Immune-related therapeutics: an update on antiviral drugs and vaccines to tackle the COVID-19 pandemic

The coronavirus disease 2019 (COVID-19) pandemic rapidly spread globally. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, is a positive-sense single-stranded RNA virus with a reported fatality rate ranging from 1% to 7%, and people with immune-compromised conditions, children, and older adults are particularly vulnerable. Respiratory failure and cytokine storm-induced multiple organ failure are the major causes of death. This article highlights the innate and adaptive immune mechanisms of host cells activated in response to SARS-CoV-2 infection and possible therapeutic approaches against COVID-19. Some potential drugs proven to be effective for other viral diseases are under clinical trials now for use against COVID-19. Examples include inhibitors of RNA-dependent RNA polymerase (remdesivir, favipiravir, ribavirin), viral protein synthesis (ivermectin, lopinavir/ritonavir), and fusion of the viral membrane with host cells (chloroquine, hydroxychloroquine, nitazoxanide, and umifenovir). This article also presents the intellectual groundwork for the ongoing development of vaccines in preclinical and clinical trials, explaining potential candidates (live attenuated-whole virus vaccines, inactivated vaccines, subunit vaccines, DNA-based vaccines, protein-based vaccines, nanoparticle-based vaccines, virus-like particles and mRNA-based vaccines). Designing and developing an effective vaccine (both prophylactic and therapeutic) would be a long-term solution and the most effective way to eliminate the COVID-19 pandemic.

Development and optimization of metoclopramide containing polymeric patches: impact of permeation enhancers

Abstract The study is aimed to develop a monolithic controlled matrix transdermal patches containing Metoclopramide as a model drug by solvent casting method. Eudragit L100, Polyvinylpyrrolidone K-30, and Methylcellulose were used in different ratios and Polyethylene glycol 400 added as a plasticizer. Resulting patches were evaluated for their physicochemical characters like organoleptic characters, weight variation, folding endurance, thickness, swelling index, flatness, drug content, swelling index, percentage erosion, moisture content, water vapor transmission rate and moisture uptake. Formed patches were also evaluated through Fourier transform spectroscopy (FT-IR), X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Scanning Electron Microscopy (SEM). Results of SEM unveiled smooth surface of drug-loaded patches. In-vitro dissolution studies were conducted by using dissolution medium phosphate buffer saline pH 7.4. Effect of natural permeation enhancers was elucidated on two optimized formulations (Z4 and Z9). Different concentrations (5%-10 %) of permeation enhancers i.e. Olive oil, Castor oil and Eucalyptus oil were evaluated on Franz diffusion cell using excised abdominal rat skin. Z4-O2 (Olive oil 10%) had enhanced sustain effect and flux value (310.72) close to the desired flux value. Z4-O2 followed Higuchi release model (R2= 0.9833) with non-fickian diffusion release mechanism (n=0.612)

Clinical Applications of Dual-Energy CT

Dual-energy CT (DECT) provides insights into the material properties of tissues and can differentiate between tissues with similar attenuation on conventional single-energy imaging. In the conventional CT scanner, differences in the X-ray attenuation between adjacent structures are dependent on the atomic number of the materials involved, whereas in DECT, the difference in the attenuation is dependent on both the atomic number and electron density. The basic principle of DECT is to obtain two datasets with different X-ray energy levels from the same anatomic region and material decomposition based on attenuation differences at different energy levels. In this article, we discuss the clinical applications of DECT and its potential robust improvements in performance and postprocessing capabilities.

Clinical Applications of Dual-Energy CT

Dual-energy CT (DECT) provides insights into the material properties of tissues and can differentiate between tissues with similar attenuation on conventional single-energy imaging. In the conventional CT scanner, differences in the X-ray attenuation between adjacent structures are dependent on the atomic number of the materials involved, whereas in DECT, the difference in the attenuation is dependent on both the atomic number and electron density. The basic principle of DECT is to obtain two datasets with different X-ray energy levels from the same anatomic region and material decomposition based on attenuation differences at different energy levels. In this article, we discuss the clinical applications of DECT and its potential robust improvements in performance and postprocessing capabilities.

