Aldehyde dehydrogenase is used by cancer cells for energy metabolism

We found that non-small-cell lung cancer (NSCLC) cells express high levels of multiple aldehyde dehydrogenase (ALDH) isoforms via an informatics analysis of metabolic enzymes in NSCLC and immunohistochemical staining of NSCLC clinical tumor samples. Using a multiple reaction-monitoring mass spectrometry analysis, we found that multiple ALDH isozymes were generally abundant in NSCLC cells compared with their levels in normal IMR-90 human lung cells. As a result of the catalytic reaction mediated by ALDH, NADH is produced as a by-product from the conversion of aldehyde to carboxylic acid. We hypothesized that the NADH produced by ALDH may be a reliable energy source for ATP production in NSCLC. This study revealed that NADH production by ALDH contributes significantly to ATP production in NSCLC. Furthermore, gossypol, a pan-ALDH inhibitor, markedly reduced the level of ATP. Gossypol combined with phenformin synergistically reduced the ATP levels, which efficiently induced cell death following cell cycle arrest.

Blockade of P-Glycoprotein Decreased the Disposition of Phenformin and Increased Plasma Lactate Level

This study aimed to investigate the in vivo relevance of P-glycoprotein (P-gp) in the pharmacokinetics and adverse effect of phenformin. To investigate the involvement of P-gp in the transport of phenformin, a bi-directional transport of phenformin was carried out in LLC-PK1 cells overexpressing P-gp, LLC-PK1-Pgp. Basal to apical transport of phenformin was 3.9-fold greater than apical to basal transport and became saturated with increasing phenformin concentration (2-75 µM) in LLC-PK1-Pgp, suggesting the involvement of P-gp in phenformin transport. Intrinsic clearance mediated by P-gp was 1.9 µL/min while passive diffusion clearance was 0.31 µL/min. Thus, P-gp contributed more to phenformin transport than passive diffusion. To investigate the contribution of P-gp on the pharmacokinetics and adverse effect of phenformin, the effects of verapamil, a P-gp inhibitor, on the pharmacokinetics of phenformin were also examined in rats. The plasma concentrations of phenformin were increased following oral administration of phenformin and intravenous verapamil infusion compared with those administerd phenformin alone. Pharmacokinetic parameters such as Cmax and AUC of phenformin increased and CL/F and Vss/F decreased as a consequence of verapamil treatment. These results suggested that P-gp blockade by verapamil may decrease the phenformin disposition and increase plasma phenformin concentrations. P-gp inhibition by verapamil treatment also increased plasma lactate concentration, which is a crucial adverse event of phenformin. In conclusion, P-gp may play an important role in phenformin transport process and, therefore, contribute to the modulation of pharmacokinetics of phenformin and onset of plasma lactate level.

Effect of phenformin hydrochloride on pharmacokinetics of puerarin in rats / 中国中药杂志

<p><b>OBJECTIVE</b>To study the effect of phenformin hydrochloride that may be illegally added in traditional Chinese medicine preparations on the pharmacokinetics of puerarin in rats.</p><p><b>METHOD</b>Rats were randomly divided into the single pueraria group and the phenformin hydrochloride combined with pueraria group. After oral administration in the two groups, their bloods were sampled at different time points to determine the drug concentration of puerarin in rat blood and calculate pharmacokinetic parameters.</p><p><b>RESULT</b>After oral administration with pueraria extracts and phenformin hydrochloride combined with pueraria extracts, the two groups showed main pharmacokinetic parameters as follows: Cmax were (2.39 +/- 1.01), (1.03 +/- 0.35) mg x L(-1), respectively; Tmax were (0.50 +/- 0.09), (1.5 +/- 0.5) h, respectively; Ke were (0.153 +/- 0.028), (0.172 +/- 0.042) h(-1), respectively; t(1/2) were (4.65 +/- 0.86), (4.20 +/- 0.81) h, respectively; AUC(0-t), were (5.73 +/- 2.60), (5.45 +/- 1.81) mg x h x L(-1), respectively; AUC(0-infinity) were (6.72 +/- 2.89), (6.26 +/- 1.88) mg x h x L(-1), respectively. Compared with the single puerarin group, the Cmax was significantly decreased (P < 0.05) and the Tmax was markedly longer (P < 0.01) than the hydrochloride combined with pueraria group.</p><p><b>CONCLUSION</b>Phenformin hydrochloride can slow down the absorption process of puerarin and change the pharmacokinetic process of puerarin to some extent.</p>

Levels of lactic acid, normal level & its relation to food, glucose, cholesterol, raised blood urea and phenformin therapy.

1. The level of lactic acid was found to be 25 mg percent in 95 percent of 186 normal Indians. There was no difference due to sex and age. 2. Level of lactic acid was estimated in blood of normal persons and diabetics Type II patients to observe the effects of food and glucose. There was no change except the level of lactic acid was in higher but in normal range. 3. Hyperglycemia of over 300 mg raised the blood lactic acid in 25 percent of patients. 4. Lactic acid was not affected by hypercholesteremia but was raised in 60 percent of cases with raised blood urea. 5. Lactic acid was found to remain within normal limits in 48 type II diabetics treated with phenformin dose varying from 50 mg to 225 mg per day. The duration of treatment varied from one year to seven years.

