Mapping the effect of drugs on ACE2 as a novel target site for COVID-19 therapy.

Angiotensin converting enzyme 2 (ACE2) has potentially conflicting roles in health and disease. COVID-19 coronavirus binds to human cells via ACE2 receptor, which is expressed on almost all body organs. Boosting the ACE2 receptor levels on heart and lung cells may provide more cellular enter to virus thereby worsening the infection. Therefore, among the drug targets, ACE2 is suggested as a vital target of COVID-19 therapy. This hypothesis is based on the protective role of the drugs acting on ACE2. Therefore, this review discusses the impact and challenges of using ACE2 as a target in the current therapy of COVID-19.

Removal of chlorophenols from wastewater using commercial acid washed activated carbon.

The presence of chlorophenols in wastewater represents a serious challenge for its treatment and its further reuse. In this study, the use of commercial acid washed activated carbon as sorbent material for the removal of 2 chlorophenol, 2,4 dichlorophenol and 2,4,6 trichlorophenol from synthetic. aqueous solutions is evaluated. Variables affecting the uptake of these compounds (weight of sorbent material, pH, temperature and shaking time) are investigated to achieve the optimum conditions of removal process. The kinetics of the uptake process indicated that the process was best explained using a pseudo-second order model. As well, the adsorption of the studied chlorophenols on commercially available AC followed the Freundlich isotherm. The thermodynamic parameters further indicated the favorability of the process and that the adsorption was primarily physical in nature enhanced by chemisorptions.

Effect of ketamine on cocaine-induced immunotoxicity in rats.

The abuse of cocaine (COC) with ketamine (KET) is currently popular among young drug abusers and has been associated with increased risk of human immunodeficiency virus (HIV) infection. The effect of subacute exposure to COC and KET alone and in combination on the immune system was assessed in adult male Sprague-Dawley (SD) rats. To simulate the route and mode of human exposure, rats were treated with COC alone (5 mg/kg, i.v.), KET alone (100 mg/kg, p.o.) or KET followed immediately by COC (same doses and routes of administration) once-a-day for 7 consecutive days. Rats were sacrificed 30 minutes following the last treatment. Total circulating leukocyte and lymphocyte counts were decreased with relative neutrophilia, whereas immunoglobulin M (IgM) antibody response to sheep erythrocytes (SRBCs) was increased in animals treated with COC. Moreover, treatment with COC alone increased serum interleukin-10 (IL-10) concentration; however, it did not affect serum interferon gamma (INF-gamma) concentration. Spleen histology showed hyperplasia of white pulp whereas thymus gland demonstrated mild cortical degeneration. On the other hand, KET treatment did not produce any significant change of any of these parameters. However, when coadministered with COC, significant reduction of bodyweight, spleen/bodyweight, and thymus/bodyweight ratios with degeneration of splenic white pulp and thymic cortex occurred. Moreover, the primary immunoglobulin response to SRBC and serum IL-10 concentration were decreased without significant change in serum IFN-gamma or circulating leukocytic counts. COC caused a significant increase in serum corticosterone concentration that KET effectively prevented. On the other hand, a significant increase in plasma and tissue concentrations of norcocaine (NC) resulted following KET and COC administration in combination. Daily SKF-525A pretreatment at a dose of 30 mg/kg, i.p., for 7 days 1 hour prior to KET and COC in combination effectively reversed the effects of this combination on body weight, organ/bodyweight ratios, histopathology, and serum IgM and IL-10 concentrations without affecting leukocytic counts. On the other hand, SKF-525A pretreatment did not change the immunomodulatory effects of COC compared to non-pretreated animals. The results suggest that COC-induced immunomodulation most likely occurred through neuroendocrinal mechanisms. On the other hand, enhanced oxidative metabolism of COC in the presence of KET-induced immunosuppression.

Oral cocaine produces dose-related hepatotoxicity in male mice.