Manuka honey enhanced sensitivity of HepG2, hepatocellular carcinoma cells, for Doxorubicin and induced apoptosis through inhibition of Wnt/ß-catenin and ERK1/2

BACKGROUND: Recently, there is increasing awareness focused on the identification of naturally occurring anticancer agents derived from natural products. Manuka honey (MH) has been recognized for its biological properties as antimicrobial, antioxidant, and anticancer properties. However, its antiproliferative mechanism in hepatocellular carcinoma is not investigated. The current study focused mainly on investigating the molecular mechanism and synergistic effect of anticancer properties of MH on Doxorubicin (DOX)-mediated apoptotic cell death, using two different p53 statuses (HepG2 and Hep3B) and one non-tumorigenic immortalized liver cell line. RESULTS: MH treatment showed a proliferative inhibitory effect on tested cells in a dose-dependent manner with IC50 concentration of (6.92 ± 0.005%) and (18.62 ± 0.07%) for HepG2 and Hep3B cells, respectively, and induced dramatic morphological changes of Hep-G2 cells, which considered as characteristics feature of apoptosis induction after 48 h of treatment. Our results showed that MH or combined treatments induced higher cytotoxicity in p53-wild type, HepG2, than in p53-null, Hep3B, cells. Cytotoxicity was not observed in normal liver cells. Furthermore, the synergistic effect of MH and Dox on apoptosis was evidenced by increased annexin-V-positive cells and Sub-G1 cells in both tested cell lines with a significant increase in the percentage of Hep-G2 cells at late apoptosis as confirmed by the flow cytometric analysis. Consistently, the proteolytic activities of caspase-3 and the degradation of poly (ADP-ribose) polymerase were also higher in the combined treatment which in turn accompanied by significant inhibitory effects of pERK1/2, mTOR, S6K, oncogenic ß-catenin, and cyclin D1 after 48 h. In contrast, the MH or combined treatment-induced apoptosis was accompanied by significantly upregulated expression of proapoptotic Bax protein and down-regulated expression of anti-apoptotic Bcl-2 protein after 48 h. CONCLUSIONS: Our data showed a synergistic inhibitory effect of MH on DOX-mediated apoptotic cell death in HCC cells. To our knowledge, the present study provides the first report on the anticancer activity of MH and its combined treatment with DOX on HCC cell lines, introducing MH as a promising natural and nontoxic anticancer compound.

Acute toxicity study of a polysaccharide based hydrogel from linseed for potential use in drug delivery system

ABSTRACT Linseed hydrogel (LSH) was evaluated by acute toxicity for its potential application in oral drug delivery design. White albino mice and rabbits were divided in four groups (I-IV) and different doses of LSH (1, 2 and 5 g/kg body weight) were given except to the control group (I) that was left untreated. Rabbits were monitored for eye irritation, acute dermal toxicity and primary dermal irritation, whereas, body weight, food and water consumption, hematology and clinical biochemistry, gross necropsy and histopathology of vital organs were scrutinized in mice. LSH was considered safe after eye irritation test as no adverse signs or symptoms were seen in the eye. In dermal toxicity and irritation study, skin of treated rabbits was found normal in color without any edema or erythema. After oral administration, there was no sign of any abnormalities in treated group animals (II-IV). The hematology and clinical biochemistry of treated group animals was comparable with the control group. Histopathology of vital organs has not shown any lesion or abnormalities. In the light of these outcomes, it can be concluded that LSH is not a hazardous biomaterial and could be incorporated as an excipient in oral and dermal preparations.

Appraisal of acute oral toxicity of glucuronoxylan hydrogel from Mimosa pudica seeds

Glucuronoxylan hydrogel (GXH) isolated from M. pudica seeds was assessed for acute toxicology in albino mice that were alienated into four groups. Three groups, i.e., II, III and IV received GXH at a dose of 1, 2 and 5 g/kg, respectively while group I was retained untreated and provided routine diet. After administering GXH, mice were examined for vomiting, diarrhea, allergy and tremors for 8 h. All animals were carefully observed for food and water consumption at 1, 2, 3, 7 and 14 day after administering GXH. At the end of studies, blood samples were drawn for investigation of hematological and biochemical parameters. All animals were sacrificed, relative body weight of vital organs was calculated and their histopathology was studied. It was concluded that there was insignificant difference in body weight, behavioral pattern, food and water intake among treated and control groups. Haematology and biochemistry of blood samples from all groups were found analogous. Histopathological evaluation of vital body organs exhibited no lesions in all groups. Ocular, cardiac and dermal safety of GXH was also established on albino rabbits.

