The Debackle that Sucked the Marrow of Life

A look into the sordid state of Health Care Delivery Systems in Pakistan; Deaths from the so-called “P.I.C Syndrome”; How it has shaken our trust in the pills we buy and the leaders we “TRY” !

On Dec 15, 2011, 56-year old Abdul Ghaffur (AG) reported to Mayo Hospital Lahore with bleeding from his nose. AG was a known patient of Diabetes and also Ischemic Heart Disease (IHD), a condition that leads to heart attack if not managed continually for life. Although he didn’t complain of fever or body aches, and the cold weather didn’t suggest Dengue Fever, yet his Dengue Serology was sent as the City had just three months back recovered from the worst Dengue Endemic. What the Mayo doctors didn’t know was that scores of patients with similar complaints were presenting at all other major tertiary care hospitals Jinnah, Allama Iqbal, Ganga Raam, and Lahore General Hospital. It was a trailer of what was to come in the running month, hordes of heart patients with bleeding from nose, in stools and in vomits, rashes, and various grades and types of skin darkening reported to the Emergency Rooms of the above facilities.

What set these patients from Dengue sufferers was the absence of fever and an abnormally cold spell that was unfavorable to any Aedes Aegypti larval growth. And what bound them was their P.I.C cards and the common illnesses for which they received free medicines from P.I.C. AG’s Dengue Test turned up negative and it took the most skilled Physicians at Mayo almost 19 days (4th Jan, 2012) to realize that AG’s bone marrow(BM) had shut down and he had a mysterious darkening if his face and limbs. By 11th Jan, 2012 a one-off inter-hospital coordination established that all 465 patients belonged to P.I.C. AG died on 15th Jan, 2012 despite the best available care. His White Blood Cells_ the cavalry of human body’s defence against any bug entering it had fallen too low after the BM stopped making them and his Diabetes had further weakened his ability to fight the massive infections that ultimately took his life.

By Jan 26th, 2012 seventy-nine of the ‘465’ patients died. By 2nd Feb, 2012, the count had soared to 130 odd. Almost all of the dead dying because their old age, weakened defences and a bone marrow that failed to regain its functions despite treatment, made fighting the subsequent infections impossible with antibiotics alone. Even today, despite the Royal Free Hospitals’ (Britian) suggested treatment (Leucovorin/Folinic Acid) few more lost their life…

So was the Anti-Malarial Drug, Pyrimethamine the real bugaboo behind this massacre? (as suggested by the Britians’ Medicine & Healthcare Regulatory Agency (MHRA) preliminary findings). Does it explain all the complaints these patients presented with at hospitals or is something else at play? How can our health care professionals miss the classic presentations of Pyrimethamine Toxicity if the patients only suffered its excessive dosing?

Political zealots like Mian Shahbaz Sharif talk of devolution of Drug Regulatory Authority (DRA) and bashing of Federal Govt over its clandestine plots to kill Punjabis, but even prior to this 18th Amendment did we really have a DRA? One word, NO! We never had a Drug Adverse Effect Reporting Centre (AERC) or a Defective Medicine Reporting Centre (DMRC), both of which work under the MHRA, and we can always lease out the job of finding the solution to our drug-disasters to such ‘Farangi’-agencies! This same MHRA carries around 1000 inspections on the Pharmaceutical Manufacturers and wholesalers every year. Ostensibly, we never felt any need for such meticulous checks on anyone making faulty drugs or recycling infected and used syringes and selling them in bulk to anyone interested. Even after 65 years and a P.I.C massacre all we see is a ‘Zardari’ sitting in Efroze Chemicals Karachi and secretly plotting against Punjabis! Bollocks!

Our ‘thirst’ to discover the secrets Pharmaceutical Industries lock in their pills is quenched once we validate the existence of the active-ingredient in the pill. A pill is alot more than just the active drug. It’s an amalgam of the active-ingredient in marriage with certain binding agents and additives that influence how fast the drug gets released from the pill, protect it from destruction and help it get absorbed in the body. Leaving the Pharmaceutical industry unchecked over how it formulated its pills was a grave error we have committed for almost four decades now. Our Drug Testing Labs (DTLs) are ill-equipped to detect any intentional or accidental adulteration beyond quantifying the presence of the one active drug-ingredient in a pill. “The Drug Testing Lab just carries on tests to confirm presence of active ingredients in the specimens & the other materials or excepients in the medicine are not tested” (C.M investigation team report(CMIT), Para 5).

Pharmaceutical industries blamed the P.I.C doctors for giving an overdose of Cardiovastin (Simvastatin), alleging that 80mg was prescribed to patients. And that the brown spots on Cardiovastin tablets (normally white in color) was due to the Calcium Carbonate coating that oxidized and changed color. Both these claims apparently had the aim of spreading confusion and creating diversion to save their necks. No doctor prescribes Cardiovatin over 40mg owing to the severe muscle pains that the patients suffer as a side effect of the drug. And CMIT report clearly states in paragraph 5 that the brown spots were present not only on the surface (where tablet is coated) but also on the inner core, thus refuting these claims. The Drug testing Lab also declared two out of five Cardiovastin samples “substandard” – a term that apparently meant the tablets lacked the quantity of the active drug as stated on the pack.

