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Biomedical subjects

R Krishna

Publications and source records attributed to R Krishna.

At least 37 records · Page 2Linked to original sources
PubMed2000

Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs.

In recent years, there has been an increased understanding of P-glycoprotein (P-GP)-mediated pharmacokinetic interactions. In addition, its role in modifying the bioavailability of orally administered drugs via induction or inhibition has been also been demonstrated in various studies. This overview presents a background on some of the commonly documented mechanisms of multidrug resistance (MDR), reversal using modulators of MDR, followed by a discussion on the functional aspects of P-GP in the context of the pharmacokinetic interactions when multiple agents are coadministered. While adverse pharmacokinetic interactions have been documented with first and second generation MDR modulators, certain newer agents of the third generation class of compounds have been less susceptible in eliciting pharmacokinetic interactions. Although the review focuses on P-GP and the pharmacology of MDR reversal using MDR modulators, relevance of these drug transport proteins in the context of pharmacokinetic implications (drug absorption, distribution, clearance, and interactions) will also be discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Should all patients with candidaemia have an ophthalmic examination to rule out ocular candidiasis?

PURPOSE: To determine the incidence of ocular candidiasis and length of ophthalmic follow-up required to rule out ocular candidiasis in candidemia patients. METHODS: We prospectively studied patients with candidemia at our institution. Eligibility criteria included a dilated ophthalmological examination within 72 h of fungemia. Patients without ocular candidiasis on initial examination had follow-up dilated ophthalmoscopy performed at 1, 2, 4, 12 and 24 weeks. RESULTS: Between May 1996 and March 1997 a total of 50 patients with fungemia were identified of whom 31 were included in the study; 15 excluded patients died before an initial examination was performed. The overall incidence of ocular candidiasis was 26% (8/31 patients), all manifested as chorioretinitis. Five patients (16%) had ocular candidiasis on their initial examination. One of 21 patients (5%) without ocular candidiasis on initial examination developed ocular candidiasis within 1 week. Two of 16 patients (13%) without ocular candidiasis on initial examination or at 1 week follow-up developed ocular candidiasis within 2 weeks. No evidence of ocular candidiasis occurred in the 12 patients with follow-up at 4 weeks, the 8 patients with follow-up at 12 weeks and the 4 patients with follow-up at 24 weeks. CONCLUSION: The incidence of ocular candidiasis among hospitalized patients is clinically significant. We recommend ophthalmological follow-up for development of ocular candidiasis for at least 2 weeks after an initial negative eye examination.

Aged↗
PubMed2000

Surgically induced astigmatism after photorefractive keratectomy with the excimer laser.

PURPOSE: To evaluate retrospectively the effect of spherical excimer laser photorefractive keratectomy (PRK) on astigmatism. METHODS: Four hundred seventy consecutive eyes of patients who had PRK for the treatment of myopia without astigmatic keratotomy, PRK reoperation, or other surgical procedures were evaluated in a retrospective clinical study. PRK was performed using the Summit Apex excimer laser with attempted corrections from 1 to 7 diopters (D) of myopia. Preoperative and postoperative astigmatism was determined by manifest refraction refined with a 0.25-D Jackson cross cylinder and evaluated with vector analysis. RESULTS: Eighty-five ( 18%) eyes continued to have a spherical refraction after PRK, 53 (11%) eyes had the same preoperative astigmatism, and 332 (71%) eyes had a change in magnitude of astigmatism > or =0.25 D after spherical PRK. The absolute change in astigmatism magnitude irrespective of axis was +0.4 +/- 0.4 (standard deviation) D at 6 months after PRK. Eyes with change in astigmatism power tended to have higher preoperative myopia and higher preoperative astigmatism. Vector analysis revealed surgically induced astigmatism was 0.68 +/- 0.50 D (range, 0-3.25 D) at 1 month and 0.56 +/- 0.47 D (range, 0-3.1 D) at 12 months after spherical PRK. CONCLUSION: Spherical excimer laser PRK is associated with significant surgically induced astigmatism that is likely related to decentration of the ablation, excimer laser beam irregularities, and variations in wound healing across the ablated zone. Surgically induced astigmatism will complicate attempts to correct astigmatism simultaneously at the time of PRK and suggest that such attempts are likely to be problematic for lower levels of astigmatism.

Adult↗
PubMed1999

Characterization of a transcriptional activator controlling trichothecene toxin biosynthesis.

