Antidiabetic activity of a polyherbal formulation (DRF/AY/5001).

The herbal formulation, DRF/AY/5001, elicits hypoglycemic/antidiabetic effects in both normal and experimentally induced hyperglycemic (epinephrine and alloxan) rats. Further, herbal formulation treatment can significantly alter the pattern of glucose tolerance in normal and diabetic rats. It is possible that the herbal formulation may act through both, pancreatic and extra-pancreatic mechanism(s). The DRF/AY/5001 also elicited a significant antioxidant effect in alloxan diabetic rats as reflected by its ability to inhibit lipid peroxidation and to elevate the enzymatic antioxidants in pancreatic tissue. The histopathological studies during the long-term treatment have shown to ameliorate the alloxan induced histological damage of islets of Langerhans. The inhibitory effects on biochemical and histological parameters induced by herbal formulation at a dose of 600 mg/kg were almost comparable to that of standard drug, glibenclamide (4 mg/kg). The present study demonstrates that herbal formulation exhibits promisisng antidiabetic activity and helps to maintain good glycemic and metabolic control.

Phytotoxicity of volatile oil from Eucalyptus citriodora against some weedy species.

A study was undertaken to explore the phytotoxicity of volatile essential oil from Eucalyptus citriodora Hook. against some weeds viz. Bidens pilosa, Amaranthus viridis, Rumex nepalensis, and Leucaena leucocephala in order to assess its herbicidal activity. Dose-response studies conducted under laboratory conditions revealed that eucalypt oils (in concentration ranging from 0.0012 to 0.06%) greatly suppress the germination and seedling height of test weeds. At 0.06% eucalypt oil concentration, none of the seed of test weeds germinated. Among the weed species tested, A. viridis was found to be the most sensitive and its germination was completed inhibited even at 0.03%. Not only the germination and seedling growth, even the chlorophyll content and respiratory activity in leaves of emerged seedlings were severely affected. In A. viridis chlorophyll content and respiratory activity were reduced by over 51% and 71%, respectively, even at a very low concentration of 0.06%. These results indicated an adverse effect of eucalypt oils on the photosynthetic and energy metabolism of the test weeds. A strong negative correlation was observed between the observed effect and the concentration of eucalypt oil. Based on the study, it can be concluded that oil from E. citriodora possess strong inhibitory potential against weeds that could be exploited for weed management.

Anti-inflammatory, antiarthritic and analgesic activity of a herbal formulation (DRF/AY/4012).

Anti-inflammatory, antiarthritic and analgesic effect of a herbal product (DRF/AY/4012) was evaluated in animal models. Herbal product treatment induced a dose dependent anti-inflammatory activity in acute inflammatory models (carrageenin and egg-albumin induced rat hind paw edema). It also elicited promising anti-inflammatory activity in chronic inflammatory models (cotton pellet granuloma and Freund's adjuvant induced polyarthritis in rats). Further, the product inhibited the increased level of serum lysosomal enzyme activity viz. serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase and the lipid peroxidation in liver. In Freund's adjuvant induced polyarthritis, herbal product reduced the increased level of hydroxy proline, hexosamine and total protein content in edematous tissue. The product also exhibited mild to moderate analgesic activity in acetic acid induced writhing in mice. The LD50 value of the herbal product was more than 16 gm/kg by oral route in mice. The product has distinct advantages over the existing agents and deserves further developmental studies.

2-Benzoxazolinone (BOA) induced oxidative stress, lipid peroxidation and changes in some antioxidant enzyme activities in mung bean (Phaseolus aureus).

2-Benzoxazolinone (BOA), a well-known allelochemical with strong phytotoxicity, is a potential herbicidal candidate. The aim of the present study was to determine whether phytotoxicity of BOA is due to induction of oxidative stress caused by generation of reactive oxygen species (ROS) and the changes in levels of antioxidant enzymes induced in response to BOA. Effect of BOA was studied on electrolyte leakage, lipid peroxidation (LP), hydrogen peroxide (H(2)O(2)) generation, proline (PRO) accumulation, and activities of antioxidant enzymes-superoxide dismutase (SOD, 1.15.1.1), ascorbate peroxidase (APX, 1.11.1.11), guaiacol peroxidase (GPX, 1.11.1.7), catalase (CAT, 1.11.1.6) and glutathione reductase (GR, 1.6.4.2) in Phaseolus aureus (mung bean). BOA significantly enhanced malondialdehyde (MDA) content, a product of LP, in both leaves and roots of mung bean. The amount of H(2)O(2), a product of oxidative stress, and endogenous PRO increased many-fold in response to BOA. Accumulation of PRO, MDA and H(2)O(2) indicates the cellular damage in the target tissue caused by ROS generated by BOA. In response to BOA, there was a significant increase in the activities of scavenging enzymes SOD, APX, GPX, CAT, and GR in root and leaf tissue of mung bean. At 5 mM BOA, GR activity in roots showed a nearly 22-fold increase over that in control. The present study concludes that BOA induces oxidative stress in mung bean through generation of ROS and upregulation of activities of various scavenging enzymes.