computational structural analysis of functional attributes of hypodermin A and B proteins: a way forward for vaccine development

Hypodermosis is a parasitic disease of cattle. The pathogenicity of the disease is attributed to Hypodermin proteins [Hypodermin A, Hypodermin B and Hypodermin C]. Studies suggest that Hypodermin proteins may be defined as Serine proteases and collagenases. The structure of both proteases Hypodermin A and Hypodermin B were modeled using the Swiss-model server followed by its validation using Procheck, Errat and Verify-3D. Afterwards, both Hypodermin A and Hypodermin B were docked against collagen in order to study its interaction with respective Hypodermin proteins. The structure of both Hypodermin A and Hypodermin B showed more bent towards hydrophobic nature, as more beta sheets were present in them. Both structures were also superimposed to check out similarities and differences present between them. Serine, Aspartic acid, Histidine, Glutamic acid and Lysine are found as interacting residues that are involved in hydrogen bonding with collagen. The interactions are found in the active domain region of Hypodermin proteins. The interacting residues were present in the active region of the hypodermin proteins thus validating the docking studies. This study may help in the drug development against hypodermosis with least side effects

large infantile capillary hemangioma of the eyelid with 5 years follow-up

A five-day baby girl presented with a large mass involving the right upper and lower eyelid obstructing the visual axis completely. She was treated with intralesional triamcinolone acetonide injection under general anesthesia but no change in size of the tumor was observed. Oral beta blocker, propranolol, 1 mg/kg body weight, was given at three months. After two months, no significant change in tumor size was seen. The tumor was managed by surgical excision. There was no effect of intralesional triamcinolone acetonide and oral beta blockers. Even with surgical excision, there was recurrence of tumor

A Case of Sub Hepatic Perforated Appendicitis Presented as Multiple Gas Containing Subcapsular Hepatic Abscesses.

Appendicitis is the most common acute surgical condition of the abdomen. The diagnosis of acute appendicitis can often be made clinically. When the appendix is situated in an abnormal position, the diagnosis of acute appendicitis becomes difficult. Delayed diagnosis or misdiagnosis of subhepatic appendicitis might lead to perforations of the appendix, which is a clinical emergency. Liver abscess as a complication of appendicitis was first described in 1898 by Dieulafoy. The majority of pyogenic liver abscesses are caused by infection originating in the biliary or intestinal tracts. Pyogenic liver abscess is a rare complication of acute appendicitis. Multiple pyogenic liver abscesses are not frequently reported in the literature, but the overall mortality is high, if left with no treatment or not treated early. We have reported a case of subhepatic perforated appendix presented with multiple subcapsular liver abscesses.

Prophylactic rectal nsaids in the prevention of post-ercp pancreatitis

Objective: To evaluate the effectiveness of rectal non-steroidal anti-inflammatory drugs [NSAIDs] using diclofenac in preventing pancreatitis following ERCP

Methodology: It was a randomized, double blinded, placebo controlled study carried out at Surgical Unit-l, Holy Family Hospital, Rawalpindi from May 2013 to April 2014. A total of 108 patients were included and randomly assigned in each of study and placebo groups. Group I patients received 100 mg of diclofenac per rectally while group II patients received a glycerine suppository per rectally [placebo] before the start of ERCP. Post ERCP pancreatitis [PEP] was diagnosed by clinical evaluation and raised serum amylase levels after four hours of the procedure in both groups [study vs control]

Results: Out of 108 patients 32 were males and 76 were females. Mean age was 46.09 +/- 12.31 in group I, while it was 42.93 +/- 14.69 in Group II. Mean serum amylase level, 4 hours after ERCP, was 184.70 +/- 36.34 in the diclofenac group, while it was 388.20 +/- 57.27 IU/L in the control group. Thirty one patients were diagnosed with Post ERCP pancreatitis, out of which nine patients belonged to the study group and twenty two were of the control group [P = 0.000]