Trichothecene biosynthetic pathway genes are localized within a gene cluster in Fusarium sporotrichioides and require the zinc-finger containing protein, TRI6, for expression. We show here that TRI6 is able to bind within the promoter regions of nine different pathway genes and that TRI6 binding is involved in pathway gene activation. TRI6 binding occurs at three distinct sites in the TRI5 promoter, all of which contain the sequence TNAGGCCT. DNA fragments from the promoter regions of six other pathway genes containing this sequence are also substrates for TRI6 binding. Specific nucleotide changes in the TNAGGCCT sequence dramatically reduced TRI6 binding. Analysis of TRI6 binding within the TRI3 and TRI11 promoters and the TRI4-TRI6 intergenic region which do not contain the TNAGGCCT motif suggests that the minimum sequence required for TRI6 binding is YNAGGCC. Two potential TRI6 binding sites, T4A and T4B, were identified within the intergenic region for the divergently transcribed TRI4 and TRI6 genes. Alteration or deletion of the T4A site resulted in the loss of nearly all in vitro TRI6 binding and was correlated with the loss of promoter activity in vivo as measured by the expression of mutant TRI4(p)/GUS fusions. This establishes a physiological role for TRI6 binding and demonstrates that TRI6 is directly involved in the regulation of pathway gene expression. To determine if a predicted Cys2His2 zinc-finger motif at the C-terminus of TRI6 is involved in DNA binding, a C187A mutant was constructed in TRI6 using site-directed mutagenesis. The C187A mutant did not bind promoter DNA fragments, supporting the role of C187 in DNA binding. In addition, a TRI6 homologue in the distantly related macrocyclic trichothecene pathway of Myrothecium roridum (MRTRI6) was also shown to bind to the same TRI5 and TRI4 promoter fragments bound by TRI6. Together, these data confirm our previous proposal that TRI6 is an activator of trichothecene pathway gene expression and that DNA binding employs the C-terminal region of TRI6 containing three predicted Cys2His2 zinc fingers.

Fusarium↗
PubMed1999

Doxorubicin encapsulated in sterically stabilized liposomes exhibits renal and biliary clearance properties that are independent of valspodar (PSC 833) under conditions that significantly inhibit nonencapsulated drug excretion.

Coadministration of anticancer drugs and multidrug resistance modulators directed against P-glycoprotein over-expressed in tumors also results in nonspecific blockade of this drug efflux pump in excretory tissues such as the liver and kidneys. These interactions often result in impaired renal and biliary clearance for anticancer agents such as doxorubicin (DOX). In the present investigation, we characterized the excretory processes associated with liposomal DOX administration to elucidate how liposome encapsulation may bypass adverse pharmacokinetic interactions between DOX and (3'-keto-Bmt1)-(Val2)-cyclosporin (Valspodar). Renal and biliary clearance properties of liposome-encapsulated DOX were compared with those for nonencapsulated DOX in the presence and absence of Valspodar using an instrumented rat model with implanted jugular vein and bile duct catheters for continuous sampling. Two types of liposomal DOX formulations were used, a drug-permeable egg phosphatidyl choline/cholesterol system and a sterically stabilized polyethylene glycol/1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol system to establish the relative roles of liposome-encapsulated and released drug on the pharmacokinetic and excretion alterations induced by Valspodar. DOX and its primary metabolites were quantitated using high-performance liquid chromatography. When Valspodar was coadministered with nonencapsulated DOX, 3.5- and 37.5-fold reductions in renal clearance (CLr) and biliary clearance (CLb), respectively, were observed, which resulted in increased plasma DOX concentrations and total exposure. However, Valspodar-induced alterations in CLr and CLb were less profound with egg phosphatidyl choline/cholesterol DOX (1.7- and 2.0-fold reductions, respectively) and negligible with the long-circulating polyethylene glycol-containing liposomal formulation. These results indicate that liposomes may circumvent Valspodar-induced DOX pharmacokinetic changes by reducing the rate of drug excretion in liver and kidney tissue to a level that is within the renal and biliary excretion capacity in the presence of P-glycoprotein blockade.

Animals↗
PubMed1998

Long-term follow-up of extracapsular cataract extraction and posterior chamber intraocular lens implantation in patients with uveitis.