Cocaine remains a widely abused substance. While most addicts take cocaine intranasally, a considerable number abuse cocaine by mouth. It has been assumed that after oral exposure cocaine is hydrolyzed in the stomach rendering it ineffective. This study investigated the effect of orally administered cocaine on liver function and integrity as well as its effect on liver and blood antioxidative enzymes. Male CF-1 mice were orally administered either 0, 5, 10 or 20 mg cocaine/kg body weight and sacrificed 24 h after the last treatment. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured as markers of liver injury. Blood and liver glutathione (GSH) levels were determined as well as the activities of glutathione peroxidase (GPx) and catalase (CAT). In addition, the activity of liver glutathione reductase (GRx) was also measured. The results demonstrated that oral cocaine caused hepatotoxicity in a dose dependent manner. Serum ALT and AST were elevated while blood GSH concentration decreased in all cocaine treated animals. In addition, there was a significant dose dependent decrease in the activities of GPx and CAT in blood and liver of cocaine treated animals. However, hepatic GSH content and GRx activity manifested a significant increase, particularly in the group, which received 20 mg/kg cocaine. This study is the first to demonstrate that cocaine-induced hepatotoxicity results following the oral route of administration.

Oral bioaccessibility of trivalent and hexavalent chromium in soil by simulated gastric fluid.

Chromium is found in soil from natural sources and anthropogenic activities. The ingestion of soil contaminated with chromium especially by children can have toxic consequences. Therefore, it is important to quantify the oral bioaccessibility of chromium in chromium in contaminated soil. In this study, chromium-51 as chromic (III) chloride and sodium chromate (VI), was mixed with an Atsion sandy soil and a Keyport clay soil and stored for 4 mo at either 21-25 degrees C or 2-4 degrees C. Utilizing simulated gastric conditions, the oral bioaccessibility of chromium in soil was determined. When the effects of soil on the bioaccessibility of chromium were compared, the data revealed the the bioaccessibility of chromium (III) from the clay soil was significantly lower than from the sandy at 21-25 degrees C. However, at 2-4 degrees C, more chromium (III) was extracted by synthetic gastric fluid from the clay soil than from the sandy soil. Temperature was also a factor as evidenced by the higher bioaccessibility of chromium (IV) in the sandy soil at 2-4 degrees C and of both chromium species in the clay soil at the same temperature. Reduction of the soluble chromium (VI) chemical to the nonsoluble chromium (III) compound in the acidic soils by naturally occurring organic matter in soil would explain the lower bioaccessibilty of chromium (VI) at 21-25 degrees C. At 2-4 degrees C, the data indicate that the rate of chromium (VI) reduction to chromium (III) was slowed. Although the results of this study are limited to one low concentration of chromium (III) and chromium (VI) and indicate that the bioaccessibility of chromium in soil can range between 18% and 72%, the data also suggest that there may be a potential health hazard from oral exposure to chromium in heavily contaminated sites. Therefore, more extensive research should be conducted to determine if thes findings can be extended to environmentally relevant concentrations.

The role of enzyme induction and inhibition on cypermethrin hepatotoxicity.

Cypermethrin at different concentrations (100, 200, 400 and 800 ng ml(-1)) was incubated with a primary culture of rat hepatocytes. Cypermethrin was cytotoxic to rat hepatocytes at concentrations of 200 ng ml(-1)or greater. Toxicity was measured by a decrease in cell viability and leakage of ALT and AST enzymes into the culture medium. The role of cytochrome P450 in the hepatotoxicity of cypermethrin insecticide was investigated in fresh hepatocytes isolated either from phenobarbital pretreated rats or control rats and coincubated with SKF525A. Pretreatment with phenobarbital strongly protected the hepatocytes against the cypermethrin induced loss of cell viability percentage and increased enzyme leakage percentage. Coincubation of the hepatocytes with SKF525A, a well-known cytochrome P450 inhibitor, substantially potentiated the effect of cypermethrin on cell viability and enzyme leakage. These results suggest that the cytocidal hepatotoxicity of cypermethrin in primary hepatocyte culture depends on its parent compound and phenobarbital, as a cytochrome P450 inducer, could be of therapeutic value.

Geographic information systems as a tool for control program management for schistosomiasis in Egypt.