Could an expired Cardiovastin or Isotab ever cause such fatal reactions? Drugs only lose the strength in their actions when expired. Never turn in to poisons or evoke fatal reactions.

Propaganda from Pharmaceutical Industries is a knee-jerk reflex from their perspective. Absence of any Drug Regulatory Authority in Pakistan has dealt a severe blow to them as well. International market now sees the lack of any DRA and DTLs as a potential hazard and have backed out from importing drugs from our generic-dominated Pharmaceutical industry. Indeed the export vision of USD 500 Million Dollars by 2013 will be hard to accomplish for this industry unless the govt treats this issue with seriousness of intent. Yet the Pakistan Pharmaceutical Manufacturers Association (PPMA) doesn’t even deem it fit to address this issue on their official web site or press releases.

We have failed once again. We failed to analyse the preliminary Reports from Britians’ MHRA Labs corroborated by Intertek Analytical Labs Switzerland and later by Central Drug Labs (CDL). They have set off as many queries as they answered.

MHRA report detected presence of Pyrimethamine in two out of four Isotab-20 samples (not all four) detected by employing Liquid Chromatography coupled to Mass Spectrometry (LC-MS) and Gas Chromatography coupled to Mass Spectrometry (GC-MS), both of which we lack the technological capacity to perform. It only estimated (didn’t confirm) that 50mg of Pyrimethamine was found in each of the two Isotab-20 tablets. The Intertek Analytical Labs Switzerland employed a more precise and accurate method to test and quantify the Pyrimethamine_ Nuclear Magnetic Resonance (NMR) in addition to LC-MS, and their results were: 20mg Pyrimethamine and 15mg Isotab in a tablet that should have had 20 mg Isotab (Isosorbide-5-mononitrate). The Central Drug Labs estimated 56mg Pyrimethamine in the Isotab tablet they analysed.

If all these findings are considered reliable, it reflects strongly on two aspects, one, how poor the quality control is that exists at the manufacturing level that the drug not only had been contaminated with large quantities of an Anti-Malarial but even the active ingredient (isosorbide-5-mononitrate) was only 75% of the stated quantity on the pack (15mg instead of 20mg), two, the lack of standard at our Drug Testing Labs which failed to even detect the lower than permissible quantities of active-ingredient in Isotab-20 or deliberately tempered with reports that they published out of collusion with the suppliers. “This is an open secret that DTL tests are arranged by the supplier companies and no due care and caution is taken by the purchasing authority.” (C.M.I.T report, Paragraph 16).

Did our Doctors also fail to zero in on the cause of the Bone Marrow suppression suffered by these patients? Bone Marrow suppression caused by Pyrimethamine high therapeutic dose or overdose has a classic picture: the patients’ blood cells have larger than normal size. A finding termed in medical jargon as Megaloblastic Anemia. Fact is, almost none of the patients had larger than normal Red Blood Cells on their Complete Blood Picture (CBC). Any able Pathologist can detect Megaloblastic anemia even by looking at a Cervical Pap Smear, a clinical test performed routinely in women over 40 years of age, such is the classic picture of the condition. Yet, we didn’t see it. Govt Hospital Labs lack quality but such a finding being missed in four major tertiary care hospitals is not even a remote possibility.

The Royal Free Hospital London also suggested in the preliminary report that the lack of liver damage in these patients (no liver enzymes were raised) also does not add up with Pyrimethamine overdose, doubting their own findings yet we totally rushed to conclusions here in Punjab! The finding has alot of bearing. Liver helps the body inactivate and get rid of 70% of the total Pyrimethamine. In case of an overdose, liver is bound to get overloaded with its detoxification function and get damaged itself, which is not the case in our patients!
Lastly, not even Pyrimethamine explains the wide range and intensities of skin Pigmentation and sloughing that these patients have suffered. Some have had their whole bodies darkened remarkably. Some just faces, or limbs or trunk or combinations of these and other body sites.

Most Drugs we use have each been developed after at least twelve years of expensive (100-200 Million USD per drug) and detailed clinical trials in the U.S.A. with experiments and observations ranging from animals to normal people and finally the target patient populace! The adverse reactions thus documented are very exhaustive. Still, is it possible that Pyrimethamine can cause a bone marrow suppression with normal sized blood cells? (a picture termed as Aplastic anemia with Normocytic Normochromic cells). Well yes, new effects of drugs are always possible. Is it probable? No. What is probable is more than one kind of drug reactions or contaminations at work in the affected patient cohort! Certainly, if it’s just Pyrimethamine, the use of Leucovorin/ Folinic Acid should help all patients recover fully within this week.

Mosquitos and their killer-drugs have plagued Punjab and its people for too long now. They need break from such tragic tales of death.