OBJECTIVE: The objective of the study was to determine the long-term outcome of patients with uveitis who underwent extracapsular cataract extraction (ECCE) and posterior chamber intraocular lens (PCIOL) implantation. DESIGN: Retrospective review. PARTICIPANTS: Twenty-eight patients (36 eyes). INTERVENTION: Extracapsular cataract extraction and PCIOL implantation. MAIN OUTCOME MEASURES: Level of best-corrected Snellen visual acuity, change in visual acuity, length of follow-up, long-term findings, and complications. RESULTS: In long-term follow-up (mean, 81.4 months), 94% of eyes had visual acuity improvement compared with preoperative levels. Average change in visual acuity for all eyes was an improvement of 6.4 Snellen lines; 75% of eyes were 20/40 or better. The prevalences of cystoid macular edema (CME), epiretinal membrane (ERM), and posterior capsule opacification (PCO) were 56%, 56%, and 58%, respectively. CONCLUSIONS: Patients with uveitis who are treated with ECCE with PCIOL implantation can have successful visual results in long-term follow-up despite the prevalence of PCO or macular abnormalities such as CME and ERM.

Cataract↗
PubMed1998

Pseudotumor cerebri sine papilledema with unilateral sixth nerve palsy.

A 17-year-old woman presented with a history of 1-week of headache and 3 days of horizontal diplopia. Examination revealed 20/20 vision in both eyes, no papilledema, and an abduction deficit in her left eye. Lumbar puncture revealed an opening pressure of 440 mm H2O. After treatment with acetazolamide, the headache and abduction deficit resolved. Papilledema never developed. This is a unique case of pseudotumor cerebri sine papilledema with a unilateral abduction deficit. We suggest that young women with headache and unilateral abduction deficits may be unrecognized cases of pseudotumor cerebri.

Abducens Nerve↗
PubMed1997

Liposomal doxorubicin circumvents PSC 833-free drug interactions, resulting in effective therapy of multidrug-resistant solid tumors.

Conventional methods that are used to overcome multidrug resistance (MDR) often involve the coadministration of chemosensitizers and anticancer drugs. The cyclosporin analogue SDZ PSC 833 [(3'-keto-Bmt1)-(Val2)-cyclosporin] (PSC 833) has been shown to possess powerful chemosensitization properties in vitro, in addition to being intrinsically nontoxic. However, coadministration of PSC 833 with anticancer drugs, such as daunorubicin, doxorubicin (DOX), and Taxol, have resulted in the exacerbation of anticancer drug toxicity, which is due to altered anticancer drug pharmacokinetics. Here, we hypothesized that optimization of the anticancer drug delivery, using liposomal carriers, may, by avoiding these adverse interactions, offer a significant advantage over nonencapsulated drugs. Toxicity studies were conducted in normal BDF1 mice, with i.v. DOX (free or liposome encapsulated) administration and p.o. PSC 833 in single and multiple dosage regimens over a 15-day study period. p.o. administration of PSC 833, at a dose of 100 mg/kg, reduced the maximum tolerated dose (MTD) of i.v administered free drug by 2.5-3-fold, in single- and multiple-dose regimens. In contrast, PSC 833 administration resulted in only a 20% reduction of the MTD for DOX encapsulated in 100-nm 1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol liposomes (55:45 molar lipid ratio) in a single-dose regimen and had no effect on the liposomal DOX MTD for the day 1, 5, and 9 treatment schedule. Modest modulation of P-glycoprotein-mediated MDR was observed in the murine P388/ADR solid tumor model when PSC 833 was administered with free DOX at the MTD. In contrast, liposomal DOX combined with PSC 833 resulted in tumor growth inhibition that was comparable to that observed for drug-sensitive P388/WT tumors. This efficacy of P388/ADR tumors treatment was dependent on PSC 833 because treatment with liposomal DOX alone provided significantly less antitumor activity. Pharmacokinetic and tissue distribution data demonstrated that DOX encapsulated in 1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol liposomes exhibited comparable plasma elimination and tissue distribution properties in the presence and absence of PSC 833, whereas free DOX displayed reduced plasma elimination rates and altered tissue distribution in the presence of PSC 833. These results provide evidence that PSC 833 can induce P-glycoprotein modulation and chemosensitize MDR tumors in the absence of altered DOX pharmacokinetics when liposomal carriers are used. This suggests that the improved tumor selectivity of anticancer drugs that are administered in liposomal formulations may avoid the complications that are associated with free drug-MDR-reversing agent combinations and enhance the therapy of multidrug-resistant tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Implications of thrombocytosis in giant cell arteritis.

PURPOSE: To bring attention to the implications of thrombocytosis in giant cell arteritis. METHOD: Case report. Platelet counts were measured before and after corticosteroid therapy in a patient with biopsy-proven giant cell arteritis. RESULT: Platelet counts were increased before corticosteroid therapy was begun and returned to normal levels after corticosteroid therapy was instituted. CONCLUSION: Platelet counts in a patient with giant cell arteritis may have diagnostic, therapeutic, and prognostic value.