During a 4-year study a geographic information system (GIS) risk model was constructed for predicting the relative risk of schistosomiasis in Kafr El-Sheikh governorate, Egypt. A 1-year 1990-1991 time series on diurnal temperature difference (dT) prepared from the advanced very high resolution radiometer (AVHRR) sensor on the NOAA-11 satellite was used to develop a regional risk model for the Nile delta based on thermal-hydrological domains. A May 15, 1990 Landsat TM scene (path 177, Row 38) was used to develop a local 'village-scale' environmental risk model based on higher resolution satellite sensor data (30 m picture element size at earth surface). Four of ten classes derived from a tasseled cap (Tcap) transformation of the Landsat TM scene were shown to be significantly related to a 5-year Schistosoma mansoni prevalence database from the Ministry of Health. A risk model was developed based on dT and the proportional area of the four Tcap classes in 5 km(2) buffer zones centered on rural health unit (RHU) reporting units. Available historical data on S. mansoni and its snail host Biomphalaria alexandrina, as well as recent field collected data were gathered and incorporated as separate themes. Model validation was done using data collected on snail population bionomics-infection rates, water quality, underground water table and cercariometry at 13 hydrologically representative sites. The role of soil type, water table and water quality was studied at 79 of 154 rural health unit sites. The model permitted retrieval of relevant data by RHU point location. For the first time in Egypt, the Kafr El-Sheikh GIS schistosoma prediction model can support MOH efforts to make more accurate control program decisions based on environmental predilection sites of endemic Schistosomiasis mansoni.

In vitro penetration of soil-aged mercury through pig skin.

The dermal bioavailability of mercury "aged" in soil for 3 mo was compared to that of pure mercury (without soil) and to mercury in brief contact with soil (16 h). Studies were conducted in vitro with [203Hg]mercuric chloride on dermatomed male pig skin by flow-through diffusion cell methodology. Less than 0.5% of the initial mercury dose penetrated through skin into receptor fluid after each treatment. The majority of pure mercury became covalently bound to skin. However, a short contact time with either an Atsion (sandy) or Keyport (clay) soil significantly decreased the total penetration of mercury (sum of receptor fluid and skin) by 40%. After aging, a 95% reduction in total penetration was observed for the compound relative to chemical without soil. Both soils bind mercury more strongly with time, as evidenced by larger quantities of radioactivity in soil and smaller amounts in skin decontaminate after aging than in soil for 16 h. Decreased mercury bioavailability with aging indicates lower health risk and reduced need for soil cleanup.

Teratogenic effect of ketamine and cocaine in CF-1 mice.

Pregnant CF-1 mice were used to study the teratogenic effect of ketamine and cocaine, alone and in combination. The dose of ketamine was 50 mg/kg and that of cocaine was 20 mg/kg, given intravenously (tail) once daily (these doses of ketamine and cocaine are comparable to doses used by addicted humans). Treatment was started from day 6 to day 15 of gestation, and dams were sacrificed on day 18. There were significant decreases in the fetal weight and length in the combined group. Skeletal defects such as incomplete ossification of skull bones and vertebrae were observed in both the cocaine and combined group, compared with the control. An increased frequency of cerebral and abdominal hemorrhages as well as hydrocephalus and hydronephrosis was observed in the combined group. This study showed that fetal exposure to ketamine and cocaine in combination was more teratogenic than each drug alone in CF-1 mice.

Effects of omeprazole on ethanol lesions.

Male Sprague-Dawley rats were used to study the effects of omeprazole on normal and ethanol damaged gastric mucosa, and to estimate plasma gastrin levels following the administration of omeprazole for 2 weeks. The dosage of omeprazole was 50 mg/kg body weight, once daily via gavage. In omeprazole treated animals, serum gastrin levels showed statistically significant increases compared with the control and ethanol treated animals. Our results indicate that omeprazole has no protective effect on ethanol-induced alterations in gastric mucosa and, in fact, appears to produce worsened lesions. In achlorohydric doses, omeprazole can induce significant gastrin levels with consequent hypertrophy and hyperplasia of enterochromaffin-like cells and somatostatin cells. It is believed that this powerful drug should be reserved for patients who are refractory to standard H(2)-receptor antagonist therapy.

Hepatotoxicity of flunitrazepam and alcohol in vitro.