Antifungal activity of the volatile oil of Eucalyptus citriodora.

The volatile oil extracted from the leaves of Eucalyptus citriodora showed a wide spectrum of antifungal activity.

Effect of parthenin--a sesquiterpene lactone from Parthenium hysterophorus--on early growth and physiology of Ageratum conyzoides.

A study was undertaken to assess the effect of parthenin--a sesquiterpene lactone from Parthenium hysterophorus--on the germination, growth, and some associated physiological changes in Ageratum conyzoides. The study reveals that germination and growth of A. conyzoides was severely reduced by parthenin in the concentration range of 50, 100, and 200 microM, while at 400 microM a complete inhibition of germination was observed. The radicle length of A. conyzoides was reduced more than the plumule length. Further, the content of the photosynthetic pigment chlorophyll was appreciably reduced in the leaves of test plants spray treated with parthenin at 200 microM concentration. However, this inhibitory effect declined with the passage of time and at 10 days after treatment only a 25% reduction in chlorophyll content was observed compared to 76% on the first day after spray. Likewise, the cellular respiration measured through 2,3,5-triphenyl tetrazolium chloride was found to be less in the treated leaves, and the inhibitory response also declined with time. The content of proteins and carbohydrates decreased with the passage of time after parthenin treatment. The specific activities of the enzymes protease and alpha- and beta-amylase were also adversely affected in the parthenin treated leaves. In the case of protease. the activity decreased with passage of time while those of the amylases increased. Thus, we conclude that parthenin affects the germination and growth of A. conyzoides by altering the contents of some macromolecules and the specific activities of some enzymes. Such observations may be helpful in further exploring parthenin's mode of action.

Post-OKT3 induction therapy CD complex response predicts renal allograft rejection.

CD complex response to cessation of induction with OKT3 may be predictive of rejection. Twenty-seven patients receiving renal allografts and OKT3 induction immunosuppression were retrospectively analyzed for CD complex repopulation and allograft rejection. Flow cytometric monitoring was utilized in all patients. Responder status groups were identified based on CD complex repopulation, with fast responders demonstrating CD complex repopulation above the determined cohort mean. Slow responders had repopulation below this mean. Student's t test yielded P<0.01 (CD2), P<0.02 (CD3), and P<0.01 (CD8). Nonresponder patients were identified with repopulation below the mean, but flat compared with depletion. All nine fast responders lost their graft or were treated for rejection. No slow responder experienced graft loss or rejection episodes. One nonresponder was treated for rejection. CD complex activity following OKT3 cessation correlates with future rejection. Identification of responder status provides insight into propensity to reject, allowing individual tailoring of immunosuppression to patient response.

Methylprednisolone pharmacokinetics and pharmacodynamics in chronic renal failure.

Methylprednisolone (MP) pharmacokinetics and its directly suppressive effects on cortisol secretion and cell trafficking were compared in 6 chronic renal failure (CRF) subjects and 6 healthy controls. After IV administration of MP 0.6 mg/kg as Solu-Medrol, the pharmacokinetics of methylprednisolone were similar. The clearance was about 280 ml/hr/kg, volume of distribution was 1.1 l/kg, t1/2 was 2.7 hr, and fraction unbound was 0.2. Physiologic pharmacodynamics models were applied for the suppression of cortisol secretion and recirculation of basophils, T-helper cells, and T-suppressor cells. The net response (area under the curve) and inhibitory concentrations (IC50) of methylprednisolone for each pharmacodynamic parameter were similar in both groups. As the pharmacokinetics of other corticosteroids are altered in CRF, the lack of pharmacokinetic/dynamic changes of methylprednisolone may offer a therapeutic advantage for CRF patients.

Pharmacokinetics of quinapril and its active metabolite, quinaprilat, in patients on chronic hemodialysis.