Conclusion: Per-rectal administration of diclofenac suppository prior to ERCP results in significant reduction in the frequency of ERCP induced pancreatitis

Can rubber band ligation replace hemorrhoidectomy as a treatment of choice for 3rd degree hemorrhoids: a review

Hemorrhoids are a common cause of rectal bleeding with a prevalence of 4 to 40% worldwide, varying in different geographical locations. The current treatment modality for 3rd degree hemorrhoids includes hemorrhoidectomy, but newer methods like rubber band ligation are rapidly gaining popularity. The purpose of our review was to establish if rubber band ligation can replace the traditional hemorrhoidectomy for the treatment of 3rd degree hemorrhoids.All databases were searched for relevant studies. A total of sixteen studies were included in the review. Current national and international literature points out that the results of rubber band ligation are comparable to hemorrhoidectomy and there are lesser complications associated with rubber band ligation.Reviewing the current recommendations, results, evidence and literature, our study recommends rubber band ligation as the treatment of choice for 3rd degree hemorrhoids

Is routine histopathology of gall bladder after laparoscopic cholecystectomy needed?: a local perspective

Background: Laparoscopic Cholecystectomy is one of the most commonly performed routine operation in modern general surgery. All surgical specimens are routinely sent for histopathology. A wide spectrum of variations is seen under the microscope. Rarely, carcinoma is discovered on histopathological examination. The purpose of the article was to identify and elaborate the major histopathological findings of gallbladder after laparoscopic cholecystectomy in a tertiary health care hospital in Pakistan

Methods: This was a retrospective study and included histopathological specimens of gall bladder after cholecystectomy from February 2004 to April 2013. Data was analysed using MS Excel and SPSS 19.0

Results: Total number of cases: 8376, Chronic Cholecystitis: 7705, Acute or chronic cholecystitis with empyema, mucocele or gangrene: 554, Adenocarcinoma: 91, Adenomatous polyp: 3, Squamous cell carcinoma: 5, Papillary carcinoma: 3, Clear cell carcinoma: 4, Adenosquamous carcinoma: 2, Xanthogranulomatous changes: 54, Dysplasia: 13 and Cholesterosis: 1050

Conclusion: Considering the evidence from our study and the evidence from the literature reviewed, it can be concluded that prevalence of all kinds of gall bladder disease, benign or malignant including carcinoma is no different from the rest of the world. Routine histopathology of gall bladder can be omitted without compromising patient safety as proven and practiced by many centers across the globe

Frequency of hypomagnesemia in patients with uncontrolled type II diabetes mellitus

Objective: The objective of this study was to determine the frequency of Hypomagnesemia in patients with uncontrolled type II diabetes mellitus

Study Design: Cross-sectional study

Place and Duration of Study: Department of Medicine, PNS Shifa Naval Hospital Karachi, from Jul 2012 to Dec 2012 over a period of six months

Material and Methods: In this study, three hundred and twenty three patients of uncontrolled diabetes mellitus type-II on oral hypoglycemic agents for more than five years, presenting to medical OPD, were recruited. All patients fulfilled inclusion and exclusion criteria. Blood samples of all patients for serum HbA1c and serum magnesium levels were analyzed at the time of enrollment. Statistical analysis was done on SPSS 20

Results: Out of 323 patients, 243 [75.23%] were males and 80 [24.76%] were females with the age ranging from 40 - 65 years [mean age and SD 54.76 +/- 6.43]. Hypomagnesemia was found in 117 patients, without any significant difference in men and women [38.45% and 35.39% respectively]. The mean duration of diabetes was 12.5 years [ranging from 5 to 22 years]. By frequency test in SPSS-20, the highest frequency of hypomagnesemia [49.42%] is seen in [8.6-9.0] HbA1c group while lowest frequency hypomagnesemia [15.38%] is seen in [>10.0] HbA1c level group mean standard deviation and p-value calculated by Pearson correlation statistic in SPSS-20 for quantitative variables [HbA1c, Magnesium level]