Flunitrazepam (FNZ) is a benzodiazepine derivative more potent than diazepam. FNZ abuse in the US has emerged in the last few years and has a growing popularity among young people and drug abusing populations. Ethanol (EtOH) consumption with FNZ enhances euphoria and onset of action. It is postulated that FNZ and EtOH cause liver cell injury. In this study, hepatocytes are employed to study the hepatotoxicity of FNZ, EtOH and their combination (FNZ-EtOH). Hepatocytes (2x10(6) cells/ml) isolated from male Sprague-Dawley rats were exposed to saline, FNZ, EtOH or FNZ-EtOH in combination. The uptake of 0.4% trypan blue and the leakage of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes into the incubation media were used to assess cell membrane damage of hepatocytes. Where metabolism of FNZ is nearly complete through several hepatic pathways, animal pretreatment with Phenobarbital was used to study the effect of microsomal enzyme induction on cellular injury. FNZ (0.16mm), EtOH (32.56mm) or their combination caused a significant (P<0.05) decrease in cell viability. Compared with control, FNZ and FNZ-EtOH in combination caused significant AST leakage over the 2-hour incubation period. EtOH alone caused significant AST leakage after 2 hours of incubation. The leakage of ALT enzyme was significant for FNZ, EtOH and FNZ-EtOH over the 2-hour incubation period. While FNZ alone did not produce any significant enzymatic leakage in the Phenobarbital pretreated groups, the leakage of ALT and AST were significant for FNZ-EtOH in combination as early as 30 minutes of incubation. A significant depletion (P<0.05) of glutathione (GSH) was observed for EtOH and FNZ-EtOH in combination treated samples. This investigation suggests that FNZ and EtOH cause hepatotoxicity, and their combinations have an additive effect in increasing liver toxicity. Induction of microsomal enzymes revealed that FNZ is more hepatotoxic than the metabolites. And FNZ alone has no effect on GSH content.

Pharmacokinetics of acrylamide after oral administration in male rats.

Acrylamide (AMD) is a commonly used industrial chemical. However, it produces a dying back type of peripheral neuropathy in animals and man. This study was performed to investigate the pharmacokinetics of AMD after oral administration at 50 mg/g ([1-(14)C]AMD) in male Sprague-Dawley rats. Absorption from the gastrointestinal tract was rapid and radioactivity was detected in blood 5 min post-administration. The peak plasma concentration occurred 38 min after administration and was equivalent to 47 µg/ml. The elimination pattern for plasma was fitted to a one-compartment model with 6 h half-life. However, in the blood the elimination pattern was fitted to a two-compartment model with 7.93 and 374 h for distribution and elimination phases, respectively. Tissue concentrations of radioactivity determined at 28 and 144 h post-administration differed substantially. After 28 h the highest activity was in the gastric content, followed by stomach, lung, bone marrow and skin, while after 144 h the order of total radioactivity was lung>bone marrow>esophagus. The activities in the rest of the organs in both experiments were very low. The excretion study revealed that the kidney is the major route of elimination and the majority of radioactivity in urine was excreted during the first 12 h. The feces contained approximately 10% of the administered dose after 144 h. This study indicated that AMD is rapidly absorbed from the rat's gastrointestinal tract, distributed and eliminated from the body. AMD bound but did not accumulate in the erythrocytes or the neural tissues.

Ethanol does not increase the hepatotoxicity of cocaine in primary rat hepatocyte culture.

Rat hepatocytes were utilized to investigate the role of cocaine metabolism and the contribution of ethylcocaine formation to cocaine-induced liver damage. Hepatocytes were prepared from rats pretreated with saline, phenobarbital or ethanol and exposed to cocaine, ethanol, or their combination. Hepatotoxicity was assessed by lactate dehydrogenase (LDH) leakage and was correlated with cocaine metabolism which was assessed quantitatively using HPLC. Only phenobarbital-pretreatment produced increases in LDH leakage from cultures exposed to cocaine. This increase in LDH release occurred simultaneous to a decrease in benzoylecognine formation and a marked increase in norcocaine generation. Exposing cultures to ethanol alone did not result in LDH leakage from hepatocytes. Furthermore, including ethanol in cultures treated with cocaine did not enhance the LDH leakage produced by cocaine alone. This study confirms quantitatively that cocaine-induced hepatotoxicity is mediated through cocaine oxidative events and is enhanced by microsomal induction produced by phenobarbital. The finding that ethylcocaine formation was maximal in the ethanol-pretreatment group where no toxicity was observed suggests that ethylcocaine is not the agent responsible for the hepatotoxicity observed in this study.