The pharmacokinetics of quinapril and its active metabolite, quinaprilat, were evaluated in 12 patients with end-stage renal disease (ESRD) on chronic hemodialysis. Each subject received a single 20-mg oral dose of quinapril 4 hours before a 4-hour hemodialysis treatment. Serial dialysate and blood samples were obtained over 4 and 96 hours, respectively. Samples were analyzed for quinapril and quinaprilat concentrations by gas chromatography. Mean tmax and Cmax values for quinapril were 1.2 hours and 129 ng/mL, respectively. Only one patient had detectable quinapril dialysate concentrations which accounted for 2.8% of the quinapril dose. Mean apparent plasma clearance for quinapril was 1275 mL/min with a mean half-life of 1.7 hours. Quinapril was extensively de-esterified to its diacid metabolite, quinaprilat. Mean tmax and Cmax for quinaprilat were 4.5 hours and 671 ng/mL, respectively. Mean apparent plasma clearance for quinaprilat was 24.0 mL/min with a mean half-life of 17.5 hours. As with quinapril, quinaprilat was not readily dialyzable. Only 5.4% of the administered quinapril dose was recovered as quinaprilat during a single hemodialysis treatment. In view of these results, supplemental quinapril doses need not be routinely given to patients following hemodialysis. Overall, quinapril and quinaprilat pharmacokinetics in patients with ESRD on chronic hemodialysis were not markedly different from those previously observed in patients with moderate to severe renal dysfunction (CLcr less than 29 mL/min) not yet requiring hemodialysis (RDND).

Pharmacokinetics of ampicillin (2.0 grams) and sulbactam (1.0 gram) coadministered to subjects with normal and abnormal renal function and with end-stage renal disease on hemodialysis.

The single-dose pharmacokinetics of intravenously administered ampicillin (2.0 g) and sulbactam (1.0 g) were studied in normal subjects and in patients with various degrees of creatinine clearance (CLCR). Six normal subjects (CLCR, greater than 60 ml/min), six patients with mild renal failure (CLCR, 31 to 60 ml/min), four patients with severe renal failure (CLCR, 7 to 30 ml/min), and four patients requiring maintenance hemodialysis (CLCR, less than 7 ml/min) were studied. The terminal half-lives for ampicillin and sulbactam more than doubled in patients with severe renal failure compared with subjects with normal renal function and mild renal insufficiency. CLCR significantly correlated with ampicillin (r = 0.88) and sulbactam (r = 0.54) total body clearance. Mean steady-state volume of distribution and nonrenal clearance for ampicillin and sulbactam were not affected by renal function. Hemodialysis approximately doubled the ampicillin and sulbactam total body clearance. Mean totals of 34.8 +/- 4.0% of the ampicillin dose and 44.7 +/- 3.2% of the sulbactam dose were removed during a 4-h hemodialysis treatment. A slight rebound in concentrations in serum after hemodialysis was observed for both drugs in all four subjects. In hemodialysis patients, the ampicillin half-life was 17.4 +/- 8.0 h and the sulbactam half-life was 13.4 +/- 7.4 h. The ampicillin and sulbactam half-lives were appreciably altered during the hemodialysis period (means of 2.2 and 2.3 h, respectively). The nearly parallel decrease in total body clearance, with volume of distribution and nonrenal clearance remaining relatively constant, suggests that the same ratio of ampicillin to sulbactam is appropriate regardless of renal function. An adjustment of the ampicillin (2.0 g) and sulbactam (1.0 g) dose to twice daily would be appropriate in patients with a CLCR between 7 and 30 ml/min. Doses should be given every 24 h for those undergoing maintenance hemodialysis. On hemodialysis days, doses should be given after hemodialysis.

Circulating concentrations of di(2-ethylhexyl) phthalate and its de-esterified phthalic acid products following plasticizer exposure in patients receiving hemodialysis.

The degree of exposure to the plasticizer di(2-ethylhexyl) phthalate (DEHP) was assessed in 11 patients undergoing maintenance hemodialysis for the treatment of renal failure. The amount of DEHP leached from the dialyzer during a 4-hr dialysis session was estimated by monitoring the DEHP blood concentration gradient across the dialyzer. Circulating concentrations of the biologically active products of DEHP de-esterification, viz., mono(2-ethylhexyl) phthalate (MEHP) and phthalic acid, were also determined during the dialysis session. On the average, an estimated 105 mg of DEHP was extracted from the dialyzer during a single dialysis session, with a range of 23.8 to 360 mg. The rate of extraction of DEHP from the dialyzer was correlated with serum lipid content as expressed by the sum of serum cholesterol and triglyceride concentrations (r = +0.65, p less than 0.05). Time-averaged circulating concentrations of MEHP during dialysis (1.33 +/- 0.58 micrograms/ml) were similar to those of DEHP (1.91 +/- 2.11 micrograms/ml). Blood concentrations of phthalic acid (5.22 +/- 3.94 micrograms/ml) were higher than those of the esters. The length of time patients had been receiving regular dialysis treatment was not a determinant of circulating concentrations of DEHP or MEHP. In contrast, time-averaged circulating concentrations of phthalic acid correlated strongly with the duration (in years) of dialysis treatment (r = +0.92, p less than 0.001). The results indicated substantial exposure to DEHP during hemodialysis and that the de-esterified products of DEHP are present in significant concentrations in the systemic circulation. Further study is needed to assess the contribution of these metabolites to the biological actions of DEHP in man.