Conclusion: Hypomagnesemia is frequent in poorly controlled type-II diabetes mellitus having increased level of HbA1c. So it may be prudent in clinical practice to periodically monitor plasma magnesium and HbA1c in type-II diabetes mellitus patients

Outcome of burr-hole craniostomy for chronic subdural hematoma

OBJECTIVE: Objective of this study is to determine the outcome of Burr-hole craniostomy for chronic subdural hematoma [CSDH]

STUDY DESIGN: A descriptive study

SETTING: Department of Neurosurgery, Liaquat University Hospital, Jamshoro study period 15th September 2010 to 16th March 2012

METHODS: All patients of either gender presented with clinical and radiological evidence of CSDH and undergoing burr-hole craniostomy. The outcome evaluated by postoperative improvement of patients using Glasgow Coma Scale and Markwalder scale

RESULTS: Among 33 subjects, the mean age of the patients was 65.94 years with age ranges between 30 - 88 years with majority males [63.6%]. 57.6% had history of trauma and 66.7% presented with complain of headache. A significant improvement in the Post-Operative Markwalder grade and Glasgow coma scale [p<0.01] noticed as compare to pre-operative Markwalder grade and Glasgow coma scale

CONCLUSION: Burr hole Craniostomy with closed drainage system under local anesthesia is a good choice of treatment. In CSDH, Burr hole Craniostomy is safe and results are comparable to those of the major series of the literature as the surgical procedure is standardized

Frequency of thyroid dysfunction during TFT in interferon and ribavirin therapy in patients with chronic hepatitis C

Objective: To determine the frequency of thyroid dysfunction among patients of chronic hepatitis C [HCV] infection receiving combination of interferon-alpha and ribavirin therapy

Study Design: Cross-sectional study

Place and Duration of Study: Department of Medicine, PNS Shifa Naval Hospital Karachi, from September 2012 to March 2013 over a period of six months

Patients and Methods: In this study, 170 diagnosed patients of chronic HCV [confirmed by anti-HCV and HCV RNA-positive] presenting to medical OPD with normal thyroid functions were recruited. All patients fulfilled inclusion and exclusion criteria. They were prescribed IFN-alpha 2b [3 million units subcutaneously 3 days a week] and oral preparation of antiviral drug ribavirin [800 to 1200 mg daily in divided doses according to weight]. At the end of 12 weeks of combination antiviral therapy, their thyroid profile was worked up. Serum TSH, free T4 and T3 levels were determined by chemiluminescence technique in chemical pathology lab of the hospital. Statistical analysis was done on SPSS 17

Results: Out of 170 patients, 83 [48.82%] were females and 87 [51.18%] were males with the age ranging from 22-46 years [mean +/- SD: 33.86 +/- 5.32]. After 12 weeks of antiviral therapy, thyroid functions were normal in 156/170 [91.76%] patients, whereas in 14/170 [8.24%] cases thyroid dysfunction was observed. Out of those patients having thyroid dysfunction, 10/14 [71.42%] were hypothyroid whereas 4/14 [28.58%] had hyperthyroidism

Conclusion: Managing patients of chronic HCV with combination antiviral therapy comprising IFN-alpha 2b and ribavirin can cause thyroid dysfunction. These patients should be monitored before and during treatment to avoid complications and poor compliance

Selection of Appropriate Artificial Maxillary Central Incisor Size Using Dimensions of Hard Palate

To determine the ratio between width of hamular notches and maxillary central incisors' width at cervical, incisal and contact points. Cross–sectional descriptive study. Department of Prosthodontics, Armed Forces Institute of Dentistry, Rawalpindi from Feb 2010 to Aug 2010. Impressions of the maxillary jaw of 125 subjects were made and casts were obtained. A precise caliper was used to make the measurement ofthe widths of the maxillary central incisors at three different levels; the incisal edge [IW], at the level of interdental contact points [ConW] and in the cervical region [CerW]. The hamular width [HW] was measured between the most mesial demarcation point of the left and the right hamular notches.The ratios between the hard palate width [HW] and maxillary central incisor widths at all the three levels [IW, ConW, CerW] were calculated.Data was analyzed using SPSS 16. Of the125 subjects, 52 [41.6%] were males and 73 [58.4%] were females while mean age of the subjects was 26.56 years. Ratios HW/CerW, HW/IW and HW/ConWwere calculated as 6.08+0.18mm, 5.9+0.17mm and 5.81+ 0.17mm. The HW can be used as a preliminary method for determining the width of the maxillary central incisor