Effect of alcohol and/or cocaine on blood glutathione and the ultrastructure of the liver of pregnant CF-1 mice.

Alcohol and cocaine are abused by the general population as well as by pregnant women. Since alcohol and cocaine are hepatotoxic, pregnant mice were used to study the effect of alcohol and/or cocaine on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and on liver ultrastructure. Also, blood glutathione (GSH) and GSH related enzymes such as glutathione reductase (GSH-Rx) and glutathione peroxidase (GSH-Px) were studied. The mice were treated with 0.6 g/kg ethanol twice daily via gavage and/or 20 mg/kg of cocaine hydrochloride intravenously once daily. The treatment was from day 6 to 15 of gestation and these studies were performed at day 18. Our results indicated a significant increase in AST level after treatment with ethanol alone or in combination with cocaine. The blood GSH levels decreased significantly in all the treated groups compared to the control. The activity of GSH-Px was significantly decreased only in the ethanol and cocaine combination group compared to the control. Histopathological studies indicated that co-administration of ethanol and cocaine lead to a significant potentiation in liver toxicity as indicated by increased fatty infiltration.

Effect of propofol on perception of pain in mice: mechanisms of action.

The latencies of pain threshold to different subhypnotic doses (12.5, 25 and 50 mg kg-1) of propofol, an anaesthetic, administered intraperitoneally (i.p.) into male mice were measured using a hot plate method. The possible mechanism of pain control by propofol was also investigated through blocking beta-endorphin receptors and measuring serum level of beta-endorphin. Morphine (1.5 mg kg-1; i.p.) was used as a reference of reduction of pain sensation. The results showed that propofol in doses of 25 and 50 mg kg-1 significantly (P < 0.01) increased the latency of pain threshold but a lower dose (12.5 mg kg-1) failed to produce any significant change. This indicates that propofol reduced pain and this effect is dose-dependent. Propofol prevents hyperalgesia produced by prostaglandin PGE2, (0.5 mg kg-1, i.p.; P < 0.01). Pretreatment with naloxone (1.0 mg kg-1, i.p.) abolished significantly (P < 0.01) the antinociceptive action of propofol. Furthermore, serum level of beta-endorphin was increased (P < 0.01) after propofol injection particularly at the peak time of propofol action. The serum level of corticosterone was also increased (P < 0.01) at the time of beta-endorphin release. It was concluded that propofol can control pain and this action may be centrally modulated through the opioid system rather than at the level of the spinal cord.

Trials for control of ixodid ticks using pheromone acaricide tick decoys.

Experimental application of Hyalomma dromedarii pheromone-impregnated in cyfluthrin (pyrethroid) decoys on experimentally infested camels revealed efficacy rate of 85.33%, while the control group showed normal pattern of tick engorgement. This study proved the rapid movement of males toward decoys and some males took the mounting position with such decoys. On the other side, the same decoys (H. dromedarii) when used on naturally infested cattle with Boophilus annulatus did not even disturb the Boophilus ticks indicating that B. annulatus contain specific pheromones which should be furtherly identified.

Kinetics and rat locomotor activity following cocaine and lidocaine administration.

Cocaine abuse is a widespread problem in the USA. Illicit cocaine is usually never found in pure form but is adulterated with other agents, among which are the local anesthetics such as lidocaine. Adulteration of cocaine with another active agent allows the potential for various drug-drug interactions to occur. The presence of an additional active agent in illicit cocaine samples can complicate the pharmacological and toxicological responses elicited and possibly the mode of emergency medical care thereafter. When studying drug interactions, both the kinetic and dynamic aspects of each agent must be considered. This study investigated the plasma time course and tissue distribution of cocaine and lidocaine alone and in combination following a 5 mg kg(-1) intravenous injection in rats. The plasma time course of cocaine and lidocaine in combination did not differ from that seen when each drug was alone. Tissue contents were without change when administered alone or in combination at 5, 10 and 15 min following treatment. However, rats treated with cocaine and lidocaine in combination had significantly greater locomotor activity initially than animals treated with cocaine alone. The results suggest that cocaine and lidocaine interact on a pharmacodynamic basis without a change in the drug level of each agent.