Significance of isomerization in hydroxocobalamin.

Hydroxocobalamin is present in fairly large proportions both in foods and in the human body and apparently plays an important biological role. Since cyanocobalamin seems to play hardly any significant biochemical role in healthy humans, several physicians prefer to administer hydroxocobalamin to vitamin B12 deficient patients. We find that hydroxocobalamin in solution isomerizes very readily at room and lower temperatures. Our observations raise the question whether "Mother Nature" has gone awry in using an easily convertible substance like hydroxocobalamin or that the new isomeric forms play some significant role. These observations may also have a bearing on the reported occurrence of unidentified corrinoids in animal tissues, human red cells, liver and brain.

Photo-induced changes in proteins associated with floral induction in Amaranthus.

A. caudatus f. albiflorus, A. caudatus f. caudatus and A. tricolor var. tristis are qualitative SD plants with photo-inductive requirements of six, three and five, 8-hr photoperiodic cycles, respectively, for macroscopic inflorescence initiation. The total protein content gradually increased in both stem and leaves with an increasing number of inductive photoperiodic cycles. In both stem and leaves of all three plant types, two electrophoretically separable new water-soluble protein bands appeared with completion of their respective photo-inductive requirements for inflorescence initiation. In the stem of A. caudatus f. caudatus, a third band appeared after the plants had received only a single SD cycle. The new proteins formed concurrently with photoperiodic floral induction differed electrophoretically from plant to plant even though all plants used in the experiment were short-day plants and closely related taxonomically.

Treating acute hypertensive crisis with sodium nitroprusside.

In patients with dangerously elevated diastolic blood pressures, the titrated intravenous administration of sodium nitroprusside usually reduces blood pressure to near-normal levels in less than an hour. This rapid reduction of pressure is well tolerated by hypertensive patients and probably diminishes the morbidity from renal and cardiac failure and stroke. The side effects of sodium nitroprusside treatment are minimal.

Double spike in the electropherogram of a myeloma serum, from Bence Jones protein.

Serum from a 71-year-old man with multiple myeloma complicated with renal failure showed a monoclonal IgG lambda. A second spike appearing in the serum protein electropherogram, suggesting a biclonal gammopathy, was found to be due to lambda Bence Jones protein (29.9 g/liter). Lambda Bence Jones protein was also found in smaller concentration (3.8 g/liter) in the urine. Tetramers of Bence Jones protein were not demonstrable by gel filtration and ultracentrifugation, and renal failure was probably the main reason for this very high concentration of Bence Jones protein in the serum.

Monoclonal IgE with renal failure.

Only four cases of immunoglobulin E (IgE) monoclonal "gammapathies" have been reported previously. Discussed here is a 57 year old man who presented with hypertension and the nephrotic syndrome. A monoclonal IgE-kappa component (0.6 mg/ml), which did not appear as an M spike on protein electrophoresis, was demonstrated by immunoelectrophoresis in the serum and urine. The patient's condition deteriorated rapidly due to renal failure, and he died five weeks after the diagnosis was made. Pathologic examination disclosed extensive glomerular lesions, but amyloid was not detected by light or electron microscopy. The possible relationship between the monoclonal gammapathy and kidney impairment is discussed.

Digoxin pharmacokinetics: role of renal failure in dosage regimen design.

Radioimmunoassayed serum concentration and urinary excretion data for digoxin from azotemic patients were characterized using a 2-compartment open model. Urinary excretion rates of digoxin as well as serum concentration data are needed to accurately characterize the disposition of the drug. Seven patients with renal failure showed highly variable steady-state volumes of distribution (V-ss-D equals 195 to 489 liters/1.73 m-minus2) and t1/2beta values (1.5 to 5.2 days). This variability is a major limiting factor in the use of dosage regimen nomograms that assume a constant V-ss-D and a rigorous relationship between t1/2beta and creatinine clearance (Cl-CR). Body clearance (Cl-B) is a parameter that is affected by both elimination and distribution of drugs. A linear relationship between Cl-B and renal clearance of digoxin or Cl-CR was found and was used to develop a model-independent approach to calculation of maintenance doses of digoxin. Several methods for calculating steady-state serum concentrations of digoxin (C-ss-p) were compared with actual measurements obtained in 16 chronically medicated patients. Optimum computation of C-ss-p is obtained by use of digoxin renal and body clearances. Variability in the digoxin:creatinine renal clearance ratio is the major limiting factor in prediction of digoxin dosage regimens.