Pattern of early loss of deciduous molars and a cross sectional study

A cross-sectional study was conducted at the Department of Oral and Maxillofacial Surgery of Fatima Jinnah Dental College, Karachi to find out the factors responsible for premature loss of deciduous molars in children aged three to nine years. All children aged 3 - 9 years visiting the Dental OPD of Fatima Jinnah Dental College Karachi for extraction of deciduous molars from Feb 2011 to Feb 2012 were included in the study. 256 children format the study group. The data were collected on a predesigned Proforma filled by a single operator. Parameters taken into consideration were age, sex, tooth brushing and reasons for extraction. In this study 176 were male and 80 female. Overall 368 deciduous molars were extracted, 237 deciduous molars were extracted in males and 131 in females. Among the investigated subjects, 17% of children reported no tooth-brushing. Caries was the commonest cause of premature loss of deciduous molars accounted for 96.1% followed by tooth fracture 2.3% and malocclusion 1.6%. The frequency of only one deciduous molar loss was 67.2%. Maximum deciduous molar loss 50.7% was observed in children aged 8 years. Most commonly extracted tooth was mandibular left first deciduous molar [37.7%]. Results of this study suggested that improper tooth-brushing dental caries and no-treatment of carious deciduous molars were major risk factors in its early loss

To evaluate clinical efficacy of intravenous midazolam alone and along with propofol for sedation in patient management during interventional endoscopic procedures

Ample patient's sedation is a requisite for most interventional endoscopic procedures. A study was conducted to evaluate clinical efficacy of sedation using short acting anesthetic propofol with midazolam than midazolam alone in patient management during diagnostic and therapeutic endoscopic procedures. Prospective observational study. This study was conducted at radiology suite and endoscopy unit, by Department of Medicine, Gastroenterology and Hepatology Division, Holy Family Hospital, Rawalpindi, from 23-12-2009 to 21-6-2010. A total of ninety two patients undergoing endoscopic procedures randomly received either midazolam [n = 47, group A] or propofol plus midazolam [n= 45, group B] sedation. Patient vital sign's were noted as well as recovery scores, patient's tolerance of the procedure [visual analog scale]. Modified Richmond Agitation-Sedation Score [RASS Scale] was used to assess degree of sedation. The immediate and intermediate recovery was assessed using Steward's recovery score and Post Anesthesia Discharge score [PADS] respectively. Chi- square test value was 79.23 with P value of 0.001 and is significant, while Correlation co-efficient[r] value was 0.800 and the correlation was significant at 0.02 level. Propofol along with midazolam is safe for interventional endoscopic procedures under adequate patient monitoring and is more effective than sedation with midazolam alone as post procedural recovery is concerned while sedation efficacy being similar

Tooth shade perceptibility of undergraduate students, house surgeons and postgraduate residents

The objective of the study was to assess the shade perception abilities of undergraduate students in comparison to house surgeons and postgraduate residents on the basis of their clinical experience and technical education and training received on tooth shade selection. For this, a cross-sectional comparative study was carried out on a sample of 80 subjects, equally divided into two groups: Group I included undergraduate students and Group II included graduates doing house job or postgraduate training. All subjects were randomly divided into two further groups: the ET-group, which received proper education and training in shade selection; the non-ET-group, which did not receive such education. A shade selection exercise was devised using two Vitapan Classical shade guides. The number of correct matches established the participant's score, which was used in data analysis through the Chi-square test. Only 10 participants scored the maximum of 4 points including 2 students of Group I [2.5%] and 8 postgraduate residents of Group II [10.0%]. All of them belonged to the ET-group, which was a significant finding [P<0.05]. It was concluded that clinical experience and technical education and training received enables the observer to perform better at shade selection