatory responses and their attendant symptomatologies via their interaction with FcR-bearing inflammatory cells.