Tratamiento de intoxicaciones / Treatment of the intoxications

Se trataron 8 pacientes intoxicados por diferentes métodos: hemoperfusión, hemodiálisis, diálisis peritoneal afectados de diferentes tóxicos (se desarrolla botulismo, bromato de potasio y metanol), se discuten las indicaciones de tratamiento

Effect of bed time intermediate acting insulin in NIDDM subjects refractory to a combination of sulphonylureas and biguanides.

The effect of a single dose of intermediate acting (Lente) insulin given subcutaneously at 9.00 P.M. in 22 NIDDM subjects refractory to a combination of Sulphonylureas and Biguanides was analysed. Euglycemia was achieved and maintained during the study period of three months with a mean insulin requirement of 14.22 +/- 5.98 units/day. Plasma FFA, Total cholesterol, triglyceride and VLDL-cholesterol also showed significant reduction. The level of FFA modulates hepatic glucose production, which in turn correlates positively with the fasting blood glucose. The therapeutic modality of bed time Lente Insulin based on physiological principles is an effective way of achieving glycemic control in NIDDM subjects who have become non-responsive to oral hypoglycemic agents.

Biguanide-induced lactic acidosis.

Phenformin-induced lactic acidosis has been thought to be rare in India due to a high carbohydrate intake, use of suboptimal doses of phenformin and a lesser prevalence of alcoholism, as compared to Western countries. We studied the blood lactate levels of 31 non-insulin dependent diabetics (Group A) before and after treatment with phenformin, 75 mg/day for 4 weeks. Blood lactate rose significantly after treatment (mean +/- SEM 16.6 +/- 1.2 mg/dl to 30.7 +/- 2.2; p less than 0.01). Seven patients from this group had blood lactic acid level greater than 72 mg/dl. Six of these patients were restudied off treatment and after 4 weeks of phenformin therapy. The arterial blood pH, pCO2, pO2 and bicarbonate remained unchanged on treatment although a significant rise in blood lactic acid was reconfirmed in these 6 patients. Another group of 12 patients on phenformin for more than six months had significantly lower blood lactate levels as compared to group A (mean +/- SEM 20.2 +/- 1.8 mg/dl vs 30.7 +/- 2.2 mg/dl; p less than 0.01) indicating the possibility of a process of adaptation on prolonged treatment. This possibility was confirmed by a serial follow-up study of 11 patients for a 6 month period on phenformin therapy. A case of biguanide-induced lactic acidosis diagnosed and treated by us is described.

El sindrome de la regresion caudal.(A proposito de un caso). / Caudal regression syndrome. (Apropos of a case)

Aunque en 1972 Assemany denomino al sindrome de la regresion caudal, embriopatia diabetica phocomelica y dio de esta forma gran enfasis a la enfermedad metabolica presente en la madre, mas recientemente se ha precisado que solo en el 16% de tales ninos esta presente la diabetes en la madre y que solo en el 1% de los recien nacidos de madre diabetica se hace presente esta malformacion, aunque en nuestro servicio esta ha sido solo del 0,2%. Se discuten algunos fenomenos en relacion con las malformaciones en el hijo de madre diabetica, como son la lesion vascular presente en la madre de modo de tratemienro y el grado de control metabolico al momento de iniciar la gestacion, haciendose enfasis en que esta paciente tenia al momento de iniciado el embarazo un control metabolico que pudo ser calificado de "malo" con perfil promedio en 24 horas de 195 mg% (glucosa-oxidasa)

Effects of jambolan seed treatment on blood sugar, lipids and urea in streptozotocin induced diabetes in rabbits.

In New Zealand rabbits a single intravenous injection of streptozotocin (STZ 65 mg/kg) elevated the levels of blood sugar to 340 mg percent, which was associated with glycolysis, ureamia, hypercholesterolemia, hypertriglyceridemia and loss of body weight. Oral administration of jambolan seed (1 g/kg) in casein diet significantly lowered the elevated postmeal (1 1/2 hr after) values of blood sugar, cholesterol, FFA and triglyceride down to levels comparable to phenformin. Jambolan seed treatment failed to check ureamia. Weight loss was checked by phenformin and jambolan seed but the gain was not equivalent to that recorded in nondiabetic control. Like phenformin, jambolan seed too failed to control glycogenolysis in STZ-induced diabetes.

El fenformin y la actividad fibrinolitica en la trombosis venosa recurrencial. / Phenformin and fibrinolitic activity in recurrent venous thrombosis

Se realiza un estudio con el objetivo de determinar el efecto del fenformin sobre la actividad fibrinolitica en los pacientes que presentan trombosis venosa recurrencial (TVRC). Se estudiaron 10 pacientes a quienes se les diagnostico dicha enfermedad en el servicio de flebolinfologia del Instituto de Angiologia en el periodo comprendido de marzo a septiembre de 1980 y que al examen de laboratorio presentaban alteraciones de la actividad fibrinolitica. Se determino el porcentaje de lisis de sangre total y la lisis de euglobulina antes y despues del tratamiento en cada uno de los pacientes, y se compararon estos dos grupos de valores, a traves del estadistico (no parametrico) para muestras pareadas, sin encontrarse diferencias estadisticamente significativas entre los mismos, aunque se observa tendencia al aumento de la actividad fibrinolitica despues del tratamiento