Aged↗
PubMed1996

Spontaneous collapse of primary acquired iris stromal cysts.

PURPOSE: To describe the spontaneous collapse of primary acquired iris stromal cysts. METHODS: We reviewed the medical records, clinical findings, and ultrasonography of two patients who had been followed up for primary acquired iris stromal cysts. RESULTS: During follow-up, both patients experienced spontaneous collapse of their cysts, which resulted in membrane formation on the peripheral corneal endothelium, localized peripheral anterior synechiae, ectropion uveae, and slightly peaked pupil. CONCLUSION: Primary acquired iris stromal cysts may undergo spontaneous collapse, resulting in clinical findings similar to other anterior segment disorders.

Anterior Eye Segment↗
PubMed1996

Carboxymethylcellulose-sodium based transdermal drug delivery system for propranolol.

Propranolol, a beta-adrenoceptor blocker, suffers from a high degree of first-pass metabolism resulting in very low bioavailability (< 10%) following administration with conventional oral formulations. To circumvent this significant therapeutic hurdle, we formulated a carboxymethylcellulose-sodium (CMC-Na) based transdermal system for propranolol and evaluated the patch for its in-vitro and in-vivo performance. In-vitro permeation studies using the excised hair-free rat skin model resulted in 66.54% permeation at the end of 24 h in a modified Franz diffusion cell. This zero-order permeation profile was characterized by a drug permeation rate of 52.87 +/- 11.63 micrograms cm-2 h-1. Skin irritation studies in rats (n = 5), evaluated for flare-and-wheal with respect to a formalin control, indicated that the drug-containing patch evoked only a mild response over a 7-day period. Preliminary in-vivo studies in male albino rabbits (n = 3), indicated that plasma drug levels averaged 11.75 +/- 3.40 ng mL-1 in a 24-h study period before patch removal.

Administration, Cutaneous↗
PubMed1995

Sensitive fused-silica capillary gas chromatographic assay using electron-capture detection for indomethacin in ovine fetal fluids.

A sensitive gas chromatographic (GC) method with electron-capture detection (ECD) has been developed to quantitate indomethacin (IND) in plasma, urine, amniotic, and tracheal fluids obtained from the pregnant sheep model. IND and the internal standard, alpha-methylindomethacin (alpha-Me-IND) are extracted by a simple liquid-liquid extraction procedure using ethyl acetate and derivatized with N-methyl-N-(tert.-butyldimethyl-silyl)trifluoroacetamide (MTBSTFA) at 60 degrees C for 50 min. The limit of quantitation (LOQ) is 1 ng/ml with a C.V. < 10% and signal-to-noise ratio > 10. Recoveries from all fluids were greater than 80%. Calibration curves were linear over the range of 1-32 ng/ml with a coefficient of determination (r2) > 0.999. Inter- and intra-day coefficients of variation were < 10% at concentrations of 2-32 ng/ml, and < 20% at the LOQ. Applicability of the developed method is demonstrated for a pharmacokinetic study of IND samples collected following long-term infusion of IND in a chronically instrumented ovine fetus.

Acetamides↗
PubMed1995

Circadian rhythm of intraocular pressure: a rat model.

The purpose of this study was to examine whether there is a circadian rhythm of intraocular pressure (IOP) in the Lewis rat. Therefore, 20 Lewis rats (40 eyes) were subjected to an alternating 12-hour-light and 12-hour-dark cycle. Using a Tono-Pen 1, IOP was measured every 2 h between 6 a.m. and 12 midnight and every 3 h between 12 midnight and 6 a.m. for 2 consecutive days. These measurements in the Lewis rat revealed a reproducible circadian rhythm with a peak at 8 p.m. and a trough at 6 a.m. In conclusion, when using the Lewis rat as an animal model in longitudinal studies that involve the IOP, the IOP should be measured at the same time each day to correct for diurnal variations. Additionally, Lewis rats may be a useful model to study the causes of circadian rhythms of IOP and for pharmacologic studies of new glaucoma medications.

Animals↗
PubMed1992

Difficult intubation stylohyoid ligament calcification.

Intubation was difficult and traumatic in a 40-year-old patient presented for emergency oesophagoscopy because the diagnosis of stylohyoid ligament calcification was not suspected. High probability of stylohyoid ligament calcification should be suspected when there is difficulty in lifting the epiglottis and fibre-optic laryngoscopy is suggested as the best way to tackle this problem to prevent trauma and possible risk of regurgitation and aspiration especially in emergency situation.

Adult↗