Hepatoprotective activity of thymoquinone in isolated rat hepatocytes.

Thymoquinone, the active constituent of Nigella sativa, was tested in isolated rat hepatocytes as a hepatoprotective agent against tert-butyl hydroperoxide (TBHP) toxicity. TBHP (2 mM) was used to produce oxidative injury in isolated rat hepatocytes and caused progressive depletion of intracellular glutathione (GSH), loss of cell viability as evidenced by trypan blue uptake and leakage of cytosolic enzymes, alanine transaminase (ALT) and aspartic transaminase (AST). Preincubation of hepatocytes with 1 mM of either thymoquinone or silybin, which is a known hepatoprotective agent, resulted in the protection of isolated hepatocytes against TBHP induced toxicity evidenced by decreased leakage of ALT and AST, and by decreased trypan blue uptake in comparison to TBHP treated hepatocytes. Both thymoquinone and silybin prevented TBHP induced depletion of GSH to the same extent. Although thymoquinone protected the liver enzymes leakage, the degree of protection was less than that caused by silybin.

The role of oestradiol on the dermal penetration of phenol, alone or in a mixture, in ovariectomized rats.

The human body, as well as that of animals, is almost entirely covered by skin. As a result, skin is considered the first line of defence against various types of chemicals. Many factors can affect the rate of dermal penetration of these agents either by enhancing or decreasing penetration. The aim of this study was to demonstrate the effect of oestradiol on the dermal penetration of phenol, a major chemical found in industry and hazardous waste sites. The effect of oestradiol on the dermal penetration of phenol was assessed by applying (14)C-phenol alone or in combination with trichloroethylene (TCE) to dermatomed female and male rat back skin samples in flow-through diffusion cells for 16 hours. The penetration of phenol alone was significantly lower in the ovariectomized group compared with female controls. Oestradiol restoration increased the dermal penetration of phenol alone while TCE enhanced phenol penetration in the ovariectomized group to reach control values. When the ovariectomized group receiving testosterone was treated with phenol alone or with the phenol-TCE mixture, the dermal penetration of phenol resembled the control males. These findings revealed that oestradiol plays a major role in increasing the penetration of phenol either alone or in a mixture.

Acrylamide toxicity in isolated rat hepatocytes.

Acrylamide (ACR) is an important industrial chemical used primarily in the production of polymers and co-polymers. Acrylamide is mainly neurotoxic to experimental animals as well as humans and has also been shown to be mutagenic and carcinogenic. The present study was designed to investigate the toxicity of ACR on isolated rat hepatocytes. The hepatocytes were isolated by collagenase perfusion method and were incubated with different concentrations of ACR (0.1, 1, 10mm) for 2 hours. Cell viability by trypan blue exclusion and leakage of the enzymes such as alanine transaminase (ALT) and aspartate transaminase (AST) were determined. Reduced glutathione (GSH), glutathione S-transferase (GST) activity were also measured. A significant decrease in the cell viability was observed after exposure to 10mm ACR for 30min, while 1mm ACR caused a significant decrease in the viability after 60min. ALT leakage was parallel to the cell viability. AST leakage was significantly increased at 30min of incubation with 10mm ACR, whereas 2 hours of incubation was required for the leakage of AST from rats hepatocytes with 1mm ACR. 10mm ACR decreased significantly GSH as early as 30min, while GSH level was decreased at 60min after exposure to 1mm ACR. Also, the GST activity increased with increasing the dose of ACR. Cytochrome P450 concentration was decreased after exposure to 10mm ACR. The effect of ACR on cell viability, ALT and AST leakage, GSH and GST activity was time and dose dependent.